stilbenes and Neoplasm-Metastasis

Cancer is a major cause of death. The outcomes of current therapeutic strategies against cancer often ironically lead to even increased mortality due to the subsequent drug resistance and to metastatic recurrence. Alternative medicines are thus urgently needed. Cumulative evidence has pointed out that pterostilbene (

Topics: Antineoplastic Agents; Apoptosis; Complementary Therapies; Endoplasmic Reticulum Stress; Humans; MicroRNAs; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Stilbenes

Cancer is one of the leading causes of death worldwide. Chemotherapy and radiotherapy are the conventional primary treatments for cancer patients. However, most of cancer cells develop resistance to both chemotherapy and radiotherapy after a period of treatment, besides their lethal side-effects. This motivated investigators to seek more effective alternatives with fewer side-effects. In the last few years, resveratrol, a natural polyphenolic phytoalexin, has attracted much attention due to its wide biological effects. In this concise review, we highlight the role of resveratrol in the prevention and therapy of cancer with particular focus on colorectal and skin cancer. Also, we discuss the molecular mechanisms underlying its chemopreventive and therapeutic activity. Finally, we highlight the problems associated with the clinical application of resveratrol and how attempts have been made to overcome these drawbacks.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Autophagy; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Female; Humans; Inflammasomes; Male; Mice; Neoplasm Metastasis; NF-E2-Related Factor 2; Phytoalexins; Rats; Resveratrol; Sesquiterpenes; Skin Neoplasms; Stilbenes

The epithelial-to-mesenchymal transition (EMT) has received significant interest as a novel target in cancer prevention, metastasis, and resistance. The conversion of cells from an epithelial, adhesive state to a mesenchymal, motile state is one of the key events in the development of cancer metastasis. Polyphenols have been reported to be efficacious in the prevention of cancer and reversing cancer progression. Recently, the antimetastatic efficacy of polyphenols has been reported, thereby expanding the potential use of these compounds beyond chemoprevention. Polyphenols may affect EMT pathways, which are involved in cancer metastasis; for example, polyphenols increase the levels of epithelial markers, but downregulate the mesenchymal markers. Polyphenols also alter the level of expression and functionality of important proteins in other signaling pathways that control cellular mesenchymal characteristics. However, the specific proteins that are directly affected by polyphenols in these signaling pathways remain to be elucidated. The aim of this review is to analyze current evidence regarding the role of polyphenols in attenuating EMT-mediated cancer progression and metastasis. We also discuss the role of the most important polyphenol subclasses and members of the polyphenols in reversing metastasis and targeting EMT. Finally, limitations and future directions to improve our understanding in this field are discussed.

Topics: Chemoprevention; Epithelial-Mesenchymal Transition; Flavonoids; Humans; Hydroxybenzoates; Lignans; Neoplasm Metastasis; Polyphenols; Stilbenes

Epithelial-mesenchymal transition (EMT) plays a key role in tumor progression. The cells undergoing EMT upregulate the expression of cell motility-related proteins and show enhanced migration and invasion. The hallmarks of EMT in cancer cells include changed cell morphology and increased metastatic capabilities in cell migration and invasion. Therefore, prevention of EMT is an important tool for the inhibition of tumor metastasis. A novel preventive therapy is needed, such as treatment of natural dietary substances that are nontoxic to normal human cells, but effective in inhibiting cancer cells. Phytoestrogens, such as genistein, resveratrol, kaempferol and 3,3'-diindolylmethane (DIM), can be raised as possible candidates. They are plant-derived dietary estrogens, which are found in tea, vegetables and fruits, and are known to have various biological efficacies, including chemopreventive activity against cancers. Specifically, these phytoestrogens may induce not only anti-proliferation, apoptosis and cell cycle arrest, but also anti-metastasis by inhibiting the EMT process in various cancer cells. There have been several signaling pathways found to be associated with the induction of the EMT process in cancer cells. Phytoestrogens were demonstrated to have chemopreventive effects on cancer metastasis by inhibiting EMT-associated pathways, such as Notch-1 and TGF-beta signaling. As a result, phytoestrogens can inhibit or reverse the EMT process by upregulating the expression of epithelial phenotypes, including E-cadherin, and downregulating the expression of mesenchymal phenotypes, including N-cadherin, Snail, Slug, and vimentin. In this review, we focused on the important roles of phytoestrogens in inhibiting EMT in many types of cancer and suggested phytoestrogens as prominent alternative compounds to chemotherapy.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Genistein; Humans; Indoles; Kaempferols; Neoplasm Metastasis; Neoplasms; Phytoestrogens; Resveratrol; Stilbenes

Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells become mesenchymal cells, gaining fibroblast-like properties and displaying reduced intercellular adhesion and increased motility. EMT plays an important role in cancer metastasis. Suppressing or reversing EMT is therefore an important way of controlling various cancers. Phytochemicals are important sources of anticancer lead molecules. Natural products have been shown to safely suppress or reverse EMT via the inhibition of associated signalling pathways in various cancer cells. In the present review, we discuss the relevant factors and the role of EMT in cancer metastasis. We then present examples of phytochemicals with a role in the inhibition and reversal of EMT in various cancers, focusing on reports from 2012 to 2016.

Topics: Antineoplastic Agents, Phytogenic; Carotenoids; Epithelial-Mesenchymal Transition; Flavonoids; Gene Expression; Humans; Isoflavones; Neoplasm Metastasis; Phenols; Phytochemicals; Polyphenols; Resveratrol; Signal Transduction; Stilbenes; Tea

Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives. Furthermore, tubulin is a highly validated molecular target of many direct anticancer agents routinely used as front-line chemotherapeutics. The unique vascular targeting properties of the combretastatins have somewhat overshadowed their development as direct anticancer agents and the delineation of the various cell death pathways and anticancer properties associated with such chemotherapeutics. Moreover, the ongoing clinical trial of OXi4503 (combretastatin-A1 diphosphate) together with preliminary preclinical evaluation for the treatment of refractory acute myelogenous leukemia has successfully highlighted both the indirect and direct anticancer properties of combretastatins. In this review, we discuss the development of the combretastatins from nature to the clinic. The various mechanisms underlying combretastatin-induced cell cycle arrest, mitotic catastrophe, cell death, and survival are also reviewed in an attempt to further enhance the clinical prospects of this unique class of VTAs.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Hypoxia; Cell Movement; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Spindle Apparatus; Stilbenes; Tubulin Modulators

Anaplastic thyroid cancer (ATC) is a rare and deadly malignancy. There is a need to speed up and support clinical research. This review article focuses on the new molecules that have been developed for the treatment of this aggressive tumor.. Improvement in the knowledge of pathogenesis and genetics of ATC led to the development of a variety of new molecules that may be used to treat this disease. In summary, these molecules are proteasome inhibitors, Aurora kinase inhibitors, vascular targeting agents, and gene therapies. All these molecules demonstrated a potentially therapeutic activity in metastatic ATC. To date, the largest prospective randomized multicenter, open-label, trial was conducted with combretastatin-A4.. More efficient drugs need to be developed through multinational efforts.

Topics: Antineoplastic Agents, Phytogenic; Humans; Neoplasm Metastasis; Randomized Controlled Trials as Topic; Stilbenes; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

A plant kingdom is considered as a gold mine for the discovery of many biologically active substances with therapeutic values. Resveratrol (3,5,4'-trihydroxystilbene), a naturally occurring polyphenol, exhibits pleiotropic health beneficial effects including anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. Currently, numerous preclinical findings suggest resveratrol as a promising nature's arsenal for cancer prevention and treatment. A remarkable progress in dissecting the molecular mechanisms underlying anti-cancer properties of resveratrol has been achieved in the past decade. As a potential anti-cancer agent, resveratrol has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. The compound significantly inhibits experimental tumorigenesis in a wide range of animal models. Resveratrol targets many components of intracellular signaling pathways including pro-inflammatory mediators, regulators of cell survival and apoptosis, and tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. This review summarizes the diverse molecular targets of resveratrol with a special focus on those involved in fine-tuning of orchestrated intracellular signal transduction.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Apoptosis; Carcinogens; Cell Survival; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Protein Kinase C; Resveratrol; Signal Transduction; Stilbenes

Topics: Animals; Antineoplastic Agents; Apoptosis; Arachidonic Acid; Cell Degranulation; Chemical and Drug Induced Liver Injury; Glucosides; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipid Peroxidation; Neoplasm Metastasis; Neutrophils; Phytotherapy; Polygonum; Resveratrol; Stilbenes

The antiestrogens represent a group of compounds, not necessarily steroidal, which are able to decrease the specific uptake of estrogens in vitro and in vivo by various target tissues in the rat and in man. This action is explained either by competitive binding to estrogen receptor sites or, more probably, by failure of the antiestrogen complex, translocated into the nucleus, to stimulate neoformation of receptors in the cytoplasm. This explains the transient estrogenic effect of antiestrogen. Antiestrogens used in humans are hormone specific and antagonize also non-steroidal estrogens, like stilbestrol. Three compounds have been used in advanced breast cancer with the same indications as the older hormonal treatments. They are clomiphene citrate, nafoxidine and tamoxifen. Nafoxidine and tamoxifen are probably equally active. The response rate is between 28 and 35%, with a median duration of nine months. Nafoxidine is toxic for the skin and tamoxifen is the preferred compound. A randomized trial comparing ethinyl estradiol and an antiestrogen showed similar rates of response with the two compounds in advanced breast cancer. The uniformity of results of treatment of advanced breast cancer by hormonal agents including antiestrogens and their limitations, probably justifies the present-day concept which assigns hormonal treatment a secondary role, either as a supplement to cytotoxic chemotherapy or for old and debilitated patients. However, as a supplemented to chemotherapy, hormonal agents are probably important since recent studies have shown that apparently all breast cancers have positive receptor sites, albeit in variable amounts. Because of their lack of toxicity, antiestrogens are probably the best hormonal agents available at present.

Topics: Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Clomiphene; Estrogen Antagonists; Ethinyl Estradiol; Female; Humans; Menopause; Middle Aged; Nafoxidine; Neoplasm Metastasis; Pyrrolidines; Stilbenes; Tamoxifen

Resveratrol, extracted from Chinese herbal medicine Polygonum cuspidatum, is known to inhibit invasion and metastasis of human colorectal cancer (CRC), in which long non-coding Metastasis Associated Lung Adenocarcinoma Transcript 1 (RNA-MALAT1) also plays an important role. Using MALAT1 lentiviral shRNA and over-expression constructs in CRC derived cell lines, LoVo and HCT116, we demonstrated that the anti-tumor effects of resveratrol on CRC are through inhibiting Wnt/β-catenin signaling, thus the expression of its target genes such as c-Myc, MMP-7, as well as the expression of MALAT1. In detail, resveratrol down-regulates MALAT1, resulting in decreased nuclear localization of β-catenin thus attenuated Wnt/β-catenin signaling, which leads to the inhibition of CRC invasion and metastasis. This finding of ours surely provides important pre-clinical evidence supporting future use of resveratrol in prevention and treatment of CRC.

