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Pifithrin-alpha enhances chemosensitivity by a p38 mitogen-activated protein kinase-dependent modulation of the

Hania Wehbe1, Roger Henson, Molly Lang

  • 1Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas 76508, USA.

The Journal of Pharmacology and Experimental Therapeutics
|September 20, 2006
PubMed

Insights

Pifithrin-alpha enhances gemcitabine chemotherapy for cholangiocarcinoma by targeting eukaryotic initiation factor 4E (eIF-4E). This anticancer agent shows promise for tumors with mutated p53, independent of p53 regulation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Eukaryotic initiation factor 4E (eIF-4E) is overexpressed in many cancers and influences therapy sensitivity.
  • Cholangiocarcinoma is a highly therapy-refractory cancer, often involving dysregulated cellular pathways.
  • The p53 tumor suppressor pathway is frequently altered in cancer and may interact with eIF-4E.

Purpose of the Study:

  • To investigate pifithrin-alpha as an adjunct therapy for human cholangiocarcinoma.
  • To assess the role of p53-dependent eIF-4E regulation in cellular responses to pifithrin-alpha.
  • To explore the mechanism by which pifithrin-alpha enhances chemosensitivity.

Main Methods:

  • Quantified eIF-4E expression in human cholangiocarcinomas versus normal liver tissue.
  • Utilized RNA interference to modulate eIF-4E expression and assessed gemcitabine efficacy.
  • Examined the effect of pifithrin-alpha preincubation on gemcitabine-induced cytotoxicity.
  • Investigated pifithrin-alpha's impact on eIF-4E phosphorylation, p38 MAPK, and aryl hydrocarbon receptor (AhR) signaling.
  • Performed sequencing analysis to identify p53 mutations in KMCH cells.

Main Results:

  • eIF-4E expression was elevated in human cholangiocarcinomas.
  • Modulating eIF-4E expression enhanced gemcitabine efficacy in KMCH cells.
  • Pifithrin-alpha increased gemcitabine-induced cytotoxicity in an eIF-4E-dependent manner.
  • Pifithrin-alpha activated AhR and p38 MAPK, leading to eIF-4E phosphorylation at serine 209.
  • KMCH cells harbored a functionally inactivating p53 mutation, and pifithrin-alpha's chemosensitizing effect was p53-independent.

Conclusions:

  • Pifithrin-alpha enhances chemosensitivity through a p53-independent mechanism involving AhR and p38 MAPK-mediated eIF-4E phosphorylation.
  • Pifithrin-alpha may be beneficial for enhancing chemotherapy in tumors with mutated p53.
  • Targeting eIF-4E represents a promising therapeutic strategy for cancer intervention.

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