title: Therapy of Smac mimetic SM-164 in combination with gemcitabine for pancreatic cancer.
abstract: Pancreatic cancer (PC) is a lethal solid malignancy with resistance to traditional chemotherapy. We investigated therapy of PC with SM-164 and gemcitabine alone and in combination. Survival of PC cells was reduced as the dose of SM-164 increased. SM-164 and/or gemcitabine increased the number of apoptotic and dead PC cells, and expression of cleavage fragments of caspase-3 and PARP1, and inhibited tumor xenograft growth in nude mice. The inhibitory effect of combination treatment was greater and of longer duration than monotherapy. Neither combination nor monotherapy showed any significant toxicity in vivo. Apoptosis and necrosis, decreased expression of Ki67, and increased expression of cleaved caspase-3 were observed in xenograft tumor tissues in SM164/gemcitabine-treated mice. SM-164 could be a promising new agent for treatment of PC in combination with gemcitabine.
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Ge
authors.initials: G
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: You
authors.forename: Tai-Ping
authors.initials: TP
authors.lastname: Zhang
authors.forename: Yu-Pei
authors.initials: YP
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C533467:SM 164; D014230:Triazoles; D003841:Deoxycytidine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D000093542:Gemcitabine