Topics: Aged; Antineoplastic Agents, Phytogenic; beta Catenin; Cell Line, Tumor; Cell Nucleus; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Matrix Metalloproteinase 7; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Proto-Oncogene Proteins c-myc; Resveratrol; RNA, Long Noncoding; RNA, Neoplasm; Stilbenes; Wnt Signaling Pathway

The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility.

Topics: Aged; Antineoplastic Agents, Phytogenic; Caspase 3; Combined Modality Therapy; Double-Blind Method; Female; Hepatectomy; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pilot Projects; Placebos; Postoperative Complications; Resveratrol; Stilbenes; Titanium

Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM).. Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression.. Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009).. There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bibenzyls; Carboplatin; Carcinoma; CD56 Antigen; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neural Cell Adhesion Molecules; Organophosphorus Compounds; Paclitaxel; Stilbenes; Survivors; Thyroid Neoplasms; Treatment Outcome; Young Adult

The antiestrogens represent a group of compounds, not necessarily steroidal, which are able to decrease the specific uptake of estrogens in vitro and in vivo by various target tissues in the rat and in man. This action is explained either by competitive binding to estrogen receptor sites or, more probably, by failure of the antiestrogen complex, translocated into the nucleus, to stimulate neoformation of receptors in the cytoplasm. This explains the transient estrogenic effect of antiestrogen. Antiestrogens used in humans are hormone specific and antagonize also non-steroidal estrogens, like stilbestrol. Three compounds have been used in advanced breast cancer with the same indications as the older hormonal treatments. They are clomiphene citrate, nafoxidine and tamoxifen. Nafoxidine and tamoxifen are probably equally active. The response rate is between 28 and 35%, with a median duration of nine months. Nafoxidine is toxic for the skin and tamoxifen is the preferred compound. A randomized trial comparing ethinyl estradiol and an antiestrogen showed similar rates of response with the two compounds in advanced breast cancer. The uniformity of results of treatment of advanced breast cancer by hormonal agents including antiestrogens and their limitations, probably justifies the present-day concept which assigns hormonal treatment a secondary role, either as a supplement to cytotoxic chemotherapy or for old and debilitated patients. However, as a supplemented to chemotherapy, hormonal agents are probably important since recent studies have shown that apparently all breast cancers have positive receptor sites, albeit in variable amounts. Because of their lack of toxicity, antiestrogens are probably the best hormonal agents available at present.

Topics: Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Clomiphene; Estrogen Antagonists; Ethinyl Estradiol; Female; Humans; Menopause; Middle Aged; Nafoxidine; Neoplasm Metastasis; Pyrrolidines; Stilbenes; Tamoxifen

Topics: Adult; Aged; Breast Neoplasms; Carcinoma; Clinical Trials as Topic; Female; Humans; Middle Aged; Neoplasm Metastasis; Remission, Spontaneous; Stilbenes; Tamoxifen; Time Factors

Tamoxifen (NSC-180973), a synthetic antiestrogen, was studied for efficacy and toxicity in patients with metastatic breast adenocarcinoma. Two dose levels were used, 10 mg bid and 15 mg/m2 bid, in separate groups. In the 10-mg bid dosage group, 30 of the 31 patients were considered evaluable for efficacy. Five complete and 11 partial responses were recorded, for an overall response rate of 53%. In the 15-mg/m2 bid dosage group, 44 of the 45 patients were considered evaluable for efficacy. Three complete and 16 partial responses were recorded, for an overall response rate of 43%. All 76 patients were evaluated for toxicity. Side effects were generally mild, consisting mostly of hot flushes, transient leukopenia, transient thrombocytopenia, nausea, and fluid retention. A high degree of correlation between response and positive estrogen-receptor assay suggests the value of the test as a means to select patients for tamoxifen treatment. The conclusion from this study is that tamoxifen used as a single agent is an effective drug with minimal toxicity for treatment of metastatic breast adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Stilbenes; Tamoxifen

The results of an ongoing trial randomizing patients with progressive, metastatic breast carcinoma between tamoxifen (Tam, NSC-180973) and Tam plus fluoxymesterone (Flu) (7 mg/m2 bid) are reported. Each patient received a single dose level of Tam in the range of 2-100 mg/m2 bid. The combination had a higher response rate overall (45% vs 28%) and when only the patients' soft tissue sites were analyzed (54% vs 9%, P=0.04). The time to treatment failure was longer for the combination among those patients with a response or disease stabilization (P=0.08). Response rates with Tam doses less than 12 mg/m2 bid were also higher than with doses greater than or equal to 12 mg/m2 for all patients in the study (62% vs 30%, P=0.025) and for those where only soft tissue sites were evaluable (43% vs 29%, P=0.07). Side effects were mild and consisted primarily of transient hematologic suppression, nausea, masculinization, hepatic enzyme elevations, and edema. The latter three were observed only with the Flu regimen. Leukopenia and thrombocytopenia were more frequent at Tam doses less than 12 mg/m2 bid whereas nausea was more common at higher doses. Tam doses as high as 100 mg/m2 bid were well tolerated. Tam amy be more effective at low doses, has only mild side effects, and is well tolerated at doses up to 100 mg/m2 bid. Combining Tam with Flu appears to enhance the therapeutic effectiveness.

Topics: Adult; Aged; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Fluoxymesterone; Humans; Menopause; Middle Aged; Neoplasm Metastasis; Stilbenes; Tamoxifen

Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form "micro-thrombi" with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of "micro-thrombi", and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.

Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Chemotherapy, Adjuvant; Disease Models, Animal; Drug Carriers; Epithelial-Mesenchymal Transition; Female; Heparin, Low-Molecular-Weight; Human Umbilical Vein Endothelial Cells; Humans; Male; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Nanoparticles; Neoplasm Metastasis; Neoplastic Cells, Circulating; Paclitaxel; Proof of Concept Study; Rats; Stilbenes; Theranostic Nanomedicine

Although the polymeric vascular disrupting agent (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4) nanoparticles (CA4-NPs) has great potential to inhibit cancer growth, it is still a challenge to avert tumor recurrence and metastasis after treatment. It is mainly tightly associated with hypoxia induced by CA4-NPs, which can activate many downstream genes regulating tumor growth and metastasis. Herein, to relieve a tumor hypoxia microenvironment, the mTOR inhibitor temsirolimus was employed to modulate the tumor microenvironment when treated with CA4-NPs. In vitro MTT experiments strongly verified that the combination of temsirolimus with polymeric CA4-NPs exhibited an additive toxicity to 4T1 cells. An in vivo study with the 4T1 mammary adenocarcinoma model revealed that consistent with the proposed scenario, combination therapy with CA4-NPs plus temsirolimus suppressed tumor growth significantly more strongly compared to either CA4-NPs or temsirolimus monotherapy, and the inhibition rate to 4T1 tumor with a volume of 300 mm

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Metastasis; Neoplasms; Polyethylene Glycols; Polyglutamic Acid; Polymers; Sirolimus; Stilbenes; Tumor Microenvironment

Hypoxia-activated prodrugs (HAPs) have the potential to selectively kill hypoxic cells and convert tumor hypoxia from a problem to a selective treatment advantage. However, HAPs are unsuccessful in most clinical trials owing to inadequate hypoxia within the treated tumors, as implied by a further substudy of a phase II clinical trial. Here, a novel strategy for the combination of HAPs plus vascular disrupting agent (VDA) nanomedicine for efficacious solid tumor therapy is developed. An effective VDA nanomedicine of poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs) is prepared and can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine (TPZ) therapy against metastatic 4T1 breast tumors. After treatment with the combination of TPZ plus CA4-NPs, complete tumor reduction is observed in 4T1 xenograft mice (initial tumor volume is 180 mm

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Drug Synergism; Mice; Mice, Inbred BALB C; Nanomedicine; Neoplasm Metastasis; Prodrugs; Stilbenes; Tirapazamine; Tumor Hypoxia; Xenograft Model Antitumor Assays

Pentose phosphate pathway (PPP) is a major glucose metabolism pathway, which has a fundamental role in cancer growth and metastasis. Even though PPP blockade has been pointed out as a very promising strategy against cancer, effective anti-PPP agents are not still available in the clinical setting. Here we demonstrate that the natural molecule polydatin inhibits glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP. Polydatin blocks G6PD causing accumulation of reactive oxygen species and strong increase of endoplasmic reticulum stress. These effects are followed by cell cycle block in S phase, an about 50% of apoptosis, and 60% inhibition of invasion in vitro. Accordingly, in an orthotopic metastatic model of tongue cancer, 100 mg/kg polydatin induced an about 30% tumor size reduction with an about 80% inhibition of lymph node metastases and 50% reduction of lymph node size (p < 0.005). Polydatin is not toxic in animals up to a dose of 200 mg/kg and a phase II clinical trial shows that it is also well tolerated in humans (40 mg twice a day for 90 days). Thus, polydatin may be used as a reliable tool to limit human cancer growth and metastatic spread.

Topics: Animals; Glucosephosphate Dehydrogenase; Glucosides; Humans; Male; MCF-7 Cells; Mice, Nude; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Pentose Phosphate Pathway; S Phase Cell Cycle Checkpoints; Stilbenes; Xenograft Model Antitumor Assays

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Particularly, inflammation is crucial for the progression of NSCLC. In the past few decades, the anti-tumor effects of some traditional Chinese medicinal herbs have caused much attention. This study was designed to investigate the effects of polydatin in the progression of NSCLC. CCK-8 assay, wound healing assay and western blot assay were used to assess the anti-cancer property. Consequently, we showed that polydatin inhibited proliferation and migration of NSCLC cells (A549 and H1299 cells) in a dose-dependent manner. In addition, polydatin suppressed the expression of NLRP3, ASC and pro-caspase-1in NSCLC cells. Activation of NLRP3 inflammasome counteracted the inhibitory effect of polydatin on proliferation and migration of NSCLC cells, suggesting that polydatin suppressed progression of NSCLC through inhibiting NLRP3 inflammasome activation. Furthermore, polydatin was found to down-regulate relative expression of phosphor-NF-κB p65 and activation of NF-κB pathway by TNF-α also abolished the inhibitory effect of polydatin on proliferation and migration of NSCLC cells. In conclusion, our data showed that polydatin acted as an anti-tumor agent to suppress proliferation and metastasis of NSCLC cells. The anti-tumor effect of polydatin was possibly related to the inhibition of NLRP3 inflammation via the NF-κB pathway. Our finding suggested that polydatin might be a potential therapeutic candidate in the treatment of NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glucosides; Humans; Inflammasomes; Neoplasm Metastasis; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Stilbenes

