phenanthrenes and Neoplasm-Metastasis

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Lactones; Neoplasm Metastasis; Phenanthrenes; Testolactone

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Combinations; Estradiol; Female; Humans; Hydroxyprogesterones; Lactones; Neoplasm Metastasis; Phenanthrenes; Testolactone

The constitutive activation of signal transducer and activator of transcription 3(STAT3) is associated with aggressive development and metastasis in colorectal cancer (CRC), but STAT3-targeting drugs remain elusive in clinic. Here, structure-based strategy was used to remodel the natural compound cryptotanshinone into a more effective STAT3 inhibitor LYW-6. Using the Biolayer Interferometry assay, we observed that LYW-6 exhibited specific interactions with STAT3(KD = 6.6 ± 0.7 μM). Western blot analysis and electrophoretic mobility shift assays (EMSA) showed that LYW-6 inhibited the phosphorylation of STAT3 tyrosine 705 (Tyr-705) and had slight effects on STAT1 and STAT5 phosphorylation. Western blot analysis on the upstream kinases of STAT3 confirmed that the inhibitory mechanism on p-STAT3 was independent of upstream kinases. Further investigation demonstrated that LYW-6 downregulated the expression of downstream oncogenes to inhibit cell viability, cell cycle development, and potently increased cell apoptosis in human CRC cells. The invasion and metastasis linked signaling was also blocked by LYW-6 treatment. LYW-6 was found to reduce the metastasis foci in lung on tail-lung metastasis models. In addition, it was observed that LYW-6 markedly diminished STAT3 phosphorylation in tumor tissue and significantly inhibited tumor growth on xenograft models. Tumor development on chemically-induced colorectal cancer model also significantly inhibited by LYW-6 treatment. These findings provided adequate evidence that STAT3 inhibitor LYW-6 might be a potential candidate agent for CRC treatment.

Topics: Animals; Apoptosis; Caco-2 Cells; Cell Cycle; Cell Movement; Cell Proliferation; Colorectal Neoplasms; HCT116 Cells; Humans; Mice, Inbred ICR; Mice, Inbred NOD; Mice, SCID; Molecular Docking Simulation; Neoplasm Invasiveness; Neoplasm Metastasis; Phenanthrenes; Protein Binding; STAT3 Transcription Factor; Toxicity Tests, Acute; Xenograft Model Antitumor Assays

Dihydrotanshinone I (DHTS), extracted from Salvia miltiorrhiza, was found to be the most effective compound of tanshen extracts against cancer cells in our previous studies. However, the therapeutic benefits and underlying mechanisms of DHTS on ovarian cancer remain uncertain. In this study, we demonstrated the cytocidal effects of DHTS on chemosensitive ovarian cancer cells with or without platinum-based chemotherapy. DHTS was able to inhibit proliferation and migration of ovarian cancer cells in vitro and in vivo through modulation of the PI3K/AKT signalling pathways. Combinatorial treatment of DHTS and cisplatin exhibited enhanced DNA damage in ovarian cancer cells. Overall, these findings suggest that DHTS induces ovarian cancer cells death via induction of DNA damage and inhibits ovarian cancer cell proliferation and migration.

Topics: Animals; Carcinoma, Ovarian Epithelial; Cell Death; Cell Line, Tumor; Cell Movement; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Furans; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Phenanthrenes; Phosphatidylinositol 3-Kinases; Platinum; Proto-Oncogene Proteins c-akt; Quinones; Signal Transduction; Transcription, Genetic; Zebrafish

Triptolide, the component of traditional Chinese herb, has been used as an inflammatory medicine and reported to be anti-tumor for various cancers recently. However, the effect of triptolide on Esophageal Squamous Cell Cancer (ESCC) has not yet been elucidated. In the study, we found that triptolide significantly inhibited cell proliferation, invasion, migration and survivability of ESCC cells. Moreover, we observed that triptolide induced ESCC cell cycle arrest at the G1/S phase and apoptosis through cyclin D1-CDK4/6 regulation and caspases activation. In addition, we revealed that triptolide regulates cell apoptosis and metastasis by p53 and mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, respectively. Meanwhile, the inhibitory effect of triptolide on ESCC was validated in mouse xenograft model. So, we propose that triptolide may be a candidate drug for ESCC.

