Pifithrin-α enhances chemosensitivity by a p38 mitogen-activated protein kinase-dependent modulation of the eukaryotic initiation factor 4E in malignant cholangiocytes

Hania Wehbe, Roger Henson, Molly Lang, Fanyin Meng, Tushar Patel

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Pifithrin-α is the lead compound for a novel group of small molecules that are being developed for use as anticancer agents. The eukaryotic initiation factor 4E (eIF-4E) is overexpressed in many cancers, it can mediate sensitivity to therapy, and it may be regulated by p53. We examined the utility of pifithrin-α as an adjunct to therapy for the treatment of human cholangiocarcinoma, a tumor that is highly refractory to therapy, and we assessed the involvement of p53-dependent eIF-4E regulation in cellular responses to pifithrin-α. The expression of eIF-4E was increased in human cholangiocarcinomas compared with normal liver. Modulation of eIF-4E expression by RNA interference enhanced the efficacy of gemcitabine in KMCH cholangiocarcinoma cells. Preincubation of KMCH cells with pifithrin-α enhanced gemcitabine-induced cytotoxicity in an eIF-4E-dependent manner. Furthermore, pifithrin-α increased eIF-4E phosphorylation at serine 209 via activation of p38 mitogen-activated protein kinase (MAPK). Pifithrin-α was shown to activate aryl hydrocarbon receptor (AhR) signaling and p38 MAPK activation. Sequencing analysis indicated the presence of a functionally inactivating p53 mutation in KMCH cells, and small interfering RNA to p53 did not modulate chemosensitization by pifithrin-α. Pifithrin-α enhanced chemosensitivity by a mechanism independent of p53 and involving AhR and p38 MAPK deregulation of eIF-4E phosphorylation. Thus, pifithrin-α may prove useful for enhancing chemosensitivity in tumors with mutated p53. Moreover, modulation of eIF-4E is an attractive therapeutic target for intervention in cancer treatment.

Original languageEnglish (US)
Pages (from-to)1153-1161
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume319
Issue number3
DOIs
StatePublished - Nov 24 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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