The prevalence of melanoma and the lack of effective therapy for metastatic melanoma warrant extensive and systematic evaluations of small molecules in cellular and pre-clinical models. We investigated, herein, the antitumor and anti-metastatic effects of trans-4,4'-dihydroxystilbene (DHS), a natural product present in bark of Yucca periculosa, using in vitro and in vivo melanoma murine models. DHS showed potent melanoma cytotoxicity, as determined by MTT and clonogenic assay. Further, DHS induced cytotoxicity was mediated through apoptosis, which was assessed by annexin V-FITC/PI, sub-G1 and caspase activation assays. In addition, DHS inhibited cell proliferation by inducing robust cell cycle arrest in G1-phase. Imperatively, these inhibitory effects led to a significant reduction of melanoma tumor in pre-clinical murine model. DHS also inhibited cell migration and invasion of melanoma cells, which were examined using wound healing and Transwell migration/invasion assays. Mechanistically, DHS modulated the expressions of several key metastasis regulating proteins e.g., MMP-2/9, N-cadherin, E-cadherin and survivin. We also showed the anti-metastatic effect of DHS in a melanoma mediated lung metastasis model in vivo. DHS significantly reduced large melanoma nodule formation in the parenchyma of lungs. Therefore, DHS may represent a promising natural drug in the repertoire of treatment against melanoma tumor growth and metastasis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Skin Neoplasms; Stilbenes

Alpinia nantoensis (Zingiberaceae) is an aromatic plant endemic to Taiwan, which is used as food flavoring and traditional herbal medicine. The biological activities of compounds isolated from this plant are rarely investigated.. The present study was aimed to investigate the anti-metastatic potential of trans-3‑methoxy‑5-hydroxystilbene (MHS) a major stilbene isolated from the rhizomes of A. nantonensis.. We investigated the anti-metastatic potential of MHS on human non-small cell lung carcinoma (A549) cell line using wound healing, trans-well, western blot, zymography and immunofluorescence assays.. Initial cytotoxicity assay showed that treatment with MHS did not exhibit cytotoxicity to A549 cells up to the concentration of 40 µM. Further in vitro wound healing and transwell chamber assays revealed that MHS significantly inhibited tumor cell migration in a dose-dependent manner, which is associated with inhibition of matrix mettalloprotinase-2 (MMP-2) and matrix mettalloprotinase-9 (MMP-9) at both enzyme and protein levels. The inhibition of MMPs activity by MHS was reasoned by suppression of their corresponding transcription factor, β-catenin as indicated by reduced levels of β-catenin in the nucleus. MHS also regulates epithelial-to-mesenchymal transition (EMT) by increasing E-cadherin and occludin as well as decreasing N-cadherin levels in A549 cells. Furthermore, pre-treatment with MHS significantly inhibited A549 cells migration and EMT in TGF-β induced A549 cells.. To the best of our knowledge, this is the first report demonstrating that MHS, a plant-derived stilbene has a promising ability to inhibit lung cancer cell metastasis in vitro.

Topics: A549 Cells; Alpinia; Antigens, CD; Antineoplastic Agents, Phytogenic; beta Catenin; Cadherins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Matrix Metalloproteinase 9; Neoplasm Metastasis; Rhizome; Stilbenes; Taiwan; Transforming Growth Factor beta

Polymeric fibronectin (polyFN) assembled on suspended breast cancer cells is required for metastasis. Conceivably, drugs that target such polyFN may fight against cancer metastasis. While stilbene analogs trigger pro-apoptotic effect on attached cancer cells, whether they prevent polyFN assembly and metastasis of suspended cancer cells via an apoptosis-independent manner remains unexplored.. We depleted suspended Lewis lung carcinoma (LLC) cells of polyFN by silencing the endogenous FN expression or pterostilbene (PS) to examine whether metastasis of lung cancer cells could thus be suppressed. We investigated whether PS regulates AKT-ERK signaling axis to suppress polyFN assembly in suspended LLC cells independently of apoptosis. We tested the therapeutic effects of orally administered PS against cancer metastasis.. Both FN-silencing and PS among the three stilbenoids indeed significantly reduced polyFN assembly and lung metastasis of suspended LLC cells in an apoptosis-independent manner. Mechanistically, PS-induced AKT phosphorylation (pAKT) and suppressed ERK phosphorylation (pERK) in suspended LLC cells, whereas pretreatment with a PI3K inhibitor, LY294002, effectively reduced pAKT, rescued pERK, and consequently reversed the PS-suppressed polyFN assembly on LLC cells; these pretreatment effects were then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was further overruled with U0126. Finally, we found that PS, when orally administered in experimental metastasis assays, both significantly prevented lung colonization and metastasis of LLC cells and reduced the already established tumor growth in the mouse lungs.. PS suppressed AKT/ERK-regulated polyFN assembly on suspended LLC cells and pulmonary metastasis. PS possesses potency in both preventing and treating lung metastasis of lung cancer cells in apoptosis-independent and apoptosis-dependent manners, respectively.

Topics: Animals; Apoptosis; Carcinoma, Lewis Lung; Fibronectins; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mice; Neoplasm Metastasis; Polymerization; Proto-Oncogene Proteins c-akt; Stilbenes

To explore the impact of Resveratrol (RSV) on the angiogenic potential of activated platelets and to elucidate the underlying mechanism.. Vascular endothelial growth factor concentrations were measured by enzyme-linked immunosorbent assay. Capillary tube formation assay was used to examine the impact of RSV on the angiogenic potential of activated platelets. The levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP) in the supernatant were evaluated using corresponding enzyme-linked immunosorbent assay kits. Immunoblotting assays were used to determine the expression of vasodilator-stimulated phosphoprotein and Akt phosphorylation. A pulmonary metastasis experiment with male nude mice model was performed to test the effect of RSV on pulmonary metastasis and angiogenesis in vivo.. RSV inhibited platelets-mediated angiogenic responses induced by adenosine diphosphate (ADP)ADP through increased cGMP generation and cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation along with reduced intracellular Ca. RSV is a potential therapeutic drug for the prevention of tumor metastasis by interrupting the platelet-tumor cell amplification loop.

Topics: A549 Cells; Adenosine Diphosphate; Animals; Antineoplastic Agents, Phytogenic; Blood Platelets; Calcium; Cell Adhesion Molecules; Drug Screening Assays, Antitumor; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms; Mice, Nude; Microfilament Proteins; Neoplasm Metastasis; Neovascularization, Pathologic; Phosphoproteins; Proto-Oncogene Proteins c-akt; Resveratrol; Stilbenes; Vascular Endothelial Growth Factor A

A rat model was developed to enable direct administration of hyperpolarized. Rat P22 sarcomas were implanted into the right inguinal fat pad of BDIX rats such that the developing tumors received their principle blood supply directly from the right superior epigastric artery. Hyperpolarized. Intra-arterial infusion of hyperpolarized. The model maximizes tumor substrate/drug delivery and minimizes T

Topics: Animals; Arteries; Carbon Isotopes; Drug Delivery Systems; Epigastric Arteries; Female; Femoral Vein; Gadolinium; Magnetic Resonance Spectroscopy; Male; Neoplasm Metastasis; Neoplasms; Optical Imaging; Perfusion; Phosphorylation; Pyruvic Acid; Rats; Spectrophotometry; Stilbenes

2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a major component of Polygonum multiflorum Thunb (He-Shou-Wu), has been reported to exhibit antioxidant and anti-inflammatory effects. However, its anti-metastatic effect against colorectal cancer is still unclear. In this study, cell migration, invasion and adhesion abilities as well as metastasis-associated protein and NF-κB pathway signaling factor expression were analyzed after treating HT-29 cells with THSG. According to the results, the migration and invasiveness of HT-29 cells were reduced after treatment with 5 or 10 mM THSG (p<0.05). Additionally, the levels of matrix metalloproteinase-2 (MMP-2) and phosphorylated VE-cadherin in HT-29 cells were reduced and the transepithelial electrical resistance (TEER) of EA.hy926 endothelial cell monolayers was increased after incubation in THSG for 24 h (p<0.05). Cell adhesion ability and the E-selectin and intercellular adhesion molecule-1 (ICAM-1) protein levels were reduced when EA.hy926 endothelial cells were treated with THSG (p<0.05). In addition, the cytoplasmic phosphorylation of IκB, the nuclear p65 level and the DNA-binding activity of NF-κB were reduced after treating HT-29 or EA.hy926 cells with 5 or 10 mM THSG (p<0.05). These results suggest that THSG inhibits HT-29 cell metastasis by suppressing cell migration, invasion and adhesion. Furthermore, THSG inhibits metastasis-associated protein expression by suppressing NF-κB pathway activation.

Topics: Cell Movement; Colorectal Neoplasms; Glucosides; HT29 Cells; Humans; Neoplasm Metastasis; NF-kappa B; Signal Transduction; Stilbenes

The Akt/adenosine monophosphate protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway has emerged as a critical signaling nexus for regulating cellular metabolism, energy homeostasis, and cell growth. Thus, dysregulation of this pathway contributes to the development of metabolic disorders such as obesity, type 2diabetes, and cancer. We previously reported that a combination of grape polyphenols (resveratrol, quercetin and catechin: RQC), at equimolar concentrations, reduces breast cancer (BC) growth and metastasis in nude mice, and inhibits Akt and mTOR activities and activates AMPK, an endogenous inhibitor of mTOR, in metastatic BC cells. The objective of the present study was to determine the contribution of individual polyphenols to the effect of combined RQC on mTOR signaling. Metastatic BC cells were treated with RQC individually or in combination, at various concentrations, and the activities (phosphorylation) of AMPK, Akt, and the mTOR downstream effectors, p70S6 kinase (p70S6K) and 4E binding protein (4EBP1), were determined by Western blot. Results show that quercetin was the most effective compound for Akt/mTOR inhibition. Treatment with quercetin at 15μM had a similar effect as the RQC combination in the inhibition of BC cell proliferation, apoptosis, and migration. However, cell cycle analysis showed that the RQC treatment arrested BC cells in the G1 phase, while quercetin arrested the cell cycle in G2/M. In vivo experiments, using SCID mice with implanted tumors from metastatic BC cells, demonstrated that administration of quercetin at 15mg/kg body weight resulted in a ~70% reduction in tumor growth. In conclusion, quercetin appears to be a viable grape polyphenol for future development as an anti BC therapeutic.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents, Phytogenic; Breast; Breast Neoplasms; Catechin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Female; Humans; Mice, Nude; Mice, SCID; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Quercetin; Resveratrol; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases; Vitis

Naturally occurring agents, such as resveratrol, have been determined to benefit health. Numerous studies have demonstrated that resveratrol has antioxidative, cardioprotective, and neuroprotective properties. However, the effect of resveratrol exerts on the metastasis of oral cancer cells remains unclear. In this study, we investigated the effect the anti-invasive activity of resveratrol on a human oral cancer cell line (SCC-9) in vitro and the underlying mechanisms.. Cell viability was examined by MTT assay, whereas cell motility was measured by migration and wound-healing assays. Zymography, reverse-transcriptase polymerase chain reaction (PCR), and promoter assays confirmed the inhibitory effects of resveratrol on matrix metalloproteinase-9 (MMP-9) expression in oral cancer cells.. We established that various concentrations (0-100 μM) of resveratrol inhibited the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced migration capacities of SCC-9 cells and caused no cytotoxic effects. Zymography and Western blot analyses suggested that resveratrol inhibited TPA-induced MMP-9 gelatinolytic activity and protein expression. In addition, the results indicated that resveratrol inhibited the phosphorylation of c-Jun N-terminal kinase (JNK)1/2 and extracellular-signal-regulated kinase (ERK)1/2 involved in downregulating protein expression and the transcription of MMP-9.. In summary, resveratrol inhibited MMP-9 expression and oral cancer cell metastasis by downregulating JNK1/2 and ERK1/2 signals pathways and, thus, exerts beneficial effects in chemoprevention.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Down-Regulation; Enzyme Activation; Head and Neck Neoplasms; Humans; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Resveratrol; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Stilbenes; Tetradecanoylphorbol Acetate; Tongue Neoplasms