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diterpenes; Epoxy Compounds; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Extracellular Signal-Regulated MAP Kinases; Humans; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Phenanthrenes; Xenograft Model Antitumor Assays

Triptolide, an extract of

Topics: Breast Neoplasms; Cell Line, Tumor; Diterpenes; Epoxy Compounds; Female; Humans; MicroRNAs; Neoplasm Metastasis; Phenanthrenes; rho GTP-Binding Proteins; Tripterygium

Osteosarcoma (OS) mainly occurs in children and adolescents, and has a high propensity for lung metastasis. Little is known about the role of SDF-1/CXCR4 axis in OS progression. AMD3100 is a specific CXCR4 antagonist. Triptolide can induce apoptosis and proliferation inhibition in various cancer cell lines.. This work aimed to investigate the effects of AMD3100 plus triptolide on the proliferation, apoptosis, invasion and metastasis of OS cells.. The expression levels of SDF-1 and CXCR4 in five OS cell lines was analyzed by qRT-PCR, western blotting and ELISA assays. The effect of AMD3100 and triptolide on the proliferation, apoptosis and invasion of U2OS cells was evaluated by CCK-8, flow cytometry and transwell assay, respectively. Orthotopic intra-tibial growth and lung metastasis mouse model of OS were employed to evaluate the inhibition effect of AMD3100 and triptolide on primary OS growth and lung metastasis.. CXCR4 protein expression was detected in HOS-8603, MG-63, U2OS and 143B but not Saos2 cells, and all these cell lines expressed SDF-1. AMD3100 plus triptolide induced proliferation inhibition and apoptosis of U2OS cells, which was attributed to the downregulation of c-Myc, survivin, cyclin D1 and increased cleaved caspase-3 and PARP. AMD3100 and triptolide also suppressed SDF-1 induced invasion of CXCR4+ U2OS cells, which was validated by decreased expression of MMP-2 and 9, VEGF, m-Calpain and β-catenin. Moreover, the phosphorylation levels of Erk1/2, Akt and STAT3, as well as the nuclear translocation and phosphorylation of NF-κB p65 in U2OS cells were also reduced by AMD3100 and triptolide. In vivo, AMD3100 and triptolide significantly reduced primary tumor growth and lung metastasis of U2OS cells.. AMD3100 combined with triptolide can reduce proliferation and metastasis, and induce apoptosis of U2OS cells, which may be related to the Erk1/2, Akt, STAT3 and NF-κB pathways.

Topics: Animals; Apoptosis; Benzylamines; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclams; Diterpenes; Down-Regulation; Epoxy Compounds; Female; Heterocyclic Compounds; Humans; Mice; Mice, Inbred C3H; Neoplasm Invasiveness; Neoplasm Metastasis; Osteosarcoma; Phenanthrenes; Signal Transduction

The epithelial-mesenchymal transition (EMT) bestows cancer cells with increased stem cell properties and metastatic potential. To date, multiple extracellular stimuli and transcription factors have been shown to regulate EMT. Many of them are not druggable and therefore it is necessary to identify targets, which can be inhibited using small molecules to prevent metastasis. Recently, we identified the ganglioside GD2 as a novel breast cancer stem cell marker. Moreover, we found that GD3 synthase (GD3S)--an enzyme involved in GD2 biosynthesis--is critical for GD2 production and could serve as a potential druggable target for inhibiting tumor initiation and metastasis. Indeed, there is a small molecule known as triptolide that has been shown to inhibit GD3S function. Accordingly, in this manuscript, we demonstrate that the inhibition of GD3S using small hairpin RNA or triptolide compromises the initiation and maintenance of EMT instigated by various signaling pathways, including Snail, Twist and transforming growth factor-β1 as well as the mesenchymal characteristics of claudin-low breast cancer cell lines (SUM159 and MDA-MB-231). Moreover, GD3S is necessary for wound healing, migration, invasion and stem cell properties in vitro. Most importantly, inhibition of GD3S in vivo prevents metastasis in experimental as well as in spontaneous syngeneic wild-type mouse models. We also demonstrate that the transcription factor FOXC2, a central downstream effector of several EMT pathways, directly regulates GD3S expression by binding to its promoter. In clinical specimens, the expression of GD3S correlates with poor prognosis in triple-negative human breast tumors. Moreover, GD3S expression correlates with activation of the c-Met signaling pathway leading to increased stem cell properties and metastatic competence. Collectively, these findings suggest that the GD3S-c-Met axis could serve as an effective target for the treatment of metastatic breast cancers.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Diterpenes; Epithelial-Mesenchymal Transition; Epoxy Compounds; Female; Forkhead Transcription Factors; Humans; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Phenanthrenes; Prognosis; Promoter Regions, Genetic; Proto-Oncogene Proteins c-met; RNA, Small Interfering; Sialyltransferases; Signal Transduction

