2010
DOI: 10.1007/s00280-009-1238-8
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Abstract: Purpose-Hypoxic tumor cells overexpressing hypoxia-inducible factor 1alpha (HIF-1α) are generally resistant to chemo/radiotherapy. We have reported that Se-methylselenocysteine (MSC) therapeutically enhances the efficacy and selectivity of irinotecan against human tumor xenografts. The aim of this study was to delineate the mechanism responsible for the observed efficacy targeting on HIF-1α and its transcriptionally regulated genes VEGF and CAIX.Methods-We investigated the mechanism of HIF-1α inhibition by MSC… Show more

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Cited by 63 publications
(86 citation statements)
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“…We recently reported that, in contrast to cytotoxic chemotherapy, treatment of mice bearing orthotopic TNBC tumors with ganetespib, which is a second-generation HSP90 inhibitor, induced the degradation of HIF-1α (but not HIF-2α), inhibited primary tumor growth, and reduced the number of ALDH + cells in the residual tumor (49), providing further evidence that HIF inhibition provides a mechanism to prevent BCSC enrichment. HIF inhibition by methylselenocysteine sensitized head and neck squamous cell carcinoma xenografts to the cytotoxic chemotherapy agent irinotecan (50), suggesting that HIF-mediated cancer stem cell enrichment in response to chemotherapy may not be restricted to breast cancer treated with gemcitabine or paclitaxel and may be blocked by other HIF inhibitors.…”
Section: Discussionmentioning
confidence: 99%
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“…We recently reported that, in contrast to cytotoxic chemotherapy, treatment of mice bearing orthotopic TNBC tumors with ganetespib, which is a second-generation HSP90 inhibitor, induced the degradation of HIF-1α (but not HIF-2α), inhibited primary tumor growth, and reduced the number of ALDH + cells in the residual tumor (49), providing further evidence that HIF inhibition provides a mechanism to prevent BCSC enrichment. HIF inhibition by methylselenocysteine sensitized head and neck squamous cell carcinoma xenografts to the cytotoxic chemotherapy agent irinotecan (50), suggesting that HIF-mediated cancer stem cell enrichment in response to chemotherapy may not be restricted to breast cancer treated with gemcitabine or paclitaxel and may be blocked by other HIF inhibitors.…”
Section: Discussionmentioning
confidence: 99%
“…Taken together with these clinical studies, our results provide compelling evidence in support of clinical trials combining HIF inhibitors and cytotoxic chemotherapy in women with TNBC. Several drugs have been shown to inhibit HIF activity (49,50,54) and are candidates for such trials.…”
Section: Discussionmentioning
confidence: 99%
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“…Furthermore, MSeA in the presence of DMOG is not able to downregulate HIF-1a in PC-3M cells, again suggesting that MSeA may be influencing hydroxylation of HIF-1a and causing its degradation. Chintala et al 48 observed that MSeA targets HIF-1a in FaDu cells, in particular through elevation in PHD2 protein. In our study, MSeA may possibly be increasing the degradation of HIF-1a in cytosol and therefore allowing less stabilization of HIF-1a in the nucleus; this would result in lower VEGF and GLUT1 expression in cells and may reduce their survival.…”
Section: Discussionmentioning
confidence: 99%
“…96 Chintala showed that Se-methylselenocysteine sensitized hypoxic tumor cells to irinotecan by targeting HIF-1α, indicating that inhibition of HIF-1α was associated with enhanced antitumor activity of irinotecan. 97 Despite evidence suggesting that HIF-1α contributes to tumor development, several studies find that the HIF-1 can also inhibit carcinogenesis. Thus, determining optimal combination of drugs to administer to any given patient remains a major obstacle to improving cancer treatment efficacy.…”
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confidence: 99%