Resveratrol (E-3,5,4'-trihydroxystilbene) is a polyphenol found in red wine that has been shown to have multiple anti-cancer properties. Although cis-(Z)- and trans-(E)-isomers of resveratrol occur in nature, the cis form is not biologically active. However, methylation at key positions of the cis form results in more potent anti-cancer properties. This study determined that synthetic cis-polymethoxystilbenes (methylated analogs of cis-resveratrol) inhibited cancer-related phenotypes of metastatic B16 F10 and non-metastatic B16 F1 mouse melanoma cells. In contrast with cis- or trans-resveratrol and trans-polymethoxystilbene which were ineffective at 10 μM, cis-polymethoxystilbenes inhibited motility and proliferation of melanoma cells with low micromolar specificity (IC50 < 10 μM). Inhibitory effects by cis-polymethoxystilbenes were significantly stronger with B16 F10 cells and were accompanied by decreased expression of β-tubulin and pleckstrin homology domain-interacting protein, a marker of metastatic B16 cells. Thus, cis-polymethoxystilbenes have potential as chemotherapeutic agents for metastatic melanoma.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Inhibitory Concentration 50; Melanoma, Experimental; Mice; Neoplasm Metastasis; Resveratrol; Stilbenes

Combretastatin A-4 (CA-4) is a natural cis-stilbene which interferes with the cellular tubulin dynamics and which selectively destroys tumour blood vessels. Its pharmacological shortcomings such as insufficient chemical stability, water solubility, and cytotoxicity can be remedied by employing its imidazole derivatives.. We studied 11 halogenated imidazole derivatives of CA-4 for their effects on the microtubule and actin cytoskeletons of cancer and endothelial cells and on the propensity of these cells to migrate across tissue barriers or to form blood vessel-like tubular structures.. A series of N-methyl-4-aryl-5-(4-ethoxyphenyl)-imidazoles proved far more efficacious than the lead CA-4 in growth inhibition assays against CA-4-resistant HT-29 colon carcinoma cells and generally more selective for cancer over nonmalignant cells. Et-brimamin (6), the most active compound, inhibited the growth of various cancer cell lines with IC50 (72 h) values in the low nanomolar range. Active imidazoles such as 6 reduced the motility and invasiveness of cancer cells by initiating the formation of actin stress fibres and focal adhesions as a response to the extensive microtubule disruption. The antimetastatic properties were ascertained in 3D-transwell migration assays which simulated the transgression of highly invasive melanoma cells through the extracellular matrix of solid tumours and through the endothelium of blood vessels. The studied imidazoles exhibited vascular-disrupting effects also against tumour xenografts that are refractory to CA-4. They were also less toxic and better tolerated by mice.. We deem the new imidazoles promising drug candidates for combination regimens with antiangiogenic VEGFR inhibitors.

Topics: Angiogenesis Inhibitors; Aniline Compounds; Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cell Movement; Chickens; Collagen; Cytoskeleton; Drug Combinations; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Laminin; Mice, Nude; Microtubules; Mitosis; Neoplasm Metastasis; Neovascularization, Physiologic; Proteoglycans; Stilbenes

Resveratrol is a phytoalexin produced by many plant species as a defence mechanism. Over the last decade, this polyphenol has been reported to be active against multiple targets associated with chronic disorders. However, its poor pharmacokinetic profile, as well as multiple discrepancies related to its in vitro and in vivo profile, has resulted not only on the study of suitable delivery systems, but the use of resveratrol derivatives. In this regard, the 3,4',5-trans-trimethoxystilbene (TMS), a natural analogue of resveratrol, has emerged as a strong candidate. TMS has an enhanced anticancer profile compared to resveratrol, exhibiting higher potency than resveratrol, as shown by multiple reports describing an improved cancer cell proliferation inhibition, induction of cell cycle arrest, decreased metastasis, reduced angiogenesis, and increased apoptosis. In this review, we provide a concise summary of results reported in the literature, related to the similarities and differences between resveratrol and TMS, and we submit to the scientific community that TMS is a promising and (still) understudied natural agent candidate, with potential applications in cancer research. Nevertheless, based on the available evidence, we also submit to the scientific community that TMS may also find a niche in any other research area in which resveratrol has been used.

Topics: Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Cell Line, Tumor; Cell Proliferation; Free Radical Scavengers; Humans; Inhibitory Concentration 50; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Resveratrol; Stilbenes; Xenograft Model Antitumor Assays

Breast cancer is the leading cause of cancer-related deaths among females in economically developing countries. Greater than 95% of breast malignancies are of epithelial origin; the induction of epithelial-to-mesenchymal transition (EMT) has been shown to initiate the metastatic process in breast carcinoma and remains the key target for drug development. Here, we examine the anti-metastatic potential of pterostilbene in modulating EMT process in breast cancer cells both in vitro and in vivo. The differential invasive ability among MCF7, Hs578t and MDA-MB-231 breast cancer cell lines were closely correlated with the expression of EMT markers, determined by Western blots and Matrigel-coated transwells assay. Pterostilbene inhibited the migratory and invasive potential of triple-negative MDA-MB-231 and Hs578t cells, accompanied by the up-regulation of E-cadherin and down-regulation of Snail, Slug, vimentin and ZEB1. Mechanistic investigations revealed a significant up-regulation of miR-205, which resulted in the reduction of Src expression in pterostilbene-treated breast cancer cells. Importantly, pterostilbene suppressed tumor growth and metastasis in MDA-MB-231-bearing NOD/SCID mice by reducing Src/Fak signaling; this observation was consistent with the negative correlations between miR-205 and Src expression in both normal and malignant breast tissues. Our findings provide supports for the usage of pterostilbene as an inhibitor of EMT process and potential candidate for adjuvant therapy.

Topics: Animals; Cadherins; Cell Line, Tumor; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; MCF-7 Cells; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; src-Family Kinases; Stilbenes; Transcription Factors; Triple Negative Breast Neoplasms; Up-Regulation; Vimentin; Xenograft Model Antitumor Assays; Zinc Finger E-box-Binding Homeobox 1

We aimed to test the ability of texture analysis to differentiate the spatial heterogeneity of (125)I-A5B7 anti-carcinoembryonic antigen antibody distribution by nano-single photon emission computed tomography (SPECT) in well-differentiated (SW1222) and poorly differentiated (LS174T) hepatic metastatic colorectal cancer models before and after combretastatin A1 di-phosphate anti-vascular therapy.. Nano-SPECT imaging was performed following tail vein injection of 20 MBq (125)I-A5B7 in control CD1 nude mice (LS174T, n=3 and SW1222, n=4), and CA1P-treated mice (LS174T, n=3; SW1222, n=4) with liver metastases. Grey-level co-occurrence matrix textural features (uniformity, homogeneity, entropy and contrast) were calculated in up to three liver metastases in 14 mice from control and treatment groups.. Before treatment, the LS174T metastases (n=7) were more heterogeneous than SW1222 metastases (n=12) (uniformity, P=0.028; homogeneity, P=0.01; contrast, P=0.045). Following CA1P, LS174T metastases (n=8) showed less heterogeneity than untreated LS174T controls (uniformity, P=0.021; entropy, P=0.006). Combretastatin A1 di-phosphate-treated SW1222 metastases (n=11) showed no difference in texture features compared with controls (all P>0.05).. Supporting the potential for novel imaging biomarkers, texture analysis of (125)I-A5B7 SPECT shows differences in spatial heterogeneity of antibody distribution between well-differentiated (SW1222) and poorly differentiated (LS174T) liver metastases before treatment. Following anti-vascular treatment, LS174T metastases, but not SW1222 metastases, were less heterogeneous.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Carcinoembryonic Antigen; Cell Line, Tumor; Colorectal Neoplasms; Diphosphates; Female; Heterografts; Humans; Iodine Radioisotopes; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Phenotype; Radiopharmaceuticals; Stilbenes; Tomography, Emission-Computed, Single-Photon

Resveratrol, a natural plant phenolic found at high concentration in red grapes, has been suggested to have a range of health benefits. Here, we tested its effects on metastatic cell behaviors. The strongly metastatic rat prostate MAT-LyLu cells were used as a model. At 20 μM, resveratrol had no effect on cellular proliferation or viability. However, it suppressed significantly 1) lateral motility by up to 25%; 2) transverse motility by 31%; and invasion by 37%. It also increased the cells' adhesion to substrate by 55%. Electrophysiologically, resveratrol inhibited voltage-gated Na(+) channel (VGSC) activity that has been shown previously to promote metastatic cell behaviors. This effect was dose-dependent with an IC50 of ∼50 μM. Voltage dependencies of current activation and peak were not affected but steady-state inactivation was shifted to more hyperpolarized potentials and recovery from inactivation was slowed. Coapplication of resveratrol with the highly specific VGSC blocker tetrodotoxin did not result in any additive effect on inhibition of both 1) VGSC activity and 2) metastatic cell behaviors. These results suggest 1) that a significant mode of action of resveratrol is VGSC blockage and 2) that resveratrol has promise as a natural antimetastatic agent.

Topics: Animals; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Male; Neoplasm Metastasis; Prostatic Neoplasms; Rats; Resveratrol; Sodium Channel Blockers; Sodium Channels; Stilbenes; Tetrodotoxin

Polyphenol compounds, present in a wide variety of natural plants, exhibit antioxidant and free radical scavenging ability and induce apoptosis in various cancer cells. However, the effect of pterostilbene on oral cancer cell metastasis has not been clarified.. The present study aimed to examine the anti-metastatic properties of pterostilbene in human oral squamous cell carcinoma (SCC)-9 cells.. In this study, pterostilbene treatment significantly inhibited migration/invasion capacities of SCC-9 cells in vitro. The results of zymography and western blotting revealed that the activities and protein levels of the MMP-2 and urokinase-type plasminogen activator (u-PA) was inhibited by pterostilbene. Western blot analysis also showed that pterostilbene inhibits the phosphorylation of Akt, extracellular signal-regulated kinase 1/2 and p38. Determinations of the mRNA levels, real-time polymerase chain reaction and promoter assays were conducted to evaluate the inhibitory effects of pterostilbene on MMP-2 and u-PA expression in SCC-9 cells. Such inhibitory effects were associated with the upregulation of tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1 and the downregulation of the transcription factors of NF-κB, SP-1 and CREB signaling pathways.. Pterostilbene may have potential use as a chemopreventive agent against oral cancer metastasis.

Topics: Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; RNA, Messenger; Stilbenes; Up-Regulation; Urokinase-Type Plasminogen Activator

The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1), which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex that mediates gene silencing. We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER), found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.

