tirapazamine and Prostatic-Neoplasms

In this study, novel cupric-tirapazamine [Cu(TPZ)

Topics: Humans; Hypoxia; Liposomes; Male; Prostatic Neoplasms; Solubility; Tirapazamine

In the present work, a copper-tirapazamine (TPZ) nanocomplex [Cu(TPZ)

Topics: Antineoplastic Agents; Biological Transport; Copper; DNA; Humans; Hypoxia; Male; Nanoparticles; Prostatic Neoplasms; Radiation-Sensitizing Agents; Spheroids, Cellular; Tirapazamine; Tumor Cells, Cultured

Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 μM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 μM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 μM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 μM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.

Topics: Alkaloids; Animals; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; E1A-Associated p300 Protein; HCT116 Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Marine Biology; Molecular Structure; Neovascularization, Pathologic; Porifera; Prostatic Neoplasms; Pyrroloiminoquinones; Quinones; Spiro Compounds; Thiazepines; Vascular Endothelial Growth Factor A

What's known on the subject? and What does the study add? Castration therapy has rather modest effects on cell death in tumours but can be enhanced by other treatments targeting tumour stroma and vasculature. This study shows that the prostate becomes hypoxic following castration and that targeting hypoxic cells during castration therapy potently enhances the effects of castration.. To explore the effects of castration therapy, the standard treatment for advanced prostate cancer, in relation to tumour hypoxia and to elicit its importance for the short- and long-term therapeutic response.. We used the androgen-sensitive rat Dunning H prostate tumour model that transiently responds to castration treatment followed by a subsequent relapse, much like the scenario in human patients. Tumour tissues were analysed using stereological methods in intact, 1 and 7 days after castration therapy.. Hypoxia was transiently up-regulated after castration therapy and correlated with the induction of tumour cell apoptosis. When castration therapy was combined with tirapazamine (TPZ), a drug that targets hypoxic cells and the vasculature, the effects on tumour cell apoptosis and tumour volume were enhanced in comparison to either castration or TPZ alone.. The present study suggests that castration-induced tumour hypoxia is a novel target for therapy.

Topics: Animals; Apoptosis; Cell Hypoxia; Disease Models, Animal; Hypoxia; Immunohistochemistry; Male; Orchiectomy; Organ Culture Techniques; Oxygen Consumption; Prostatic Neoplasms; Random Allocation; Rats; Rats, Inbred Strains; Statistics, Nonparametric; Tirapazamine; Triazines

The recent clinical successes of antiangiogenic drug-based therapies have also served to highlight the problem of acquired resistance because, similar to other types of cancer therapy, tumors that initially respond eventually stop doing so. Consequently, strategies designed to delay resistance or treat resistant subpopulations when they arise have assumed considerable importance. This requires a better understanding of the various possible mechanisms for resistance. In this regard, reduced oxygenation is thought to be a key mediator of the antitumor effects of antiangiogenic therapies; accordingly, increased hypoxia tolerance of the tumor cells presents a potential mechanism of resistance. However, hypoxia can also be exploited therapeutically through the use of hypoxic cell cytotoxins, such as tirapazamine. With this in mind, we measured the oxygenation of PC-3 human prostate cancer xenografts subjected to chronic low-dose metronomic (LDM) antiangiogenic chemotherapy using cyclophosphamide given through the drinking water. We found that LDM cyclophosphamide impairs the oxygenation of PC-3 xenografts even during relapse, coinciding with reduced microvessel density. Combination of LDM cyclophosphamide with tirapazamine results in significantly improved tumor control in the PC-3, HT-29 colon adenocarcinoma, and MDA-MB-231 breast cancer human xenograft models without having a negative effect on the favorable toxicity profile of LDM cyclophosphamide. These results provide further evidence that reduced vascular dependence/increased hypoxia tolerance may be a basis for eventual resistance of tumors exposed to long-term LDM chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Growth Processes; Cell Hypoxia; Cell Line, Tumor; Colonic Neoplasms; Cyclophosphamide; Female; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasms; Neovascularization, Pathologic; Oxygen; Prostatic Neoplasms; Tirapazamine; Triazines; Xenograft Model Antitumor Assays