Repurposing approved and abandoned non-oncological drugs is an alternative developmental strategy for the identification of anticancer
therapeutics that has recently attracted considerable attention. 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 response antagonists can be harnessed for targeted induction of cytotoxic effects in
cancer cells. Guided by gene expression array analysis and a phenotypic screen interrogating a collection of 3,7-diamino-phenothiazinium derivatives, we have identified the redox-
drug methylene blue (MB), used clinically for the infusional treatment of
methemoglobinemia, as a negative modulator of heat shock response gene expression in human metastatic
melanoma cells. MB-treatment blocked thermal (43 °C) and pharmacological (
celastrol,
geldanamycin) induction of heat shock response gene expression, suppressing Hsp70 (HSPA1A) and Hsp27 (HSPB1) upregulation at the
mRNA and
protein level. MB sensitized
melanoma cells to the apoptogenic activity of
geldanamycin, an Hsp90 antagonist known to induce the counter-regulatory upregulation of Hsp70 expression underlying
cancer cell resistance to
geldanamycin chemotherapy. Similarly, MB-cotreatment sensitized
melanoma cells to other chemotherapeutics (
etoposide,
doxorubicin). Taken together, these data suggest feasibility of repurposing the non-oncological redox
drug MB as a therapeutic heat shock response antagonist for
cancer cell chemosensitization.