The successful treatment of melanoma has been hampered by the unique biology of this cancer. Fortunately, research to further our understanding of how melanoma cells differ from normal tissues has led to the discovery of potential new avenues of attack. One promising strategy relates to targeting the excess free radicals produced by melanomas. Melanocyte transformation into cancer is associated with significant structural alterations in the melanosome. In addition to pigment production, melanosomes also protect the cell by scavenging free radicals generated by sunlight and cellular metabolism. In melanoma, the disrupted and disorganized melanosome structure reverses this process. Melanosomes found in melanoma produce free radicals, such as hydrogen peroxide, furthering DNA damage. Melanosome generation of reactive oxygen species (ROS), in tandem with those generated by cancer metabolism, activate cellular signal transduction pathways that prevent cell death. ROS activation of proto-oncogene pathways in melanoma contributes to their resistance to chemotherapy. Fortunately, it may be possible to target these free radicals, just as Paris was able to successfully target Achilles' heel. The use of agents that block ROS scavenging, such as ATN-224 and disulfiram, have been explored clinically. A recent randomized Phase II trial with elesclomol, an agent that generates ROS, in combination with paclitaxel led to improved patient survival, suggesting that this may be a viable approach to advance the treatment of melanoma.
Resveratrol, a naturally occurring polyphenol, has been reported to be an anti-tumor and chemopreventive agent. Recent data show that it may also exert anti-angiogenic effects. We hypothesized that the anti-angiogenic activity of resveratrol may be caused by modulation of tumor cell release of thrombospondin-1 (TSP1) and vascular endothelial growth factor (VEGF) into the extracellular matrix, leading to vascular endothelial cell (VEC) apoptosis. We therefore evaluated the effects of resveratrol on melanoma cell lines co-cultured with vascular endothelial cells in monolayer and in three dimensional spheroids. We found that resveratrol stimulated isolated VEC proliferation, while it caused growth inhibition of VECs grown with melanoma cells in three-dimensional co-culture. This effect was associated with increased melanoma cell expression of tumor suppressor protein 53 and matrix protein TSP1, as well as decreased hypoxia-driven expression of hypoxia inducible factor-1α and inhibition of VEGF production.
Dysregulated mRNA translation is implicated in the pathogenesis of many human cancers including chronic myelogenous leukemia (CML). Because our prior work has specifically implicated translation initiation in CML, we tested compounds that could modulate translation initiation and polysomal mRNA assembly. Here, we evaluated the activity of one such compound, CGP57380, against CML cells and explored its mechanisms of action. First, using polysomal mRNA profiles, we found that imatinib and CGP57380 could independently, and cooperatively, impair polysomal mRNA loading. Imatinib and CGP57380 also synergistically inhibited the growth of Ba/F3-Bcr-Abl and K562 cells via impaired cell cycle entry and increased apoptosis. Mechanistically, CGP57380 inhibited efficient polysomal assembly via two processes. First, it enhanced imatinib-mediated inhibition of eukaryotic initiation factor 4F induction, and second, it independently impaired phosphorylation of ribosomal protein S6 on the preinitiation complex. We also identified multiple substrates of the mTOR, Rsk, and Mnk kinases as targets of CGP57380. Finally, we found a novel negative-feedback loop to the mitogenactivated protein kinase/Mnk pathway that is triggered by CGP57380 and demonstrated that an interruption of the loop further increased the activity of the combination against imatinib-sensitive and -resistant CML cells. Together, this work supports the inhibition of translation initiation as a therapeutic strategy for treating cancers fueled by dysregulated translation.