Triptolide is an extract from Tripterygium wilfordii used in traditional Chinese medicine to treat autoimmune disorders. Triptolide has anticancer effects in vitro and is reported to impair cancer cell migration. We studied whether triptolide inhibits lung cancer cell migration and metastasis.. We determined the microRNA expression profile of triptolide-treated cells. We tested the effects of triptolide treatment on migration and invasion of lung cancer cells by using Transwell filters coated with fibronectin and Matrigel, respectively. Western blot analyses were used to compare expression of proteins involved in cell migration before and after 10 nmol/L triptolide treatment. Tail vein injections with H358 cells were performed. The mice were treated with 1 mg/kg triptolide or vehicle by intraperitoneal injection three times per week. Lung and liver metastases were compared at 9 weeks. Means of groups were compared by using a t test.. Triptolide altered the expression of microRNAs involved in cellular movement and significantly decreased migration and invasion of lung cancer cells from approximately 18 to 3 cells per field (p < 0.001). Triptolide decreases focal adhesion kinase expression, which leads to impairment of downstream signaling. Finally, triptolide-treated mice injected with lung cancer cells significantly decreased metastatic colony formation in the lungs (p < 0.01).. Triptolide decreases lung cancer cell migration and invasion in vitro and inhibits metastatic tumor formation in mice. Triptolide suppresses focal adhesion kinase, which causes deregulation of the migration machinery. These results suggest that triptolide inhibits lung cancer metastasis and should be investigated as a new lung cancer therapy.

Topics: Antineoplastic Agents, Alkylating; Cell Movement; Diterpenes; Epoxy Compounds; Humans; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Phenanthrenes; Tumor Cells, Cultured

15,16-Dihydrotanshinone I (DHTS) is a component of the traditional Chinese medicinal plant Salvia miltiorrhiza Bunge. In this study, DHTS at as low as 2.5 μg/ml concentration significantly inhibited proliferation of human benign (SW480) and malignant (SW620) colorectal cancer cells, as shown by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-diphenytetrazoliumromide (MTT) and flow cytometric analysis. Activating transcription factor (ATF)-3, a basic leucine zipper-type transcription factor, was found to be predominantly up-regulated in DHTS-treated SW480 and SW620 cells. The up-regulation of ATF3 was blocked by a c-JUN N-terminal kinase (JNK) or p38 inhibitor. Overexpression of ATF3 resulted in a significant augmentation of DHTS-induced apoptosis of SW480 cells, but resistance to DHTS-induced apoptosis of SW620 cells. These results suggest that DHTS has a strong therapeutic or preventive potential against cancer. In addition, ATF3 has a dual role in DHTS-induced apoptosis, depending on the degree of malignancy of colorectal cancer.

Topics: Activating Transcription Factor 3; Adenocarcinoma; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Furans; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Phenanthrenes; Phosphorylation; Quinones

