phenanthrenes and Melanoma

Some pharmacologic properties of nine antitumor agents from higher plants are described. The agents are vincristine, vinblastine the epiodophyllotoxin derivatives VM-26 and VP-16-213, maytansine, bruceantin, thalicarpine, camptothecin, and lapachol. When sufficient information is available, the agents are discussed with regard to their antitumor activity, mechanism of action, pharmacologic disposition, structure-activity relationships, and toxicity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aporphines; Camptothecin; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Etoposide; Humans; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Maytansine; Melanoma; Naphthoquinones; Nasopharyngeal Neoplasms; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Structure-Activity Relationship; Teniposide; Vinblastine; Vincristine

Topics: Abietanes; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Diterpenes; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Melanoma; Phenanthrenes; Phosphorylation; Plant Extracts; Salvia miltiorrhiza; Signal Transduction; Up-Regulation

Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy.. We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice.. The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.

Topics: Animals; Cell Line, Tumor; Diterpenes; Epoxy Compounds; Exosomes; Humans; Integrin alphaVbeta3; Integrins; Melanoma; Melanoma, Cutaneous Malignant; Mice; Peptides, Cyclic; Phenanthrenes; Skin Neoplasms; Tissue Distribution

Malignant melanoma is considered the most aggressive skin carcinoma with invasive growth patterns. Triptolide (TPL) possesses various biological and pharmacological activities involved in cancer treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell apoptosis by binding to DR5 highly expressed on cancer cells. Exosomes are natural nanomaterials with low immunogenicity, nontoxicity, and excellent biocompatibility and have been extensively used as emerging delivery vectors for diverse therapeutic cargos. Herein, a delivery system based on TRAIL-engineered exosomes (TRAIL-Exo) for loading TPL for targeted therapy against malignant melanoma is proposed and systematically investigated. Our results showed that TRAIL-Exo/TPL could improve tumor targetability, enhance cellular uptake, inhibit proliferation, invasion, and migration, and induce apoptosis of A375 cells through activating the extrinsic TRAIL pathway and the intrinsic mitochondrial pathway in vitro. Moreover, intravenous injection of TRAIL-Exo/TPL significantly suppressed tumor progression and reduced the toxicity of TPL in the melanoma nude mouse model. Together, our research presents a novel strategy for high-efficiency exosome-based drug-delivery nanocarriers and provides an alternative dimension for developing a promising approach with synergistic therapeutic efficacy and targeting capacity for melanoma treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Diterpenes; Drug Carriers; Drug Liberation; Epoxy Compounds; Exosomes; Humans; Male; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Phenanthrenes; RAW 264.7 Cells; S Phase Cell Cycle Checkpoints; TNF-Related Apoptosis-Inducing Ligand

The strong human immunity and the associated toxicities of attenuated Salmonella severely limit the clinical use of Salmonella in tumour suppression. In the present study, we constructed an engineered VNP20009-DNase I strain and evaluated the synergistic effects of triptolide (TPL) and VNP20009-DNase I against melanoma in mice. Our results indicated that TPL could significantly inhibit the cell growth and cell migration and significantly enhanced the apoptosis rate of B16F10 cells in vitro. The in vivo results indicated that TPL markedly improved tumour colonisation of VNP20009-DNase I and led to a larger necrotic area in the melanoma. Moreover, the combination therapy significantly suppressed tumour volume and prolonged the life span of mice (P < 0.05) by upregulating the expression of Bcl-2/Bax and Caspase-3 and by downregulating the TLR4/NF-κB signalling, the expression of p-AKT/AKT and the production of proinflammatory factors. Therefore, the sound synergistic anti-tumour effects of TPL and VNP20009-DNase I indicate that the unconventional application of TPL and biological agents, approved by the China Food and Drug Administration (CFDA), can result in improved anti-cancer therapeutic outcomes.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Deoxyribonuclease I; Disease Models, Animal; Diterpenes; Drug Carriers; Epoxy Compounds; Genetic Vectors; Humans; Melanoma; Mice; Models, Biological; Phenanthrenes; Plasmids; Salmonella; Salmonella Infections; Treatment Outcome; Vaccines, DNA

