The Anti-melanoma Effects of Heat Shock Protein Inhibitors

Abstract

BRAF inhibitor can be used as a treatment regimen for malignant melanoma cancer, but this treatment is limited by the development of drug resistance. Heat shock proteins (Hsp) have been found to be over-expressed in several cancers, suggesting the critical role of Hsps in tumor initiation and growth. This study revealed that Hsp inhibitors worked as novel anti-cancer drugs in both Vemurafenib sensitive A375 and resistant A375VR melanoma cells. Hsp inhibitors displayed potent cytotoxicity against the human malignant melanoma cells and achieved a better therapeutic effect when combined with PLX4032. In addition, Hsp90 inhibitors CAY10607 significantly inhibited cell migration in the resistant cell line A375VR, and Hsp70 inhibitor VER155008 showed a synergistic effect with PLX4032 in inhibiting cell migration in the sensitive cell line A375. Furthermore, Hsp70 inhibitor VER155008 promoted cell apoptosis significantly in both Vemurafenib sensitive and resistant melanoma cells, and the combination of Hsp70 inhibitor and Hsp90 inhibitor synergistically increased their cytotoxic effects on melanoma cells. Finally, Hsp90 inhibitor CAY10607 suppressed the activation of Akt and Erk in both Vemurafenib sensitive melanoma cell line A375 and resistant cell line A375VR, but only inhibited the activation of Akt and Erk in the sensitive cell line A375. Therefore, Hsp inhibitors can serve as novel anti-cancer drugs by inhibiting cell migration, inducing cell apoptosis, and inactivating the PI3K/Akt and Ras-Raf-Mek-Erk pathways.