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are specific types of neuroendocrine tumors that originate in the adrenal medulla or sympathetic/parasympathetic paraganglia, respectively. Although these tumors are intensively studied, a very effective treatment for metastatic PHEO or PGL has not yet been established. Preclinical evaluations of novel therapies for these tumors are very much required. Therefore, in this study we tested the effect of triptolide (TTL), a potent nuclear factor-kappaB (NF-κB) inhibitor, on the cell membrane norepinephrine transporter (NET) system, considered to be the gatekeeper for the radiotherapeutic agent 131I-metaiodobenzylguanidine (131I-MIBG). We measured changes in the mRNA and protein levels of NET and correlated them with proapoptotic factors and metastasis inhibition. The study was performed on three different stable PHEO cell lines. We found that blocking NF-κB with TTL or capsaicin increased both NET mRNA and protein levels. Involvement of NF-κB in the upregulation of NET was verified by mRNA silencing of this site and also by using NF-κB antipeptide. Moreover, in vivo treatment with TTL significantly reduced metastatic burden in an animal model of metastatic PHEO. The present study for the first time shows how NF-κB inhibitors could be successfully used in the treatment of metastatic PHEO/PGL by a significant upregulation of NET to increase the efficacy of 131I-MIBG and by the induction of apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Neoplasm Metastasis; NF-kappa B; Norepinephrine Plasma Membrane Transport Proteins; Paraganglioma; Phenanthrenes; Pheochromocytoma; Rats; RNA Interference; Transcription, Genetic; Tumor Burden

Denbinobin (5-hydroxy-3,7-dimethoxy- 1,4-phenanthraquinone), a biologically active chemical isolated from Ephemerantha lonchophylla, has been demonstrated to display anti-cancer activity. Breast cancer is the leading cause of female mortality, and the high mortality is mainly attributable to metastasis. Src kinase activity is elevated in many human cancers, including breast cancer, and is often associated with aggressive disease. In the present study, we examined the anti-metastatic effects of denbinobin through decreasing Src kinase activity in human and mouse breast cancer cells. Denbinobin caused significant block of Src kinase activity in both human and mouse breast cancer cells. Moreover, phosphorylation of the signaling molecules focal adhesion kinase, Crk-associated substrate and paxillin downstream of Src was also inhibited by denbinobin. Furthermore, denbinobin inhibited the in vitro migration, invasion and in vivo metastasis of breast cancers in a mouse metastatic model. The denbinobin-treated group showed a significant reduction in tumor metastasis, orthrotopic tumor volume, and spleen enlargement compared to the control group. In addition, transfection of breast cancer cells with a plasmid coding for a constitutively active Src prevented the denbinobin-mediated phosphorylation of Src and downstream molecules and cell migration. Our findings provide evidences that denbinobin inhibits Src-mediated signaling pathways involved in controlling breast cancer migration and metastasis, suggesting that it has therapeutic potential in breast cancer treatment.

Topics: Animals; Anthraquinones; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crk-Associated Substrate Protein; Female; Focal Adhesion Kinase 1; Humans; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Paxillin; Phenanthrenes; Phosphorylation; Signal Transduction; src-Family Kinases; Transfection

p38γ MAPK, one of the four members of p38 mitogen-activated protein kinases (MAPKs), has previously been shown to harbor oncogenic functions. However, the biologic function of p38γ MAPK in breast cancer has not been well defined. In this study, we have shown that p38γ MAPK is overexpressed in highly metastatic human and mouse breast cancer cell lines and p38γ MAPK expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. Ectopic expression of p38γ MAPK did not lead to an increase in oncogenic properties in vitro in most tested mammary epithelial cells. However, knockdown of p38γ MAPK expression resulted in a dramatic decrease in cell proliferation, colony formation, cell migration, invasion in vitro and significant retardation of tumorigenesis, and long-distance metastasis to the lungs in vivo. Moreover, knockdown of p38γ MAPK triggered the activation of AKT signaling. Inhibition of this feedback loop with various PI3K/AKT signaling inhibitors facilitated the effect of targeting p38γ MAPK. We further found that overexpression of p38γ MAPK did not promote cell resistance to chemotherapeutic agents doxorubicin and paclitaxel but significantly increased cell resistance to PJ-34, a DNA damage agent poly (ADP-ribose)-polymerase-1 (PARP) inhibitor in vitro and in vivo. Finally, we identified that p38γ MAPK overexpression led to marked cell cycle arrest in G(2)/M phase. Our study for the first time clearly demonstrates that p38γ MAPK is a promising target for the design of targeted therapies for basal-like breast cancer with metastatic characteristics and for overcoming potential resistance against the PARP inhibitor.

