HIF-1α contributes to tumour-selective killing by the sigma receptor antagonist rimcazole

We have previously reported tumour-selective killing by the sigma(sigma) receptor ligand rimcazole. We now report that rimcazole elevates hypoxia inducible factor-1 alpha (HIF-1 alpha) protein levels under normoxic conditions in colorectal (HCT-116) and mammary carcinoma (MDA MB 231) cells but fails to induce HIF-1 alpha in normal fibroblasts or mammary epithelial cells. Combining the sigma-1 agonist (+)-pentazocine with rimcazole substantially reduces the accumulation of HIF-1 alpha, confirming that the effect is mediated at least partly by antagonism of sigma-1 sites. HIF-1 alpha knockdown by RNA interference attenuates rimcazole-induced cell death in both cell types. Thus, the induction of HIF-1 alpha by rimcazole contributes to tumour cell killing. In a comparison of HCT-116p53(+/+) and HCT-116p53(-/-) cells, HIF-1 alpha levels are consistently higher after rimcazole treatment in HCT-116p53(+/+) cells. Furthermore, although rimcazole kills HCT-116p53(-/-) cells, it has a more potent apoptosis-inducing effect in HCT-116p53+/+ cells. This suggests that the presence of functional p53 protein may enhance death induction by rimcazole in part through greater induction of HIF-1 alpha p53 is not required, however, for the rimcazole-induced engagement of HIF-1 alpha in proapoptotic mode as HIF-1 alpha knockdown attenuates rimcazole-induced death to comparable extents in p53 mutant and wild-type cell systems. Knowledge of HIF-1 alpha involvement may assist the re-pro. ling of rimcazole and other sigma ligands as cancer therapeutics.