title: Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline.
abstract: Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.affiliation: Institute of Life Sciences, Bhubaneswar, Orissa, India.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Siddik
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: The University of Jordan, Department of Biological Sciences, Amman, Jordan.
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Praveen
authors.initials: P
authors.lastname: Bhoopathi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. pbfisher@vcu.edu.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D051379:Mice; D008911:Minocycline / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D013752:Tetracycline / Q000008:administration & dosage / Q000138:chemical synthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: C550162:1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; D019253:Proto-Oncogene Proteins c-bcl-2; D013752:Tetracycline; D008911:Minocycline; D006072:Gossypol