Topics: Animals; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Doxorubicin; Humans; Mice; Mitogen-Activated Protein Kinase 12; Neoplasm Invasiveness; Neoplasm Metastasis; Paclitaxel; Phenanthrenes; Phosphatidylinositol 3-Kinase; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Signal Transduction

Triptolide, a diterpene triepoxide, from the Chinese herb Tripterygium wilfordii Hook.f, exerts its anti-inflammatory and immunosuppressive activities by inhibiting the transcription factor nuclear factor-κB (NF-κB) pathway, through a mechanism not yet fully understood. We found that triptolide, in nanomolar concentrations, suppressed both constitutive and inducible NF-κB activation, but did not directly inhibit binding of p65 to the DNA. The diterpene did block TNF-induced ubiquitination, phosphorylation, and degradation of IκBα, the inhibitor of NF-κB and inhibited acetylation of p65 through suppression of binding of p65 to CBP/p300. Triptolide also inhibited the IκBα kinase (IKK) that activates NF-κB and phosphorylation of p65 at serine 276, 536. Furthermore, the NF-κB reporter activity induced by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKKβ was abolished by the triepoxide. Triptolide also abrogated TNF-induced expression of cell survival proteins (XIAP, Bcl-x(L), Bcl-2, survivin, cIAP-1 and cIAP-2), cell proliferative proteins (cyclin D1, c-myc and cyclooxygenase-2), and metastasis proteins (ICAM-1 and MMP-9). This led to enhancement of apoptosis induced by TNF, taxol, and thalidomide by the diterpene and to suppression of tumor invasion. Overall, our results demonstrate that triptolide can block the inflammatory pathway activated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK, sensitizes cells to apoptosis, and inhibits invasion of tumor cells.

Topics: Antineoplastic Agents; Cell Line; Cell Proliferation; Diterpenes; Enzyme Inhibitors; Epoxy Compounds; Gene Expression Regulation, Neoplastic; Histone Acetyltransferases; Humans; Inflammation; Leukemia; Molecular Structure; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Paclitaxel; Phenanthrenes; Signal Transduction; Thalidomide; Tumor Necrosis Factor-alpha

Topics: Abietanes; Anticarcinogenic Agents; Humans; Medical Oncology; Medicine, Chinese Traditional; Neoplasm Metastasis; Neoplasms; Phenanthrenes

To investigate the effects and possible mechanisms of tanshinone II-A, an alcohol extract of the root of Salvia miltiorrhiza Bunge, on tumor invasion and metastasis of human colon carcinoma (CRC) cells.. The effects of tanshinone II-A on invasion and metastasis of CRC cell lines HT29 and SW480 were evaluated by in vitro and in vivo assays. Western blotting was used to investigate possible molecular mechanisms of tanshinone II-A anti-cancer actions.. Tanshinone II-A inhibited migration and invasion of CRC cells in a dose-dependent manner. The inhibitory effect also depended on time, with the most significant effects observed at 72 h. Tanshinone II-A also significantly inhibited in vivo metastasis of colon carcinoma SW480 cells. It inhibited in vitro and in vivo invasion and metastasis of CRC cells by reducing levels of urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMP)-2 and MMP-9, and by increasing levels of tissue inhibitor of matrix metalloproteinase protein (TIMP)-1 and TIMP-2. Tanshinone II-A was also shown to suppress the nuclear factor-kappaB (NF-kappaB) signal.. Tanshinone II-A inhibited in vitro and in vivo invasion and metastasis of CRC cells. The effect resulted from changes in the levels of uPA, MMP-2, MMP-9, TIMP-1 and TIMP-2, and apparent inhibition of the NF-kappaB signal transduction pathway.

Topics: Abietanes; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; HT29 Cells; Humans; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Phenanthrenes; Plant Extracts; Plant Roots; Salvia miltiorrhiza; Signal Transduction; Time Factors

