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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Pifithrin- Enhances Chemosensitivity by a p38 Mitogen-Activated Protein Kinase-Dependent Modulation of the Eukaryotic Initiation Factor 4E in Malignant Cholangiocytes

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

Pifithrin- 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- 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-. 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- enhanced gemcitabine-induced cytotoxicity in an eIF-4E-dependent manner. Furthermore, pifithrin- increased eIF-4E phosphorylation at serine 209 via activation of p38 mitogen-activated protein kinase (MAPK). Pifithrin- 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-. Pifithrin- enhanced chemosensitivity by a mechanism independent of p53 and involving AhR and p38 MAPK deregulation of eIF-4E phosphorylation. Thus, pifithrin- 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.

Address correspondence to: Dr. Tushar Patel, Scott and White Clinic, Texas A&M University System Health Science Center, College of Medicine, 2401 South 31st St., Temple, TX 76508. E-mail: tpatel{at}swmail.sw.org