Topics: Acetylation; Animals; Antineoplastic Agents, Phytogenic; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Luciferases; Male; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Mice; Neoplasm Metastasis; Prostatic Neoplasms; Repressor Proteins; Resveratrol; Signal Transduction; Stilbenes; Trans-Activators; Transcription Factors; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Metastasis is one of the most threatening features of the oncogenic process and the main cause of cancer-related mortality. Several studies have demonstrated that matrix metalloproteinases (MMPs) are critical for tumor invasion and metastasis. Resveratrol (3,5,4'-trihydroxystilbene), a phenolic compound of red wine, has been reported to be a natural chemopreventive agent. However, the cancer preventive effects of piceatannol (3,5,3',4'-tetrahydroxystilbene), a metabolite of resveratrol and the underlying molecular mechanisms have not yet been fully elucidated. In this study, we report that piceatannol inhi-bits H-ras-induced MMP-2 activity and the invasive phenotype of MCF10A human breast epithelial cells harboring mutated H-ras (H-ras MCF10A cells) more effectively than resveratrol. Piceatannol attenuated the H-ras-induced phosphorylation of Akt in a time- and dose-dependent manner, whereas resveratrol, at the same concentrations, did not exert an inhibitory effect. In vitro kinase assays demonstrated that piceatannol significantly inhibited phosphatidylinositol 3-kinase (PI3K) activity and suppressed phospha-tidylinositol (3,4,5)-trisphosphate (PIP3) expression in the H-ras MCF10A cells. Ex vivo pull-down assays revealed that piceatannol directly bound to PI3K, inhibiting PI3K activity. Data from molecular docking suggested that piceatannol is a more tight-binding inhibitor than resveratrol due to the additional hydrogen bond between the hydroxyl group and the backbone amide group of Val882 in the ATP-binding pocket of PI3K.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Epithelial Cells; Female; Gene Expression Regulation; Genes, ras; Humans; Matrix Metalloproteinase 2; Mutation; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; Stilbenes; Wine

Epithelial-to-mesenchymal transition (EMT) is a cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which in turn promotes carcinoma invasion and metastasis. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenolic compound found in grapes, red wine and several other plants. Numerous reports in the literature indicate that resveratrol can suppress cancer invasion and metastasis. However, the underlying mechanisms of inhibiting metastasis by resveratrol are complex, not fully elucidated and the subject of intense scientific debate. Despite evidence indicating that EMT can be a target for resveratrol, little is known about the effect of resveratrol on lung cancer cells. Our previous studies demonstrated that TGF-β1 induces EMT to promote lung adenocarcinoma invasion and metastasis. To understand the repressive role of resveratrol in lung cancer invasion and metastasis, we sought to investigate the potential use of resveratrol as an inhibitor of TGF-β1-induced EMT development in A549 lung cancer cells in vitro. Here we show that when A549 cells are treated with TGF-β1 and resveratrol, the latter inhibits the initiation of TGF-β1-induced EMT. Our results show that 20 μM resveratrol increases expression of the epithelial phenotype marker E-cadherin and represses the expression of the mesenchymal phenotype markers, Fibronectin and Vimentin during the initiation of TGF-β1-induced EMT. Resveratrol also inhibits expression of EMT-inducing transcription factors Snail1 and Slug, although the expression of the Twist1 transcription factor remained unchanged. Resveratrol inhibits the TGF-β1-induced increase in cell adhesion, migration and invasion of A549 lung cancer cells. Taken together, our findings provide new evidence that resveratrol suppresses lung cancer invasion and metastasis in vitro through inhibiting TGF-β1-induced EMT.

Topics: Antineoplastic Agents, Phytogenic; Cadherins; Carcinoma, Non-Small-Cell Lung; Cell Adhesion; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Fibronectins; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Resveratrol; Stilbenes; Transforming Growth Factor beta1; Vimentin

Resveratrol, a polyphenol from grapes and red wine has many health beneficial effects, including protection against cardiovascular and neurodegenerative diseases and cancer. However, our group and others have provided evidence for a dual cancer promoting or inhibitory role for resveratrol in breast cancer, dependent on estrogenic or antiestrogenic activities. Moreover, much of the inhibitory effects of resveratrol have been reported from studies with high non-physiological concentrations.. We investigated the effects of a range of concentrations (0.5, 5, 50 mg/kg body weight) of resveratrol on mammary tumor development post-initiation, using immunocompromised mice.. Our findings suggest promotion of mammary tumor growth and metastasis by resveratrol at all concentrations tested in tumors derived from the low metastatic estrogen receptor (ER)α(-), ERβ(+) MDA-MB-231 and the highly metastatic ER(-) MDA-MB-435 cancer cell lines. Additionally, the activity of the migration/invasion regulator Rac, which we have previously shown to be regulated by resveratrol in vitro, was measured in tumors from resveratrol treated mice. Our results show a significant induction of tumoral Rac activity and a trend in increased expression of the Rac downstream effector PAK1 and other tumor promoting molecules following resveratrol treatment.. Taken together, our findings implicate low concentrations of resveratrol in potential promotion of breast cancer. Therefore, this study illuminates the importance of further delineating resveratrol's concentration dependent effects, particularly in breast cancer, before it can be tested in the clinic or used as a dietary supplement for breast cancer patients.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Immunologic Deficiency Syndromes; Mice; Mice, Hairless; Mice, Nude; Neoplasm Metastasis; p21-Activated Kinases; Plant Extracts; Polyphenols; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Resveratrol; Stilbenes; Vitis

Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene) is a polyphenol detected in grapes, red wine and Rheum undulatum; it has also been demonstrated to exert anticarcinogenic effects. In this study, in order to determine whether piceatannol inhibits the lung metastasis of prostate cancer cells, MAT-Ly-Lu (MLL) rat prostate cancer cells expressing luciferase were injected into the tail veins of male nude mice. The oral administration of piceatannol (20 mg/kg) significantly inhibited the accumulation of MLL cells in the lungs of these mice. In the cell culture studies, piceatannol was demonstrated to inhibit the basal and epidermal growth factor (EGF)-induced migration and invasion of DU145 cells, in addition to the migration of MLL, PC3 and TRAMP-C2 prostate cancer cells. In DU145 cells, piceatannol attenuated the secretion and messenger RNA levels of matrix metalloproteinase-9, urokinase-type plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). Piceatannol increased the protein levels of tissue inhibitor of metalloproteinase-2 in a concentration-dependent fashion. Additionally, piceatannol inhibited the phosphorylation of signal transducer and activator of transcription (STAT) 3. Furthermore, piceatannol effected reductions in both basal and EGF-induced interleukin (IL)-6 secretion. An IL-6 neutralizing antibody inhibited EGF-induced STAT3 phosphorylation and EGF-stimulated migration of DU145 cells. Interleukin-6 treatment was also shown to enhance the secretion of uPA and VEGF, STAT3 phosphorylation and the migration of DU145 cells; these increases were suppressed by piceatannol. These results demonstrate that the inhibition of IL-6/STAT3 signaling may constitute a mechanism by which piceatannol regulates the expression of proteins involved in regulating the migration and invasion of DU145 cells.

Topics: Animals; Cell Line, Tumor; Epidermal Growth Factor; Gene Expression Regulation; Humans; Interleukin-6; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Phosphorylation; Prostatic Neoplasms; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Urokinase-Type Plasminogen Activator; Vascular Endothelial Growth Factor A

Metastasis is a major cause of death in cancer patients. Our previous studies showed that pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, exhibited a potential cancer chemopreventive activity and also inhibited the growth of various human cancer cell lines via the regulation of cell cycle progression. In this study, we further evaluated the potential antimetastatic activity of pinosylvin in in vitro and in vivo models. Pinosylvin suppressed the expression of matrix metalloproteinase (MMP)-2, MMP-9 and membrane type 1-MMP in cultured human fibrosarcoma HT1080 cells. We also found that pinosylvin inhibited the migration of HT1080 cells in colony dispersion and wound healing assay systems. In in vivo spontaneous pulmonary metastasis model employing intravenously injected CT26 mouse colon cancer cells in Balb/c mice, pinosylvin (10 mg/kg body weight, intraperitoneal administration) significantly inhibited the formation of tumor nodules and tumor weight in lung tissues. The analysis of tumor in lung tissues indicated that the antimetastatic effect of pinosylvin coincided with the down-regulation of MMP-9 and cyclooxygenase-2 expression, and phosphorylation of ERK1/2 and Akt. These data suggest that pinosylvin might be an effective inhibitor of tumor cell metastasis via modulation of MMPs.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chemoprevention; Colonic Neoplasms; Cyclooxygenase 2; Humans; Lung Neoplasms; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Phosphorylation; Stilbenes

The antioxidant 3,4',5 tri-hydroxystilbene (resveratrol), a phytoalexin found in grapes, shows cancer preventive activities, including inhibition of migration and invasion of metastatic tumors. However, the molecular mechanism underlying the effect of resveratrol on tumor metastasis, especially in human metastatic lung and cervical cancers is not clear. A non-cytotoxic dosage of resveratrol causes a reduction in the generation of reactive oxygen species, and suppresses phorbol 12-myristate 13-acetate (PMA)-induced invasion and migration in both A549 and HeLa cells. Resveratrol also decreases both the expression and the enzymatic activity of matrix metalloproteinase-9 (MMP-9), and the promoter activity of PMA-stimulated MMP-9 is also inhibited. However, resveratrol does not affect either the expression or the proteolytic activity of MMP-2. Our results also show that resveratrol suppresses the transcription of MMP-9 by the inhibition of both NF-κB and AP-1 transactivation. These results indicate that resveratrol inhibits both NF-κB and AP-1 mediated MMP-9 expression, leading to suppression of migration and invasion of human metastatic lung and cervical cancer cells. Resveratrol has potential for clinical use in preventing invasion by human metastatic lung and cervical cancers.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Movement; Cell Survival; Female; HeLa Cells; Humans; Lung Neoplasms; Male; Matrix Metalloproteinase 9; Neoplasm Metastasis; NF-kappa B; Reactive Oxygen Species; Resveratrol; Stilbenes; Transcription Factor AP-1; Transcriptional Activation; Uterine Cervical Neoplasms

The consumption of foods containing resveratrol produces significant health benefits. Resveratrol inhibits cancer by reducing cell proliferation and metastasis and by inducing apoptosis. These actions could be explained by its ability to inhibit (ERK-1/2), Akt and suppressing the levels of estrogen and insulin growth factor -1 (IGF-1) receptor. How these processes are manifested into the antitumor actions of resveratrol is not clear. Using microarray studies, we show that resveratrol reduced the expression of various prostate-tumor associated microRNAs (miRs) including miR-21 in androgen-receptor negative and highly aggressive human prostate cancer cells, PC-3M-MM2. This effect of resveratrol was associated with reduced cell viability, migration and invasiveness. Additionally, resveratrol increased the expression of tumor suppressors, PDCD4 and maspin, which are negatively regulated by miR-21. Short interfering (si) RNA against PDCD4 attenuated resveratrol's effect on prostate cancer cells, and similar effects were observed following over expression of miR-21 with pre-miR-21 oligonucleotides. PC-3M-MM2 cells also exhibited high levels of phospho-Akt (pAkt), which were reduced by both resveratrol and LY294002 (a PI3-kinase inhibitor). MiR-21 expression in these cells appeared to be dependent on Akt, as LY294002 reduced the levels of miR-21 along with a concurrent increase in PDCD4 expression. These in vitro findings were further corroborated in a severe combined immunodeficient (SCID) mouse xenograft model of prostate cancer. Oral administration of resveratrol not only inhibited the tumor growth but also decreased the incidence and number of metastatic lung lesions. These tumor- and metastatic-suppressive effects of resveratrol were associated with reduced miR-21 and pAkt, and elevated PDCD4 levels. Similar anti-tumor effects of resveratrol were observed in DU145 and LNCaP prostate cancer cells which were associated with suppression of Akt and PDCD4, but independent of miR-21.These data suggest that resveratrol's anti-tumor actions in prostate cancer could be explained, in part, through inhibition of Akt/miR-21 signaling pathway.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromones; Enzyme Inhibitors; Estrogens; Flow Cytometry; Genes, Tumor Suppressor; Humans; Male; Mice; Mice, SCID; MicroRNAs; Morpholines; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Oligonucleotides; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Resveratrol; RNA, Small Interfering; Stilbenes; Wound Healing