Tanshinones are the major bioactive compounds of Salvia miltiorrhiza Bunge (Danshen) roots, which are used in many therapeutic remedies in Chinese traditional medicine. We investigated the anticancer effects of tanshinones on the highly invasive human lung adenocarcinoma cell line, CL1-5. Tanshinone I significantly inhibited migration, invasion, and gelatinase activity in macrophage-conditioned medium-stimulated CL1-5 cells in vitro and also reduced the tumorigenesis and metastasis in CL1-5-bearing severe combined immunodeficient mice. Unlike tanshinone IIA, which induces cell apoptosis, tanshinone I did not have direct cytotoxicity. Real-time quantitative PCR, luciferase reporter assay, and electrophoretic mobility shift assay revealed that tanshinone I reduces the transcriptional activity of interleukin-8, the angiogenic factor involved in cancer metastasis, by attenuating the DNA-binding activity of activator protein-1 and nuclear factor-kappaB in conditioned medium-stimulated CL1-5 cells. Microarray and pathway analysis of tumor-related genes identified the differentially expressed genes responding to tanshinone I, which may be associated with the Ras-mitogen-activated protein kinase and Rac1 signaling pathways. These results suggest that tanshinone I exhibits anticancer effects both in vitro and in vivo and that these effects are mediated at least partly through the interleukin-8, Ras-mitogen-activated protein kinase, and Rac1 signaling pathways. Although tanshinone I has a remarkable anticancer action, its potential anticoagulant effect should be noted and evaluated.

Topics: Abietanes; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Interleukin-8; Lung Neoplasms; Mice; Mice, SCID; Models, Biological; Neoplasm Metastasis; Phenanthrenes; RNA, Messenger

Triptolide (TPL), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F, was tested for its antitumor properties in several model systems. In vitro, TPL inhibited the proliferation and colony formation of tumor cells at extremely low concentrations (2-10 ng/ml) and was more potent than Taxol. Likewise, in vivo, treatment of mice with TPL for 2-3 weeks inhibited the growth of xenografts formed by four different tumor cell lines (B16 melanoma, MDA-435 breast cancer, TSU bladder cancer, and MGC80-3 gastric carcinoma), indicating that TPL has a broad spectrum of activity against tumors that contain both wild-type and mutant forms of p53. In addition, TPL inhibited experimental metastasis of B16F10 cells to the lungs and spleens of mice. The antitumor effect of TPL was comparable or superior with that of conventional antitumor drugs, such as Adriamycin, mitomycin, and cisplatin. Importantly, tumor cells that were resistant to Taxol attributable to the overexpression of the multidrug resistant gene 1 were still sensitive to the effects of TPL. Studies on cultured tumor cells revealed that TPL induced apoptosis and reduced the expression of several molecules that regulate the cell cycle. Taken together, these results suggest that TPL has several attractive features as a new antitumor agent.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Breast Neoplasms; Cell Division; Diterpenes; Epoxy Compounds; Female; Humans; Melanoma; Melanoma, Experimental; Mice; Neoplasm Metastasis; Phenanthrenes; Stomach Neoplasms; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The Eastern Cooperative Oncology Group (ECOG) conducted a Phase II trial of Bruceantin in malignant melanoma. Twenty-two patients, thirteen without prior cytotoxic chemotherapy, were entered. All patients were evaluable for response and toxicity. Dose limiting toxicity was found to be hypotension during Bruceantin infusion. Other prominent side effects were nausea, vomiting, anorexia, fever, chills, and weakness. Only minor hematologic toxicity was encountered. Two partial responses, both in previously treated patients were observed (response rate -9%). Bruceantin has only limited activity against malignant melanoma and is unlikely to contribute to systemic therapy of this disease, either as a single agent or in combinations of cytotoxic drugs.

Topics: Aged; Antineoplastic Agents, Phytogenic; Drug Evaluation; Female; Glaucarubin; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Phenanthrenes; Quassins

A phase II evaluation of bruceantin was carried out in 15 patients with refractory metastatic breast cancer. All patients had received extensive prior therapy including adriamycin, cytoxan, 5-FU, methotrexate, and a vinca alkaloid. Except for two patients with stable disease, no complete or partial response was observed. Drug toxicity, mainly nonhematologic, was severe, with nausea, vomiting, mild hypotension, and fever being the most frequently encountered.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Evaluation; Female; Glaucarubin; Humans; Hypotension; Leukocyte Count; Middle Aged; Nausea; Neoplasm Metastasis; Phenanthrenes; Quassins; Vomiting

Topics: Administration, Oral; Administration, Topical; Animals; Female; Liver Neoplasms; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms, Experimental; Papilloma; Phenanthrenes; Sex Factors; Skin Neoplasms