The Chinese herb isolate isorhapontigenin induces apoptosis in human cancer cells by down-regulating overexpression of antiapoptotic protein XIAP.
Although the Chinese herb Gnetum cleistostachyum has been used as a remedy for cancers for hundred years, the active compounds and molecular mechanisms underlying its anti-cancer activity have not been explored. Recently a new derivative of stilbene compound, isorhapontigenin (ISO), was isolated from this Chinese herb. In the present study, we examined the potential of ISO in anti-cancer activity and the mechanisms involved in human cancer cell lines. We found that ISO exhibited significant inhibitory effects on human bladder cancer cell growth that was accompanied by marked apoptotic induction as well as down-regulation of the X-linked inhibitor of apoptosis protein (XIAP). Further studies have shown that ISO down-regulation of XIAP protein expression was only observed in endogenous XIAP, but not in constitutionally exogenously expressed XIAP in the same cells, excluding the possibility of ISO regulating XIAP expression at the level of protein degradation. We also identified that ISO down-regulated XIAP gene transcription via inhibition of Sp1 transactivation. There was no significant effect of ISO on apoptosis and colony formation of cells transfected with exogenous HA-tagged XIAP. Collectively, current studies, for the first time to the best of our knowledge, identify ISO as a major active compound for the anti-cancer activity of G. cleistostachyum by down-regulation of XIAP expression and induction of apoptosis through specific targeting of a SP1 pathway, and cast new light on the treatment of the cancer patients with XIAP overexpression.
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987; Department of Medical Oncology, Sir Run Run Shaw Hospital, ZheJiang University, Hangzhou, Zhejiang 310016, China.
Yong
Y
Fang
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Yonghui
Y
Yu
Materia Medica of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Qi
Q
Hou
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Xiao
X
Zheng
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Min
M
Zhang
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Dongyun
D
Zhang
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Jingxia
J
Li
Department of Urology and Pathology, New York University School of Medicine, New York, New York 10016.
Xue-Ru
XR
Wu
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987. Electronic address: chuanshu.huang@nyumc.org.
Chuanshu
C
Huang
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D035684:Gnetum / Q000737:chemistry*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D059748:Proteolysis / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis*
D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D009363:Neoplasm Proteins; D013267:Stilbenes; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C432307:isorhapontigenin