title: Pifithrin-alpha enhances chemosensitivity by a p38 mitogen-activated protein kinase-dependent modulation of the eukaryotic initiation factor 4E in malignant cholangiocytes.
abstract: Pifithrin-alpha 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-alpha 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-alpha. 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-alpha enhanced gemcitabine-induced cytotoxicity in an eIF-4E-dependent manner. Furthermore, pifithrin-alpha increased eIF-4E phosphorylation at serine 209 via activation of p38 mitogen-activated protein kinase (MAPK). Pifithrin-alpha 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-alpha. Pifithrin-alpha enhanced chemosensitivity by a mechanism independent of p53 and involving AhR and p38 MAPK deregulation of eIF-4E phosphorylation. Thus, pifithrin-alpha 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.
authors.affiliation: Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas 76508, USA.
authors.forename: Hania
authors.initials: H
authors.lastname: Wehbe
authors.forename: Roger
authors.initials: R
authors.lastname: Henson
authors.forename: Molly
authors.initials: M
authors.lastname: Lang
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D034622:RNA Interference / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004273:DNA, Neoplasm; D039561:Eukaryotic Initiation Factor-4E; D018336:Receptors, Aryl Hydrocarbon; D003841:Deoxycytidine; D014050:Toluene; C121565:pifithrin; D048051:p38 Mitogen-Activated Protein Kinases; D000093542:Gemcitabine