We reported a precise engineered nanocapsule encapsulating a neovasculature disruption agent, combretastatin A4 (CA4) in a matrix that was made up of paclitaxel (PTX) conjugated amphiphilic polyester. The nanocapsule was able to release CA4 and PTX sequentially for temporal antiangiogenesis and anticancer activities. The nanocapsule has a small particle size at 68 nm with narrow size distribution (approximately 0.15). Cellular uptake of the nanocapsule was efficient, and detectable at as early as 20 min, and drugs sequestered in the nanocapsule could exert effective therapeutic effects on tumor neovasculature and cancer cells, respectively. Biodistribution experiments demonstrated the long circulation of nanocapsule in body fluid and the preferential accumulation of nanocapsule in tumor. Both in vivo artificial pro-angiogenesis and tumor xenograft assays demonstrated the promising therapeutic effect of the nanocapsule on tumor vasculature disruption, tumor cell proliferation inhibition and tumor cell apoptosis induction. The intrasplenic liver metastasis experiment also confirmed the liver metastatic prevention capacity of this nanocapsule. In summary, the findings indicated that this dual drug loaded nanocapsule with sequential drug delivery capacity is a promising candidate in combinatorial therapy in fighting against cancer, and may open an avenue for cancer therapy and diagnosis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Endocytosis; Endothelial Cells; Humans; Immunohistochemistry; Liver Neoplasms; Male; Mice; Nanocapsules; Neoplasm Metastasis; Neovascularization, Pathologic; Paclitaxel; Stilbenes

Resveratrol (3, 4', 5 tri-hydroxystilbene), a naturally occurring polyphenol, exhibits anti-inflammatory, antioxidant, cardioprotective and antitumor activities. We have recently shown that resveratrol can enhance the apoptosis-inducing potential of TRAIL in prostate cancer cells through multiple mechanisms in vitro. Therefore, the present study was designed to validate whether resveratrol can enhance the apoptosis-inducing potential of TRAIL in a xenograft model of prostate cancer.. Resveratrol and TRAIL alone inhibited growth of PC-3 xenografts in nude mice by inhibiting tumor cell proliferation (PCNA and Ki67 staining) and inducing apoptosis (TUNEL staining). The combination of resveratrol and TRAIL was more effective in inhibiting tumor growth than single agent alone. In xenografted tumors, resveratrol upregulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and p27(/KIP1), and inhibited the expression of Bcl-2 and cyclin D1. Treatment of mice with resveratrol and TRAIL alone inhibited angiogenesis (as demonstrated by reduced number of blood vessels, and VEGF and VEGFR2 positive cells) and markers of metastasis (MMP-2 and MMP-9). The combination of resveratrol with TRAIL further inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells than single agent alone. Furthermore, resveratrol inhibited the cytoplasmic phosphorylation of FKHRL1 resulting in its enhanced activation as demonstrated by increased DNA binding activity.. These data suggest that resveratrol can enhance the apoptosis-inducing potential of TRAIL by activating FKHRL1 and its target genes. The ability of resveratrol to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that resveratrol alone or in combination with TRAIL can be used for the management of prostate cancer.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Flavonoids; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Ki-67 Antigen; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Phenols; Polyphenols; Proliferating Cell Nuclear Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes; TNF-Related Apoptosis-Inducing Ligand

Resveratrol has been shown recently to exhibit antimetastatic effect on various human solid tumors. However, the possible molecular mechanism for its antimetastatic action needs to be elucidated. In this study, we investigated the effect of resveratrol on metastasis potential of colon carcinoma cells under normoxia and hypoxia in vitro. These results showed that, resveratrol can restrict the migration, adhesion, invasion and MMP-9 and MMP-2 secretion in Lovo cells cultured under normoxia and hypoxia. Hypoxia and iron chelator 2,2'-dipyridyl treatment can stimulate the invasion and migration enhancement of Lovo cells, while resveratrol exhibited substantial resistance on the metastasis potential stimulation by inhibiting the mRNA expression of VEGF and MMP-9 in colon carcinoma cells under normoxia and hypoxia, reducing HIF-1 alpha protein expression under hypoxia. Also, iron chelator 2,2'-dipyridyl treatment showed approximately the same effect on metastasis potential as Lovo cells cultured under hypoxia. These data demonstrated that, the antimetastatic effect of resveratrol under hypoxia were associated with the restriction of HIF-1 alpha protein expression and stabilization, which could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human tumors.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Adhesion; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Cell Survival; Colonic Neoplasms; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Resveratrol; RNA, Messenger; Stilbenes; Vascular Endothelial Growth Factor A

It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Measurement of proliferative and metastatic capacity by MTS and Matrigel invasion assays, respectively, was done and showed that NO-treated melanoma cells exhibited a higher capacity compared with control, especially metastatic Lu1205 cells. Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) is a multifunctional protein and its role in tumor biology has attracted considerable attention. To determine whether APE/Ref-1 plays a role in mediating NO stimulation of melanoma progression, we investigated the effect of DETA/NO on levels of APE/Ref-1 and related downstream targets [activator protein-1 (AP-1)/JunD, matrix metalloproteinase-1 (MMP-1), Bcl-2, and inducible nitric oxide synthase (iNOS)] by Western blot and reverse transcription-PCR analysis. Following DETA/NO treatment, APE/Ref-1 and other downstream molecules were induced. Knockdown of APE/Ref-1 or AP-1/JunD by specific small interfering RNA markedly reversed the induction by NO stress of target proteins. These results present evidence for the existence of a functional feedback loop contributing to progression and metastasis of melanoma cells. Resveratrol has been shown to be an APE/Ref-1 inhibitor and significant decreases in AP-1/JunD, MMP-1, Bcl-2, and iNOS protein levels occurred after exposure to resveratrol. This phenolic antioxidant may be an appropriate choice for combining with other compounds that develop resistance by up-regulation of these molecules.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Disease Progression; DNA-(Apurinic or Apyrimidinic Site) Lyase; Feedback, Physiological; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Models, Biological; Neoplasm Metastasis; Nitric Oxide; Resveratrol; Stilbenes; Transcription Factor AP-1

Administration of different doses of the diphenol resveratrol had no effect on the growth of an intramuscularly implanted experimental tumour, the Lewis lung carcinoma. These results do not agree with previous reports where a clear effect of resveratrol was shown on tumour burden in both mice and rats. However, administration of the diphenol had a clear anti-metastatic effect, decreasing both the number and the weight of the lung metastases. Similar effects were observed both at 5 and 25mg/kg body weight per day, resulting in an approximately 40% reduction in the number of metastases. These results suggest that resveratrol could be tentatively given as a preventive agent in cancer patients undergoing radiotherapy or chemotherapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Body Weight; Carcinoma, Lewis Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Eating; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Resveratrol; Stilbenes

To investigate the inhibitory effect of resveratrol on the metastasis-associated ability of human highly metastatic ovarian carcinoma HO-8910PM cells in vitro.. MTf assay was used to examine the cytotoxicity of resveratrol in HO-8910PM cells; Transwell Chamber assay was performed to determine the effect on invasion and migratory capacity of the cells by resveratrol; Effect on adhesion potential of HO-8910PM cells was tested by cell-Matrigel adhesion assay.. Resveratrol showed no cytotoxicity on HO-8910PM cells after 6 h treatment. Resveratrol significantly inhibited migration and adhesion capacity of HO-8910PM cells in vitro. Their inhibitory rates after treated with the chemical of 100 micromol/L for 6 h were (30. 1 +/- 10. 8) % ,(34. 27 +/- 1. 28)% , respectively. However, Resveratrol had no effect on invasion capacity of HO-8910PM cells.. Resveratrol can inhibit the migration and adhesion of HO-8910PM cells in vitro. Resveratrol might be a potential drug to inhibit tumor metastasis.

Topics: Antineoplastic Agents, Phytogenic; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drugs, Chinese Herbal; Female; Flow Cytometry; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Plants, Medicinal; Resveratrol; Stilbenes

Combretastatin A4 (CA4) is a drug that targets tumor vasculature to inhibit angiogenesis. Whether CA4 has a direct effect on gastric cancer is not known. We herein investigated the effect of CA4 on growth and metastasis of gastric cancer cells at clinically achievable concentration and explored the associated antitumor mechanisms. Nine human gastric cancer cell lines, including two metastatic gastric cancer cell lines (AGS-GFPM1/2), constitutively expressing green fluorescence protein (GFP) were used. These metastatic AGS-GFPM1/2 cells expressed a higher level of phosphorylated serine 473 on AKT (p-AKT). Our results showed that CA4 (0.02-20 microM) has significant in vitro effects on reducing cell attachment, migration, invasiveness, as well as cell cycle G2/M disturbance on p-AKT-positive gastric cancer cells. In addition, a phosphoinositide 3-kinase inhibitor, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], a specific AKT inhibitor, and 0.2 to 20 microM CA4 displayed a similar response profile on p-AKT-positive cells, suggesting that CA4-induced effect was mediated by inhibition of the PI3 kinase/AKT pathway. The results from in vivo GFP monitoring system indicated that CA4 phosphate (CA4-P; 200 mg/kg) significantly inhibited the s.c. and intra-abdominal growth of xenotransplanted AGS-GFPM2 cells in nude mice. Furthermore, CA4-P treatment showed a remarkable ability to inhibit gastric tumor metastasis as well as attenuate p-AKT expression. In conclusion, our study is the first to find that CA4 inhibited AKT activity in human gastric cancer cells. The decreased AKT activity correlated well with the CA4 antitumor growth response and decrease of metastasis. Further investigation on drugs targeting the PI3 kinase-AKT pathway may provide a new approach for the treatment of human gastric cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Survival; Humans; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Stilbenes; Stomach Neoplasms; Xenograft Model Antitumor Assays

Resveratrol has been shown to have anticarcinogenic activity. We previously found that resveratrol inhibited growth and induced apoptosis in 2 human melanoma cell lines. In this study we determined whether resveratrol would inhibit human melanoma xenograft growth. Athymic mice received control diets or diets containing 110 micromol/L or 263 micromol/L resveratrol, 2 wk prior to subcutaneous injection of the tumor cells. Tumor growth was measured during a 3-wk period. Metabolism of resveratrol was assayed by bolus gavage of 75 mg/kg resveratrol in tumor-bearing and nontumor-bearing mice. Pellets containing 10-100 mg resveratrol were implanted into the mice, next to newly palpated tumors, and tumor growth determined. We also determined the effect of a major resveratrol metabolite, piceatannol, on experimental lung metastasis. Resveratrol, at any concentration tested, did not have a statistically significant effect on tumor growth. The higher levels of resveratrol tested (0.006% in food or 100 mg in slow-release pellets) tended to stimulate tumor growth (P = 0.08-0.09). Resveratrol and its major metabolites, resveratrol glucuronide and piceatannol, were found in serum, liver, skin, and tumor tissue. Piceatannol did not affect the in vitro growth of a murine melanoma cell line, but significantly stimulated the number of lung metastases when these melanoma cells were directly injected into the tail vein of the mouse. These results suggest that resveratrol is not likely to be useful in the treatment of melanoma and that the effects of phytochemicals on cell cultures may not translate to the whole animal system.

