HIF-1α acts as a molecular target for simvastatin cytotoxicity in B16.F10 melanoma cells cultured under chemically induced hypoxia.

Our previous studies reported that one of the main mechanisms of the antitumor activity of simvastatin (SIM) in B16.F10 murine melanoma cells was associated with strong suppression of the constitutive cell production of the α subunit of the heterodimeric transcription factor hypoxia-inducible factor (HIF)-1. Thus, the present study aimed to broaden this finding under hypoxic conditions induced by incubation of B16.F10 cells with cobalt chloride, when the constitutive production of HIF-1α in these melanoma cells is amplified by inducible expression of this factor. The data demonstrated that the SIM antiproliferative effects on melanoma cells were mediated mainly via strong suppressive actions on the B16.F10 cell capacity to support tumor angiogenesis and inflammation, as a result of a high inhibition of the inducible expression of HIF-1α. However, the constitutive expression of HIF-1α was not affected by SIM, probably due to the lack of effect of this statin on nuclear factor-κB production in B16.F10 cancer cells at the concentration tested. Additionally, the present study noted slight reducing effects of SIM on tumor oxidative stress, which may contribute to the main inhibitory action of this statin on HIF-1α production in hypoxic tumor cells. Collectively, these data are valuable for future anticancer strategies based on SIM administration in combination with cytotoxic drugs that are able to counteract the constitutive expression of HIF-1α in tumors.