Identification of Novel Heat Shock Response Modulators for Experimental Anti-Melanoma Intervention

Abstract

Pharmacological induction of proteotoxic stress is rapidly emerging as a promising strategy for cancer cell-directed chemotherapeutic intervention. Due to the essential role of the cellular heat shock response in cytoprotection through the maintenance of proteostasis and suppression of apoptosis, small molecule heat shock protein (Hsp) inhibitors can be harnessed for targeted induction of cytotoxic effects in cancer cells. Recent research strongly suggests that melanoma is a malignant tumor amenable to therapeutic modulation of proteotoxic stress, particularly in situations where traditional chemotherapeutics and novel targeted therapies have failed. Based on this rationale, my graduate research has focused on the identification of redox-directed electrophilic pharmacophores capable of modulating the heat shock response for the therapeutic induction of proteotoxic stress targeting malignant human melanoma cells. The following specific aims were pursued: (1) to identify redox-directed heat shock response modulators active in malignant melanoma cells; (2) to explore melanoma cell directed activity of our lead heat shock response inducer, aurin (4-[bis(p-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one; CAS #143-74-8); and (3) to explore melanoma cell directed activity of our lead heat shock response antagonist, methylene blue (3,7-bis(dimethylamino)-phenothiazin-5-ium chloride; CAS#: 61-73-4). First, we demonstrate that the quinone methide, aurin, is a targeted Hsp90 inhibitor that induces apoptosis in human malignant melanoma cells but not in non-malignant human skin cells. Second, we have identified methylene blue as a functional antagonist of the global heat shock response which is active at the mRNA and protein levels, and have discovered that it sensitizes melanoma cells to the apoptogenic activity of the Hsp90 antagonist, geldanamycin. Taken together, these data suggest the feasibility of aurin and methylene blue as functional therapeutic heat shock response modulators targeting melanoma cells through pharmacological induction of proteotoxic stress.