Melanoma cells characteristically produce increased levels of reactive oxygen species (ROS) because of the metal-binding properties of melanin and loss of structural integrity of the melanosome. Agents that deplete gluthathione or inhibit superoxide dismutase, thereby blocking ROS scavenging mechanisms, may be selectively toxic to melanoma. To determine whether the inhibition of ROS scavenging could potentiate alkylator activity, we evaluated the activity of tetrathiomolybdate (ATN-224), a superoxide dismutase inhibitor, alone and in combination with temozolomide, on five melanoma cell lines. We also determined whether the ATN-224 would act synergistically with other agents that interfere with ROS scavenging. We found that the combination of ATN-224 and temozolomide generally exhibited additive cytotoxic effects on the cell lines tested. ATN-224 acted synergistically with buthionine sulfoximine, an agent that causes gluthathione depletion. Combinations of ATN-224 with arsenic trioxide, which may deplete glutathione, or disulfiram, an agent that interferes with recycling of glutathione, were antagonistic. These data suggest that strategically tailoring combination regimens that include ATN-224 and target ROS may be a viable approach to advance the treatment of melanoma.
Background: Topotecan [TPT] is used to treat ovarian cancer (OC) and targets topoisomerase I (Topo I). OC grows under hypoxic conditions and inevitably fails to respond to chemotherapy. Hypoxia inducible factor-1α (HIF) is an adverse prognostic factor in OC associated with drug resistance. Based on reports that topotecan downregulates HIF1α, and that HIF binds directly to p53, we determined whether TPT-mediated modulation of HIF1α would lead to increased p53 function and chemosensitivity. Methods: Three ovarian cancer cell lines were studied: CAOV3, CAOV4 and TOV112D. Direct p53:HIF binding was determined using monoclonal co-immunoprecipitation (Co-IP) of nuclear extracts from cells grown under hypoxic conditions (1% O2). The effects of TPT on ovarian cancer cell line HIF-1α and p53 levels was determined by ELISA and western blot, as well as on HIF-related downstream reporter gene products VEGF (ELISA), ABCB1 and ABCB5 (Flow Cytometry) and p53-related BAX protein levels (ELISA) and thrombospondin-1 (Thbs1) transcript levels (RT-PCR). The association between TPT effects and expression levels of Topo I (western blot) between cell lines and after Topo I knock-down by siRNA was examined. The effects of sub-lethal doses of TPT on cisplatin dose response were examined under normoxic and hypoxic conditions (XTT assay). RNA immunoprecipitation (RIP) using monoclonal and polyclonal Topo I antibodies was used to obtain HIF1α mRNA interrogated by RT-PCR using three independent HIF-specific primers. Results: Co-IP of CAOV4 and TOV112D nuclear extracts with p53-specific antibodies yielded both HIF1 α and p53 bands on western blots. TPT treated CAOV3, TOV112D, and CAOV4 cells grown under hypoxia showed a dose dependent drop in HIF-1α levels with increasing p53 levels. Hypoxia-related upregulation of vascular endothelial growth factor (VEGF), ABCB1 (p-glycoproteins) and ABCB5 was blocked in CAOV3 and TOV112D and partially blocked in CAOV4 cells after pretreatment with 25 nM TPT, a clinically achievable concentration. With respect to p53 function, increased BAX protein and Thbs1 transcript levels were seen after TPT. Cell lines grown in hypoxia compared to normoxia were more sensitive to TPT. TPT IC50 values were inversely associated with Topo I expression (r= 0.99, p<0.01). Hypoxia related resistance to cisplatin in both CAOV3 and TOV112D cells was reversed after pre-treatment with 25 nM TPT. Topo I silencing RNA (siRNA) blocked TPT-mediated inhibition of HIF-1α stabilization under hypoxic conditions. HIF-1α protein stabilization under hypoxia was unaffected by Topo I siRNA. RIP specific for Topo I yielded a HIF-specific RT-PCR product in both CAOV3 and TOV112D cells. Taken together, these data indicate that topotecan modulates HIF and p53 expression levels and reverses hypoxia related chemoresistance to cisplatin. Topotecan may act by targeting Topo 1 resident on HIF-1α mRNA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C208.
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