Topics: Animals; Anticarcinogenic Agents; Cell Division; Cell Line, Tumor; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Diet; Drug Implants; Humans; Lung Neoplasms; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Oxidation-Reduction; Resveratrol; Stilbenes; Transplantation, Heterologous

Resveratrol (Res) has been reported to possess cancer chemopreventive activity on the basis of its in vitro effects on tumor cells and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of Res on the development of mammary tumors appearing spontaneously in HER-2/neu transgenic mice at an early age. The mechanisms involved in the Res antitumor effect were evaluated by studying the immune effectiveness, tumor apoptosis and expression of mRNA and protein for HER-2/neu in tumoral mammary glands from Res-treated mice and in tumor cell lines. Res supplementation delayed the development of spontaneous mammary tumors (p < 0.001), reduced the mean number and size of mammary tumors (p < 0.0001) and diminished the number of lung metastases in HER-2/neu transgenic mice. The effects of Res were associated with downregulation of HER-2/neu gene expression and increased apoptosis both in tumoral mammary glands and in murine (N202) and human (SKBr3) tumor cell lines. Neither the basal, the IL-2-induced NK activity nor the lymphocyte number and proliferation was modified in Res-supplemented compared to control mice. Our results demonstrate that Res supplementation delays the development and reduces the metastasizing capacity of spontaneous mammary tumors in HER-2/neu transgenic mice. The antitumor effect of Res might be related to the downregulation of HER-2/neu expression and the induction of apoptosis in tumor cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Female; Flow Cytometry; Humans; In Situ Nick-End Labeling; Lung; Lymphocytes; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Neoplasm Metastasis; Receptor, ErbB-2; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Spleen; Stilbenes; Time Factors

Resveratrol is an antioxidant present in grapes and their related products. We investigated whether dietary resveratrol could inhibit the proliferation and metastasis of tumors and hyperlipidemia in Donryu rats subcutaneously implanted with an ascites hepatoma cell line of AH109A. By feeding 10 or 50 ppm resveratrol in the diet to hepatoma-bearing rats for 20 days, solid tumor growth and metastasis tended to be suppressed dose-dependently. Resveratrol (50 ppm) significantly suppressed the serum lipid peroxide level, indicating its antioxidative properties or those of its metabolite(s) in vivo. Resveratrol dose-dependently suppressed both the serum triglyceride and very-low-density lipoprotein + low-density lipoprotein (VLDL + LDL)-cholesterol levels. The hypocholesterolemic action of resveratrol is attributed, at least in part, to an increased excretion of neutral sterols and bile acids into feces. These results suggest that dietary resveratrol is hypolipidemic with a tendency for anti-tumor-growth and anti-metastasis effects in hepatoma-bearing rats.

Topics: Animals; Antioxidants; Cell Division; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Dose-Response Relationship, Drug; Fruit; Hypolipidemic Agents; Lipid Peroxides; Lipids; Liver; Liver Neoplasms, Experimental; Male; Neoplasm Metastasis; Neoplasm Transplantation; Rats; Resveratrol; Stilbenes; Thiobarbituric Acid Reactive Substances; Triglycerides; Tumor Cells, Cultured; Vitis; Wine

Resveratrol (3,4',5-trans-trihydroxystilbene), a phytoalexin present in grapes and red wine, is emerging as a natural compound with potential anticancer properties. Here we show that resveratrol can induce growth inhibition and apoptosis in MDA-MB-231, a highly invasive and metastatic breast cancer cell line, in concomitance with a dramatic endogenous increase of growth inhibitory/proapoptotic ceramide. We found that accumulation of ceramide derives from both de novo ceramide synthesis and sphingomyelin hydrolysis. More specifically we demonstrated that ceramide accumulation induced by resveratrol can be traced to the activation of serine palmitoyltransferase (SPT), the key enzyme of de novo ceramide biosynthetic pathway, and neutral sphingomyelinase (nSMase), a main enzyme involved in the sphingomyelin/ceramide pathway. However, by using specific inhibitors of SPT, myriocin and L-cycloserine, and nSMase, gluthatione and manumycin, we found that only the SPT inhibitors could counteract the biological effects induced by resveratrol. Thus, resveratrol seems to exert its growth inhibitory/apoptotic effect on the metastatic breast cancer cell line MDA-MB-231 by activating the de novo ceramide synthesis pathway.

Topics: Acyltransferases; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Division; Cell Line, Tumor; Ceramides; Enzyme Inhibitors; Female; Humans; Models, Biological; Neoplasm Metastasis; Resveratrol; Serine C-Palmitoyltransferase; Signal Transduction; Sphingomyelins; Stilbenes

In vitro, resveratrol inhibited growth of 4T1 breast cancer cells in a dose- and time-dependent manner. In vivo, however, resveratrol had no effect on time to tumor take, tumor growth, or metastasis when administered intraperitoneally daily (1, 3, or 5 mg/kg) for 23 days starting at the time of tumor inoculation. Resveratrol had no effect on body weight, organ histology, or estrous cycling of the tumor-bearing mice. Resveratrol, therefore, is a potent inhibitor of 4T1 breast cancer cells in vitro; is nontoxic to mice at 1-5 mg/kg; and has no growth-inhibitory effect on 4T1 breast cancer in vivo.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Division; Dose-Response Relationship, Drug; Female; Kinetics; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation; Resveratrol; Stilbenes; Tumor Cells, Cultured

Resveratrol is a naturally occurring phytoalexine found in medicinal plants. We found that resveratrol, at doses of 2.5 and 10 mg/kg, significantly reduced the tumor volume (42%), tumor weight (44%) and metastasis to the lung (56%) in mice bearing highly metastatic Lewis lung carcinoma (LLC) tumors, but not at a dose of 0.6 mg/kg. Resveratrol did not affect the number of CD4(+), CD8(+) and natural killer (NK)1.1.(+) T cells in the spleen. Therefore, the inhibitory effects of resveratrol on tumor growth and lung metastasis could not be explained by natural killer or cytotoxic T-lymphocyte activation. In addition, resveratrol inhibited DNA synthesis most strongly in LLC cells; its 50% inhibitory concentration (IC(50)) was 6.8 micromol/L. Resveratrol at 100 micromol/L increased apoptosis to 20.6 +/- 1.35% from 12.1 +/- 0.36% (P < 0.05) in LLC cells, and decreased the S phase population to 22.1 +/- 1.03% and 29.2 +/- 0.27% from 35.2 +/- 1.72% (P < 0.05) at concentrations of 50 and 100 micromol/L, respectively. Resveratrol inhibited tumor-induced neovascularization at doses of 2.5 and 10 mg/kg in an in vivo model. Moreover, resveratrol significantly inhibited the formation of capillary-like tube formation from human umbilical vein endothelial cells (HUVEC) at concentrations of 10-100 micromol/L; the degree of the inhibition of capillary-like tube formation by resveratrol was 45.5% at 10 micromol/L, 50.2% at 50 micromol/L and 52.6% at 100 micromol/L. Resveratrol inhibited the binding of vascular endothelial growth factor (VEGF) to HUVEC at concentrations of 10-100 micromol/L, but not at concentrations of 1 and 5 micromol/L. The degree of inhibition of VEGF binding to HUVEC by resveratrol was 16.9% at 10 micromol/L, 53.2% at 50 micromol/L and 47.8% at 100 micromol/L. We suggest that the antitumor and antimetastatic activities of resveratrol might be due to the inhibition of DNA synthesis in LLC cells and the inhibition of LLC-induced neovascularization and tube formation (angiogensis) of HUVEC by resveratrol

Topics: Angiogenesis Inhibitors; Animals; Anticarcinogenic Agents; Apoptosis; Body Weight; Carcinoma, Lewis Lung; CD4-CD8 Ratio; Cell Cycle; Disease Models, Animal; DNA; Female; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Organ Size; Polygonaceae; Resveratrol; Spleen; Stilbenes; Thymus Gland; Tumor Cells, Cultured

Trans-resveratrol, a polyphenol present in red wines and various human foods, is an antioxidant also with reported chemopreventive properties. However, whether resveratrol may exert different effects in malignant cells with a common anatomical origin yet displaying different invasive characteristics is not known. Since invasiveness and metastasis are considered to be the most insidious and life-threatening aspects for all cancers, we compared the ability of resveratrol to control growth and cell cycle transition in the highly invasive MDA-MB-435 with the minimally invasive MCF-7 breast carcinoma cells. The data revealed that resveratrol exerted a greater inhibitory effect on the MDA-MB-435 cells. A diminution of percentage of cells in G1 phase and a corresponding accumulation of cells in S phase of the cell cycle was observed. We also studied the effect of resveratrol on a panel of MDA-MB-435 cells transfected with nm23-H1 and nm23-H2 genes, which have been suggested to play a role in controlling metastasis in breast cancer cells. These cells are designated as Vbeta, 1beta, 1Tbeta, 2beta, and 2Tbeta, respectively. The control Vbeta consists of MDA-MB-435 cells transfected with bacterial beta-glucuronidase. Cells labeled 1beta and 1Tbeta correspond to those carrying beta-glucuronidase and overexpressed wild-type (His118) or mutant (Tyr118, catalytically inactive) nm23-H1 genes. The 2beta and 2Tbeta refer to cells transfected with wild-type and mutant nm23-H2 genes. The responses of these cells to resveratrol were assessed by measuring proliferation, cell cycle phase distribution, and changes in expression of several genes. These studies have shown that resveratrol (25 microM, 3 days) reduced growth of all cell types by 60-80%. Overexpression of both wild-type and catalytically inactive nm23-H1 (1beta, 1Tbeta) but not nm23-H2 (2beta, 2Tbeta) reduced the proportion of cells in G1 phase, compared to the Vbeta control cells. Little changes in expression of PCNA, Rb, p53, and bcl-2 were observed in the five cell types treated with resveratrol, compared to untreated cells. Noted exceptions included reduced expression of Rb protein and increased expression of p53 in 2beta and 2Tbeta cells, and increased expression of bcl-2 in 2beta cells, treated with resveratrol. In contrast, resveratrol upregulated expression of cathepsin D by 50-100% in all cell lines except 1beta. These results suggest that the intrinsic metastatic potential of cancer cells may affect their r

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Cycle; Chemoprevention; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Resveratrol; Stilbenes; Transfection

The ZAP-70 tyrosine kinase is essential for T cell activation by the T cell receptor. We show that ZAP-70 is also required for migration of T cells that is dependent on the integrin LFA-1. Invasion of TAM2D2 T cell hybridoma cells into fibroblast monolayers, which is LFA-1-dependent, was blocked by overexpression of dominant-negative ZAP-70 and by piceatannol but not by herbimycin A. The Syk inhibitor piceatannol blocks the Syk homologue ZAP-70, which is expressed by TAM2D2 cells, with the same dose dependence as the inhibition of invasion. Dominant-negative ZAP-70 completely inhibited the extensive metastasis formation of TAM2D2 cells to multiple organs upon i.v. injection into mice. Migration of TAM2D2 cells through filters coated with the LFA-1 ligand ICAM-1, induced by 1 ng/ml of the chemokine SDF-1, was blocked by anti-LFA-1 mAb and also abrogated by dominant-negative ZAP-70 and piceatannol. In contrast, migration induced by 100 ng/ml SDF-1 was independent of both LFA-1 and ZAP-70. LFA-1 cross-linking induced tyrosine phosphorylation, which was blocked by dominant-negative ZAP-70 and piceatannol. We conclude that LFA-1 engagement triggers ZAP-70 activity that is essential for LFA-1-dependent migration.