Metastatic melanoma is an aggressive form of skin cancer that evades various anti-cancer treatments including surgery, radio-,immuno- and chemo-therapy. TRAIL-induced apoptosis is a desirable method to treat melanoma since, unlike other treatments, it does not harm non-cancerous cells. The pro-inflammatory response to melanoma by nF κB and STAT3 pathways makes the cancer cells resist TRAIL-induced apoptosis. We show that due to to its dual action on DR5, a death receptor for TRAIL and on STAT3, Cryptotanshinone can be used to increase sensitivity to TRAIL.. The development of chemoresistance and invasive properties in melanoma cells involves several biological pathways. The key components of these pathways are represented as a Boolean network with multiple inputs and multiple outputs.. The possible mutations in genes that can lead to cancer are captured by faults in the combinatorial circuit and the model is used to theoretically predict the effectiveness of Cryptotanshinone for inducing apoptosis in melanoma cell lines. This prediction is experimentally validated by showing that Cryptotanshinone can cause enhanced cell death in A375 melanoma cells.. The results presented in this paper facilitate a better understanding of melanoma drug resistance. Furthermore, this framework can be used to detect additional drug intervention points in the pathway that could amplify the action of Cryptotanshinone.

Topics: Algorithms; Apoptosis; Biomarkers; Cell Line, Tumor; Computational Biology; Computer Simulation; Drugs, Chinese Herbal; Gene Expression Profiling; Humans; Melanoma; Mitochondria; Models, Biological; NF-kappa B; Phenanthrenes; Reproducibility of Results; Signal Transduction; Transcriptome

The weakened tumour colonization of attenuated

Topics: Animals; Biological Therapy; Combined Modality Therapy; Disease Models, Animal; Diterpenes; Epoxy Compounds; Immunosuppressive Agents; Melanoma; Mice, Inbred C57BL; Necrosis; Neovascularization, Pathologic; Neutrophils; Phenanthrenes; Salmonella; Treatment Outcome; Vascular Endothelial Growth Factor A

Transcutaneous immunization (TCI) is a non-invasive vaccination strategy targeting the skin-associated lymphoid tissue. Topical application of the TLR7 agonist imiquimod as adjuvant in combination with peptide antigens activates the innate immune system and mounts cytotoxic T lymphocyte (CTL) responses.. Based on the commercial 5% imiquimod-containing drug Aldara we aimed to develop an improved formulation with superior vaccination efficiencies. The primary target was the enhancement of mast cell activation as important key for the function of the innate immune system.. We investigated the effects of 9-phenanthrol (9-phe) on the activation of mast cells in vitro and in vivo. For TCI, we applied 0.2% 9-phe in Aldara or Aldara alone as adjuvants in combination with the MHC class I - restricted peptide SIINFEKL. To monitor vaccination, mast cell degranulation, migration of DC and frequencies of epitope-specific CTL was assessed. In a transgenic tumor model, the efficiencies of prophylactic immunization against a tumor antigen were also monitored.. 9-phe induced degranulation of mast cells in vitro and upon topical application in vivo. A mixture of 0.2% 9-phe in Aldara showed superior results regarding the migration of DC and the expansion of antigen-specific CTL. Consequently, prophylactic immunization with 0.2% 9-phe in Aldara caused enhanced protection against tumor inoculation.. Our data demonstrate that a simple modification of an adjuvant formulation can yield superior results in experimental vaccination protocols by boosting critical steps leading to the generation of an efficient CTL response.

Topics: Adjuvants, Immunologic; Administration, Cutaneous; Aminoquinolines; Animals; Calcium; Cell Degranulation; Cell Movement; Dendritic Cells; Humans; Imiquimod; Immunity, Innate; Mast Cells; Melanoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phenanthrenes; Protein Kinase Inhibitors; Skin; Skin Neoplasms; T-Lymphocytes, Cytotoxic; TRPM Cation Channels; Vaccination; Xenograft Model Antitumor Assays

