Int. J. Mol. Sci. 2013, 14(2), 4185-4202; doi:10.3390/ijms14024185
Article

Phenotypic Identification of the Redox Dye Methylene Blue as an Antagonist of Heat Shock Response Gene Expression in Metastatic Melanoma Cells

Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
* Author to whom correspondence should be addressed.
Received: 5 January 2013; in revised form: 24 January 2013 / Accepted: 29 January 2013 / Published: 19 February 2013
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Abstract: 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.
Keywords: malignant melanoma; heat shock response; Hsp70; Hsp27; methylene blue; chemosensitization

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MDPI and ACS Style

Davis, A.L.; Cabello, C.M.; Qiao, S.; Azimian, S.; Wondrak, G.T. Phenotypic Identification of the Redox Dye Methylene Blue as an Antagonist of Heat Shock Response Gene Expression in Metastatic Melanoma Cells. Int. J. Mol. Sci. 2013, 14, 4185-4202.

AMA Style

Davis AL, Cabello CM, Qiao S, Azimian S, Wondrak GT. Phenotypic Identification of the Redox Dye Methylene Blue as an Antagonist of Heat Shock Response Gene Expression in Metastatic Melanoma Cells. International Journal of Molecular Sciences. 2013; 14(2):4185-4202.

Chicago/Turabian Style

Davis, Angela L.; Cabello, Christopher M.; Qiao, Shuxi; Azimian, Sara; Wondrak, Georg T. 2013. "Phenotypic Identification of the Redox Dye Methylene Blue as an Antagonist of Heat Shock Response Gene Expression in Metastatic Melanoma Cells." Int. J. Mol. Sci. 14, no. 2: 4185-4202.

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