Promises and Challenges of Smac Mimetics as Cancer Therapeutics

被引：181

作者：

Fulda, Simone ^{[1
,2
,3
]}

机构：

[1] Goethe Univ Frankfurt, Inst Expt Canc Res Pediat, D-60528 Frankfurt, Germany

[2] German Canc Consortium DKTK, Heidelberg, Germany

[3] German Canc Res Ctr, Heidelberg, Germany

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 22期

关键词：

NF-KAPPA-B; PANCREATIC-CARCINOMA CELLS; IRRADIATION-INDUCED APOPTOSIS; TRAIL-INDUCED APOPTOSIS; MYELOID-LEUKEMIA CELLS; TNF-ALPHA; MEDIATED SENSITIZATION; ANTAGONISTS INDUCE; GLIOBLASTOMA CELLS; ANTITUMOR-ACTIVITY;

D O I：

10.1158/1078-0432.CCR-15-0365

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics. (C) 2015 AACR.

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收藏

页码：5030 / 5036

页数：7

相关论文

共 73 条

[1]

RIP1 is required for IAP inhibitor-mediated sensitization for TRAIL-induced apoptosis via a RIP1/FADD/caspase-8 cell death complex [J].

Abhari, B. A. ;

Cristofanon, S. ;

Kappler, R. ;

von Schweinitz, D. ;

Humphreys, R. ;

Fulda, S. .

ONCOGENE, 2013, 32 (27) :3263-3273

[2]

Amaravadi RK, 2013, J CLIN ONCOL, V31

[3]

Synergistic interaction of Smac mimetic and IFNα to trigger apoptosis in acute myeloid leukemia cells [J].

Bake, Vanessa ;

Roesler, Stefanie ;

Eckhardt, Ines ;

Belz, Katharina ;

Fulda, Simone .

CANCER LETTERS, 2014, 355 (02) :224-231

[4]

RIP1 Protein-dependent Assembly of a Cytosolic Cell Death Complex Is Required for Inhibitor of Apoptosis (IAP) Inhibitor-mediated Sensitization to Lexatumumab-induced Apoptosis [J].

Basit, Farhan ;

Humphreys, Robin ;

Fulda, Simone .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (46) :38767-38777

[5]

Smac mimetic and glucocorticoids synergize to induce apoptosis in childhood ALL by promoting ripoptosome assembly [J].

Belz, Katharina ;

Schoeneberger, Hannah ;

Wehner, Sibylle ;

Weigert, Andreas ;

Boenig, Halvard ;

Klingebiel, Thomas ;

Fichtner, Iduna ;

Fulda, Simone .

BLOOD, 2014, 124 (02) :240-250

[6]

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation-Induced Apoptosis [J].

Berger, Rebecca ;

Jennewein, Claudia ;

Marschall, Viola ;

Karl, Sabine ;

Cristofanon, Silvia ;

Wagner, Liane ;

Vellanki, Sri HariKrishna ;

Hehlgans, Stephanie ;

Roedel, Franz ;

Debatin, Klaus-Michael ;

Ludolph, Albert C. ;

Fulda, Simone .

MOLECULAR CANCER THERAPEUTICS, 2011, 10 (10) :1867-1875

[7]

cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination [J].

Bertrand, Mathieu J. M. ;

Milutinovic, Snezana ;

Dickson, Kathleen M. ;

Ho, Wai Chi ;

Boudreault, Alain ;

Durkin, Jon ;

Gillard, John W. ;

Jaquith, James B. ;

Morris, Stephen J. ;

Barker, Philip A. .

MOLECULAR CELL, 2008, 30 (06) :689-700

[8]

Smac mimetics and innate immune stimuli synergize to promote tumor death [J].

Beug, Shawn T. ;

Tang, Vera A. ;

LaCasse, Eric C. ;

Cheung, Herman H. ;

Beauregard, Caroline E. ;

Brun, Jan ;

Nuyens, Jeffrey P. ;

Earl, Nathalie ;

St-Jean, Martine ;

Holbrook, Janelle ;

Dastidar, Himika ;

Mahoney, Douglas J. ;

Ilkow, Carolina ;

Le Boeuf, Fabrice ;

Bell, John C. ;

Korneluk, Robert G. .

NATURE BIOTECHNOLOGY, 2014, 32 (02) :182-+

[9]

Modulation of immune signalling by inhibitors of apoptosis [J].

Beug, Shawn T. ;

Cheung, Herman H. ;

LaCasse, Eric C. ;

Korneluk, Robert G. .

TRENDS IN IMMUNOLOGY, 2012, 33 (11) :535-545

[10]

Borthakur G, 2014, P 56 ASH ANN M EXP 2

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