Melanoma is the most serious type of skin cancer because it is highly frequency of drug resistance and can spread earlier and more quickly than other skin cancers. The objective of this research was to investigate the anticancer effects of cryptotanshinone on human melanoma cells in vitro, and explored its mechanisms of action. Our results have shown that cryptotanshinone could inhibit cell proliferation in human melanoma cell lines A2058, A375, and A875 in a dose- and time-dependent manner. In addition, flow cytometry assay showed that cryptotanshinone inhibited the proliferation of human melanoma cell line A375 by blocking cell cycle progression in G2/M phase and inducing apoptosis in a concentration-dependent manner. Moreover, western blot analysis indicated that the occurrence of its apoptosis was associated with upregulation of cleaved caspases-3 and pro-apoptotic protein Bax while downregulation of anti-apoptotic protein Bcl-2. Meanwhile, cryptotanshinone could decrease the levels of reactive oxygen species (ROS). Furthermore, cryptotanshinone also blocked A375 cell migration and invasion in vitro which was associated with the downregulation with MMP-9. Taken together, these results suggested that cryptotanshinone might be a potential drug in human melanoma treatment by inhibiting proliferation, inducing apoptosis via ROS-mitochondrial apoptotic pathway and blocking cell migration and invasion.

Topics: Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Shape; Cell Survival; G2 Phase Cell Cycle Checkpoints; Humans; Melanoma; Mitochondria; Neoplasm Invasiveness; Phenanthrenes; Reactive Oxygen Species; Signal Transduction; Skin Neoplasms; Tumor Stem Cell Assay

Regulatory T cells play a key role in suppressing tumor immunity. Triptolide, a major active component isolated from the Chinese medicinal herb Tripterygium wilfordii, has been proven to possess multiple antitumor activities. Here, we investigated the effect of triptolide on regulatory T cells and on the level of IL-10, transforming growth factor-β, and vascular endothelial growth factor in tumor-bearing mice. Fifty male C57BL/6 mice were randomly grouped as follows: normal control group, model group with B16-F10 cells implanted, and three treatment groups with cyclophosphamide, triptolide-high dose, triptolide-low dose. The proportion of regulatory T cells in the spleen and axillary lymph nodes was evaluated by flow cytometric analysis. Production of cytokines IL-10, transforming growth factor-β, and vascular endothelial growth factor in serum was measured using enzyme-labeled immunosorbent assay kits. The mRNA levels of Foxp3, IL-10, and transforming growth factor-β in the spleen and vascular endothelial growth factor in tumor tissue were detected by real-time PCR. The results showed that triptolide significantly decreased the proportion of regulatory T cells and lowered the Foxp3 level in the spleen and axillary lymph nodes of tumor-bearing mice. Production of IL-10 and transforming growth factor-β in peripheral blood, and the mRNA level of IL-10 and transforming growth factor-β in the spleen were also decreased. Additionally, triptolide could remarkably inhibit production of vascular endothelial growth factor in tumor-bearing mice. In conclusion, our study demonstrated that triptolide might inhibit tumor growth by inhibiting regulatory T cells and some cytokines such as IL-10 and transforming growth factor-β, as well as production of vascular endothelial growth factor.

Topics: Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Diterpenes; Down-Regulation; Drugs, Chinese Herbal; Epoxy Compounds; Forkhead Transcription Factors; Interleukin-10; Lymph Nodes; Male; Melanoma; Mice, Inbred C57BL; Phenanthrenes; Phytotherapy; RNA, Messenger; Spleen; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tripterygium; Vascular Endothelial Growth Factor A

Numerous studies have demonstrated that triptolide induces cell cycle arrest and apoptosis in human cancer cell lines. However, triptolide-induced DNA damage and inhibition of DNA repair gene expression in human skin cancer cells has not previously been reported. We sought the effects of triptolide on DNA damage and associated gene expression in A375.S2 human malignant melanoma cells in vitro. Comet assay, DAPI staining and DNA gel electrophoresis were used for examining DNA damage and results indicated that triptolide induced a longer DNA migration smear based on single cell electrophoresis and DNA condensation and damage occurred based on the examination of DAPI straining and DNA gel electrophoresis. The real-time PCR technique was used to examine DNA damage and repair gene expression (mRNA) and results indicated that triptolide led to a decrease in the ataxia telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR), breast cancer 1, early onset (BRCA-1), p53, DNA-dependent serine/threonine protein kinase (DNA-PK) and O6-methylguanine-DNA methyltransferase (MGMT) mRNA expression. Thus, these observations indicated that triptolide induced DNA damage and inhibited DNA damage and repair-associated gene expression (mRNA) that may be factors for triptolide-mediated inhibition of cell growth in vitro in A375.S2 cells.

