title: DHA2, a synthesized derivative of bisbibenzyl, exerts antitumor activity against ovarian cancer through inhibition of XIAP and Akt/mTOR pathway.
abstract: The analysis of dihydroptychantol (DHA) and its chemically synthesized macrocyclic bisbibenzyl derivatives (DHA1, 2 and 3) led to the selection of DHA2 as a potential drug candidate for ovarian cancer. The exposure of ovarian cancer SKOV3 cells to DHA2 resulted in the downregulation of the anti-apoptotic X-linked inhibitor of apoptosis protein (XIAP) and Bcl-2 and led to caspase-independent cell death. The overexpression of XIAP reversed DHA2-induced cell death, and the depletion of XIAP had the opposite effect. DHA2 could induce autophagy, as evidenced by increases in the formation of acidic vesicular organelles and the processing of LC3B-I to LC3B-II. Pretreatment with autophagy inhibitors potentiated DHA2-mediated cell death. We showed that typical PI3K/Akt signaling was involved in DHA2-mediated cell death. The overexpression of Akt almost completely reversed DHA2-induced cell death, and the inactivation of Akt significantly facilitated DHA2-induced cell death. The administration of DHA2 to xenograft mice reduced tumor growth by causing Akt inactivation, the conversion of LC3B and proliferation inhibition. Our study demonstrates that the inhibition of XIAP and the inactivation of Akt/mTOR facilitate the efficacy of DHA2 in ovarian cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Manfei
authors.initials: M
authors.lastname: Si
authors.affiliation: Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan 250012, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Niu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Toxicology/Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China. Electronic address: lyuanhq@sdu.edu.cn.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan 250012, China. Electronic address: louhongxiang@sdu.edu.cn.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010647:Phenyl Ethers; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C539241:dihydroptychantol A; C000597844:dihydroptychantol-2; C546842:MTOR protein, human
keywords: Akt; Autophagy; Caspase-independent cell death; Ovarian cancer; mTOR