Topics: Animals; Benzoquinones; Cell Movement; Chemokine CXCL12; Chemokines, CXC; Fibroblasts; Gene Expression; Humans; Hybridomas; Integrins; Intercellular Adhesion Molecule-1; Lactams, Macrocyclic; Lymphocyte Function-Associated Antigen-1; Mice; Neoplasm Metastasis; Phosphotyrosine; Protein-Tyrosine Kinases; Quinones; Rats; Rifabutin; Stilbenes; T-Lymphocytes; Virulence Factors, Bordetella; ZAP-70 Protein-Tyrosine Kinase

Topics: Adult; Breast Neoplasms; Estradiol; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptors, Estrogen; Stilbenes

Within a period of four years 35 patients with metastatic breast cancer were treated with tamoxifen. One third had objective remissions, average duration of complete remission being 30.6 months and of partial remission 13.7 months. Mean survival time from start of tamoxifen treatment in five patients with complete remission was 30.6 months while in seven with partial remission it was 20.4 months. Nine patients with unresponsive metastases had a mean survival time of 24.3 months, the remaining 14 patients who deteriorated surviving for 11.7 months. Ten of the 12 patients who responded well were over 60 years old. Lymph-node and lung or pleural metastases were significantly reduced by treatment in four of eight and six of 15 cases, respectively. Satisfactory regression of bony metastases was never seen. Because of this, combined tamoxifen (10 mg twice daily) and methandrostenolone (1 mg twice daily) was given to an additional five patients, with one of them responding. Side effects included thrombocytopenia and hypercalcaemia.

Topics: Adult; Age Factors; Bone Neoplasms; Breast Neoplasms; Female; Humans; Hypercalcemia; Lung Neoplasms; Lymphatic Metastasis; Methandrostenolone; Middle Aged; Neoplasm Metastasis; Pleural Neoplasms; Remission, Spontaneous; Stilbenes; Tamoxifen; Thrombocytopenia; Time Factors

Tamoxifen (NSC-180973; ICI-46474) can provide palliation to patients with advanced breast cancer whose tumors contain estrogen-binding proteins (EBP). The drug is most effective in patients with bone metastasis and minimal prior therapy. In the present study, 72 patients with advanced breast cancer were evaluated for their response to oral tamoxifen therapy administered at a dose of 20 mg twice daily. Twenty-eight of 72 patients (38%) demonstrated objective responses to tamoxifen therapy. For patients with a positive EBP and no prior chemotherapy, eight of 11 (74%) responded. No patient possessing a tumor negative for EBP achieved a remission. Patients with tumors that possessed normal arylsulfatase B and glucose-6-phosphate dehydrogenase enzyme activities responded most favorably to tamoxifen therapy. These results demonstrate that tamoxifen is effective in the treatment of patients with advanced breast cancer, and EBP and specific enzymes might be useful in selecting the patients for hormone manipulation.. Tamoxifen is a synthetic nonsteroidal drug with antiestrogenic properties. This report describes the response of patients with metastatic breast cancer to tamoxifen and correlates clinical responses with tumor tissue content of cytoplasmic estrogen binding proteins (EBPs) and other biochemical parameters. Ages of patients ranged from 27 to 82 years. 7 patients were premenopausal, 63 postmenopausal, and 2 had recent endocrine ablaetion. Prior hormone therapy, radiotherapy, or chemotherapy ahd been given to all patients. Tamoxifen was given at a dose of 20 mg orally for a minimum of 4 weeks and continued if an objective remission was shown. Before therapy a biopsy specimen was taken for determination of EBP and for specific enzyme activities. Another biopsy specimen was taken for at least 8 weeks after therapy. A total of 72 patients were treated for at least 4 weeks. The overall response rate was 38%. Most frequent responses were in the over-70 age group. The median duration of response has been 9.5 months. Bony involvement responded to therapy in 21 of 28 patients. No responses were shown in 6 patients with liver metastases. Only 1 of 18 patients who had previous chemotherapy responded. Of 31 who had no prior chemotherapy, 73% achieved a remission. There was a 44% correlation between patients with a positive EBP assay and response to therapy, but none in EBP-negative patients. In this study 20 of 28 patients had normal arylsulfatase B/DNA ratios in their tumor tissue and 11 of the 20 responded to tamoxifen therapy. Patients who responded most favorably to therapy had normal G-6-PD activities. It is concluded that tamoxifen therapy may cancel the need for ablative surgery in postmenopausal patients with positive EBPs and who have had a prior response to additive hormonal treatment.

Topics: Adult; Aged; Arylsulfatases; Bone Neoplasms; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Estrogens; Female; Glucosephosphate Dehydrogenase; Humans; Lung Neoplasms; Menopause; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Protein Binding; Stilbenes; Tamoxifen

Tamoxifen (NSC-180973, ICI-46474), an antiestrogen, was administered to 39 women with stage IV breast cancer at a dose of 20 mg orally every 12 hours. Patients were selected as eligible for endocrine ablative treatment and with disease not so aggressive as to jeopardize further treatment in case the experimental drug failed. Objective remission was obtained in 19 patients (49%) with a mean duration of 11+ months and ten patients are still in remission. No progression was seen in seven patients (18%) lasting 13+ months with only one patient in relapse. Thirteen patients (33%) have failed. Objective remission was obtained in two premenopausal women even though menstrual cycles were not suppressed; bilateral oophorectomy in one of these patients induced a second remission after relapse from tamoxifen. Objective remissions were obtained in two women with proven complete hypophysectomy a direct action of antiestrogens at the tumor level. Positive estrogen receptors were suggestive of being a good predictor of response. Menopausal status and dominant site of metastasis did not affect the response to tamoxifen in this small series. Tamoxifen did not alter prolactin secretion, and side effects from the drug were usually mild and transient in nature. We conclude that tamoxifen is an effective antitumor agent in patients with stage IV breast cancer; further studies are necessary to determine whether it will equal the therapeutic effect of oophorectomy, adrenalectomy, and hypophysectomy.. Preliminary results with the use of tamoxifen in 51 27-80 year old women with Stage 4 breast cancer are presented. There were 39 patients otherwise suitable for endocrine ablative procedures and 12 who had previously had such surgery. Tamoxifen was given in doses of 20 mg orally every 12 hours. Of the 39 patients, 19 had objective remissions with a mean duration of over 11 months. 7 others had no progression of their disease for over 13 months. Of 11 patients shown to have estrogen receptors, 6 showed remissions with the antiestrogen therapy. Objective remissions were obtained in 2 premenopausal women even though menopausal cycles were not suppressed. Bilateral oophorectomy in 1 of them later induced a 2nd remission. Objective remissions were obtained in 2 women with previous complete hypophysectomy. Serum prolactin levels in 8 patients studied were not changed by tamoxifen therapy. Side effects from the drug were mild and transitory. Results obtained with tamoxifen are approaching those obtained with endocrine ablative therapy. Further studies are needed to determine if endocrine ablation can induce further significant improvement beyond that which can be obtained with antiestrogen therapy.

Topics: Adrenalectomy; Adult; Aged; Breast Neoplasms; Female; Humans; Hypophysectomy; Menopause; Middle Aged; Neoplasm Metastasis; Ovary; Prolactin; Remission, Spontaneous; Stilbenes; Tamoxifen

21 postmenopausal patients with skin or/and bone metastases of breast carcinoma received 100-120 mg daily diethyldioxystilbene diphosphate (Honvan) orally. 7 objective remissions were observed, 8 tumors remained unchanged, and 6 were progressive. In 3 cases, rapid tumor progression was suggestive of estrogenic stimulation. Side effects were the same as for other estrogens. Diethyldioxystilbene disphosphate is an active estrogenic compound in the treatment of breast carcinoma.

Topics: Breast Neoplasms; Drug Evaluation; Female; Humans; Neoplasm Metastasis; Stilbenes

Topics: Afibrinogenemia; Aged; Aminocaproates; Antineoplastic Agents; Blood Platelets; Bone Neoplasms; Chlorotrianisene; Diagnosis, Differential; Disseminated Intravascular Coagulation; Ethinyl Estradiol; Fibrinogen; Fibrinolysis; Heparin; Humans; Male; Neoplasm Metastasis; Phosphoric Acids; Prostatic Neoplasms; Stilbenes

Topics: Antineoplastic Agents; Breast Neoplasms; Dimethylamines; Estrogen Antagonists; Female; Humans; Neoplasm Metastasis; Phenols; Stilbenes

Topics: Animals; Antibody Formation; Antineoplastic Agents; Blood Coagulation; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Chemical Phenomena; Chemistry; Cyclophosphamide; Depression, Chemical; Drug Synergism; Female; Fibrinolysis; Fluorescent Dyes; Hemolysin Proteins; Hyaluronoglucosaminidase; Liver Neoplasms; Lymphatic Metastasis; Male; Mice; Mitomycins; Mononuclear Phagocyte System; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neuraminidase; Phagocytosis; Rats; Sarcoma, Yoshida; Skin Transplantation; Stilbenes; Transplantation, Heterologous; Triazines

Topics: Adenocarcinoma; Adrenal Cortex Hormones; Adrenalectomy; Breast Neoplasms; Castration; Clomiphene; Cortisone; Estrogens; Female; Humans; Hypophysectomy; Neoplasm Metastasis; Sex Chromatin; Stilbenes; Testosterone

Topics: Antineoplastic Agents; Breast Neoplasms; Castration; Diethylstilbestrol; Estrogens; Ethinyl Estradiol; Geriatrics; Hexestrol; Humans; Neoplasm Metastasis; Nitrogen Mustard Compounds; Pericarditis; Pleural Neoplasms; Stilbenes