Topics: Antineoplastic Agents, Alkylating; Ataxia Telangiectasia Mutated Proteins; BRCA1 Protein; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Comet Assay; Diterpenes; DNA Damage; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; DNA-Activated Protein Kinase; DNA-Binding Proteins; Down-Regulation; Epoxy Compounds; Gene Expression; Humans; Melanoma; Phenanthrenes; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; RNA, Messenger; Skin Neoplasms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Triptolide (TPL), a diterpene triepoxide compound, extracted from Tripterygium wilfordii Hook F. [a traditional Chinese medicinal herb (TCM)], has demonstrated great chemotherapeutic potential for the treatment of tumors. However, the anticancer mechanisms of action of TPL in human skin cancer remain to be further investigated. In this study, we used A375.S2 human melanoma skin cancer cells as a model to investigate the effect of TPL on cell death. A375.S2 cells were treated with various concentrations of TPL for different periods of time and investigated the effects on cell cycle distribution and apoptosis were investigated. The data showed that TPL induced cell morphological changes, decreased the percentage of viable cells, and induced S phase arrest and apoptosis in A375.S2 cells in a concentration- and time-dependent manner. Furthermore, we used flow cytometry analysis and the data showed that TPL promoted reactive oxygen species, NO and Ca2+ production, decreased the mitochondrial membrane potential (ΔΨm) and increased the activity of caspase-3, -8 and -9 in the A375.S2 cells. Western blot analysis showed that TPL promoted the expression of p21 and p27 but inhibited that of cyclin A and CDC25A, leading to S phase arrest. Furthermore, the data also showed that TPL promoted the expression of Fas and FasL and increased the activity of caspase-3, -8 and -9, cytochrome c, Bax, apoptosis-inducing factor (AIF) and endonuclease G (Endo G); however, the expression of Bax was decreased, leading to apoptosis. Based on these observations, TPL induces apoptosis in A375.S2 cells through Fas-, caspase- and mitochondrial-mediated pathways.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Calcium Signaling; Caspases; cdc25 Phosphatases; Cell Line, Tumor; Cell Shape; Cell Survival; Cyclin E; Diterpenes; Drug Screening Assays, Antitumor; Epoxy Compounds; Humans; Melanoma; Membrane Potential, Mitochondrial; Mitochondria; Oncogene Proteins; Phenanthrenes; Reactive Oxygen Species; S Phase Cell Cycle Checkpoints

Triptolide, a diterpenoid obtained from Tripteryglum wilfordii Hook.f, has attracted interest for its anti- tumor activities against human tumor cell lines in recent years. This report focuses on anti-proliferative and pro-apoptotic activities in human melanoma A375 cells assessed by CCK8 assay, Hoechst 33258 staining and flow cytometry. In addition, triptolide-induced arrest in the S phase was also observed. Caspase assays showed the apoptosis induced by triptolide was caspase-dependent and probably through intrinsic apoptotic pathways. Furthermore, expression of NF-κB (p65) and its downstream factors such as Bcl-2, Bcl-XL was down-regulated. Taken together, the data indicate that triptolide inhibits A375 cells proliferation and induces apoptosis by a caspase-dependent pathway and through a NF-κB-mediated mechanism.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; bcl-X Protein; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Diterpenes; Down-Regulation; Epoxy Compounds; Humans; Melanoma; NF-kappa B; Phenanthrenes; Proto-Oncogene Proteins c-bcl-2; S Phase Cell Cycle Checkpoints; Skin Neoplasms

