title: Triphendiol (NV-196), development of a novel therapy for pancreatic cancer.
abstract: Despite incremental progress in the treatment of pancreatic adenocarcinoma, the prognosis of patients remains poor. Here, we report the preclinical studies in pancreatic cancer cells that demonstrate the efficacy of triphendiol (NV-196, a synthetic isoflavene) both as a monotherapy and as a gemcitabine sensitizer. The in-vitro effects of triphendiol on the pancreatic cancer cell lines HPAC and MIAPaCa-2 were determined using cell proliferation, flow cytometry, and western blot analysis. The antiproliferative activity of triphendiol was also investigated in two xenograft models of pancreatic cancer (HPAC and MIAPaCa-2). As a monotherapy, triphendiol-inhibited cell proliferation-induced p53-independent G2/M cell cycle arrest and activation of the intrinsic (mitochondrial) apoptosis pathway. Triphendiol-induced apoptosis was caspase independent and death receptor independent, whereas cell necrosis was caspase mediated. Using combination index analysis, we have shown that pretreatment of pancreatic cancer cells with triphendiol enhanced the cytotoxic effect of gemcitabine, the standard of care used to treat advanced pancreatic cancer. In xenograft models of pancreatic cancer, the rate of tumor proliferation on mice coadministered with triphendiol and gemcitabine was significantly reduced when compared with the corresponding tumor proliferation rates from the respective monotherapy-control and vehicle-control groups. Triphendiol was recently granted Investigational New Drug status by the US Food and Drug Administration. These data justify the commencement of clinical studies investigating the utility of combining triphendiol and gemcitabine in patients with early-stage and late-stage pancreatic cancer.
authors.affiliation: Department of Surgery, U.A.B. Medical Center, Birmingham, Alabama 35294, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: McKernan
authors.forename: Ki H
authors.initials: KH
authors.lastname: Kim
authors.forename: Ayesha B
authors.initials: AB
authors.lastname: Alvero
authors.forename: Ainslie
authors.initials: A
authors.lastname: Whiting
authors.forename: John Anthony
authors.initials: JA
authors.lastname: Thompson
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.forename: Muhammad Wasif
authors.initials: MW
authors.lastname: Saif
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Husband
authors.forename: David M
authors.initials: DM
authors.lastname: Brown
authors.forename: Ewan Milne
authors.initials: EM
authors.lastname: Tytler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D007529:Isoflavones; D003841:Deoxycytidine; C541821:triphendiol; D020169:Caspases; D000093542:Gemcitabine