Phenotypic identification of the redox dye methylene blue as an antagonist of heat shock response gene expression in metastatic melanoma cells

Angela L. Davis, Christopher M. Cabello, Shuxi Qiao, Sara Azimian, Georg T Wondrak

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4185-4202
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume14
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

Heat-Shock Response
gene expression
Methylene Blue
methylene blue
Gene expression
Oxidation-Reduction
Melanoma
Coloring Agents
Dyes
dyes
shock
Gene Expression
heat
cells
drugs
cancer
Cells
induction
Pharmaceutical Preparations
Up-Regulation

Keywords

  • Chemosensitization
  • Heat shock response
  • Hsp27
  • Hsp70
  • Malignant melanoma
  • Methylene blue

ASJC Scopus subject areas

  • Computer Science Applications
  • Molecular Biology
  • Catalysis
  • Inorganic Chemistry
  • Spectroscopy
  • Organic Chemistry
  • Physical and Theoretical Chemistry

Cite this

Phenotypic identification of the redox dye methylene blue as an antagonist of heat shock response gene expression in metastatic melanoma cells. / Davis, Angela L.; Cabello, Christopher M.; Qiao, Shuxi; Azimian, Sara; Wondrak, Georg T.

In: International Journal of Molecular Sciences, Vol. 14, No. 2, 02.2013, p. 4185-4202.

Research output: Contribution to journalArticle

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