Cryptotanshinone is a major active component of Salvia miltiorrhiza, which is often used as Chinese herbal medicine in cancer therapy. Here, we systematically assessed the anti-tumor effect of Cryptotanshinone on two melanoma cell lines with low/high-metastatic capacity (B16/B16BL6).. MTT and LDH assays were used to evaluate cell growth and cytotoxicity. We assessed the effect of Cryptotanshinone on cell apoptosis or proliferation by Annexin V, TUNEL or BrdU assay. Cell cycle distribution was detected by flow cytometry. The integrity of cell cycle checkpoints was determined by mutational analyses of B-RAF and N-RAS, and the expression of cell cycle-associated proteins by western blotting.. Treatment with Cryptotanshinone had no obvious effect on cell apoptosis but significantly inhibited cell proliferation. Cryptotanshinone slightly increased the expression of p53, Chk1, and Chk2 in both B16 and B16BL6. Interestingly, Cryptotanshinone induced G1 arrest with a concomitant increase in p21 expression in B16BL6 cells. However, in B16 cells, Cryptotanshinone induced the G2/M arrest through its induction of Cdc25c. Regulation of Cyclin A1, Cyclin B1 and Cdk1/cdc2 expression might contribute to the different cell cycle patterns in B16 and B16BL6 after Cryptotanshinone treatment.. Cryptotanshinone could have diverse effects on cell cycle events in melanoma cell lines with different metastatic capacity. This property might offer an opportunity to study underlying mechanisms for the different antitumor effects of administered Cryptotanshinone in B16 and B16BL6 cells.

Topics: Animals; Apoptosis; Bromodeoxyuridine; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Female; Genes, ras; Lung Neoplasms; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Phenanthrenes; Proto-Oncogene Proteins B-raf; Salvia miltiorrhiza

Snail1 is a master regulator of the epithelial-mesenchymal transition (EMT) and has been implicated in key tumor biological processes such as invasion and metastasis. It has been previously shown that poly(ADP-ribose) polymerase-1 (PARP-1) knockdown, but not PARP inhibition, downregulates the expression of Snail1. In this study we have characterized a novel regulatory mechanism controlling Snail1 protein expression through poly(ADP-ribosyl)ation. The effect is not only limited to repression of Snail1 transcription but also to downregulated Snail1 protein stability. PARP-1 (but not PARP-2) poly(ADP) ribosylates Snail1, both in vivo and in vitro, and interacts with Snail1, an association that is sensitive to PARP inhibitors. PARP inhibition has also clear effects on EMT phenotype of different tumor cells, including Snail1 downregulation, E-cadherin upregulation, decreased cell elongation and invasiveness. Therefore, this study reveals a new regulatory mechanism of Snail1 activation through poly(ADP-ribosyl)ation with consequences in malignant transformation through EMT.

Topics: Cadherins; Cell Line, Tumor; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Fluorobenzenes; Humans; Melanoma; Neoplasm Invasiveness; Phenanthrenes; Phthalazines; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Stability; Skin Neoplasms; Snail Family Transcription Factors; Transcription Factors

The capability of PARP activity inhibitors to prevent DNA damage recovery suggested the use of these drugs as chemo- and radio-sensitisers for cancer therapy. Our research, carried out on cultured human M14 melanoma cells, was aimed to examine if PJ-34, a potent PARP activity inhibitor of second generation, was per se able to affect the viability of these cancer cells without any DNA damaging agents. Using time-lapse videomicroscopy, we evidenced that 10 microM PJ-34 treatment induced severe mitotic defects leading to dramatic reduction of cell proliferation and to cell death. PJ-34 cytotoxic effect was further confirmed by analysis of cell viability and clonogenic assay. Absence of canonic apoptosis markers allowed us to exclude this kind of cell death. No single and/or double stranded DNA damage was evidenced. Immunofluorescence analysis showed an aberrant mitotic scenario in several cells and subsequent multinucleation suggesting an atypical way for cells to die: the mitotic catastrophe. The detection of aberrant accumulation of polymerised actin inside the nucleolus was noteworthy. Taken together, our results demonstrate that, targeting PARP activity by PJ-34, cancer cell survival is affected independently of DNA damage repair. Two findings are remarkable: (a) cisplatin concentration can be reduced by three quarters if it is followed by treatment with 10 microM PJ-34 for 24 h to obtain the same cytotoxic effect; (b) effects dependent on PJ-34 treatment are reversible. Our data suggest that, to reduce the harm done to non-tumour cells during chemotherapy with cisplatin, the latter could be coupled with PJ-34 treatment.

Topics: Actins; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Cell Line, Tumor; Cell Nucleolus; Cell Proliferation; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fluorescent Antibody Technique; Humans; Melanoma; Microscopy, Video; Mitosis; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Time Factors

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