Design, Synthesis, and Biological Activity of a Potent Smac Mimetic That Sensitizes Cancer Cells to Apoptosis by Antagonizing IAPs

Zobel, Kerry; Wang, Lan; Varfolomeev, Eugene; Franklin, Matthew C.; Elliott, Linda O.; Wallweber, Heidi J.A.; Okawa, David C.; Flygare, John A.; Vucic, Domagoj; Fairbrother, Wayne J.; Deshayes, Kurt

doi:10.1021/cb600276q

Cited by 167 publications

(179 citation statements)

References 43 publications

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“…Notably, the role of cIAP1 and 2 as negative regulators of stimulus-independent classical and alternative NF-B signaling (11,12) was uncovered in studies using small-molecule IAP antagonist compounds. These compounds were designed to mimic the interaction between XIAP and its antagonist Smac (second mitochondria-derived activator of caspases) and show great promise for the treatment of cancer (26). Smac-mimetics were intended to de-repress XIAP-mediated inhibition of apoptosis in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation

Mahoney

Cheung

Mrad

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

480

410

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The cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2) proteins have been implicated in the activation of NF-B by TNF␣; however, genetic deletion of either cIAP1 or 2 did not support a physiologically relevant role, perhaps because of functional redundancy. To address this, we used combined genetic and siRNA knockdown approaches and report that cIAP1 and 2 are indeed critical, yet redundant, regulators of NF-B activation upon TNF␣ treatment. Whereas NF-B was properly activated by TNF␣ in cultured and primary cells deficient in either cIAP1 or 2, removal of both cIAPs severely blunted its activation. After treatment with TNF␣, cIAP1 and 2 were rapidly recruited to the TNF receptor 1, along with the adapter protein TNF receptor associated factor 2. Importantly, either cIAP1 or 2 was required for proper TNF receptor 1 signalosome function. In their combined absence, polyubiquitination of receptor interacting protein 1, an upstream event necessary for NF-B signaling, was attenuated. As a result, phosphorylation of the inhibitor of B kinase ␤ was diminished, and signal transduction was severely blunted. Consequently, cells missing both cIAP1 and 2 were sensitized to TNF␣-mediated apoptosis.Collectively, these data demonstrate that either cIAP1 or 2 is required for proper Rip1 polyubiquitination and NF-B activation upon TNF␣ treatment.apoptosis ͉ Receptor Interacting Protein (RIP1)

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Section: Discussionmentioning

confidence: 99%

Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation

Mahoney

Cheung

Mrad

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

480

410

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“…In comparison with Smac, Smac mimetic could cross the cell membrane and bind efficiently to its target proteins (65). It was shown that Smac mimetic possessed the ability of activating caspase-3 and caspase-7, reducing cell viability of MDA-MB-231 breast cancer cells and A2058 melanoma cells, and enhancing doxorubicininduced apoptosis (66). Together, the development of small molecules is offering not only prospects for individualized treatment but also a valuable therapeutic window to limit unwanted side effects (67,68).…”

Section: Targeting Livin By Blocking Protein Functionmentioning

confidence: 99%

Challenge and promise: roles for Livin in progression and therapy of cancer

Wang

Zhang²,

Liu

et al. 2008

Molecular Cancer Therapeutics

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Livin is a member of the inhibitors of apoptosis protein gene family, which is highly expressed in a variety of human neoplasms. Several studies have shown that down-regulation of Livin expression increases the apoptotic rate, reduces tumor growth potential, and sensitizes tumor cells to chemotherapeutic drugs. Furthermore, emerging data reveal that Livin fragments cleavaged by caspases restored paradoxical proapoptotic activity during the apoptotic process, suggesting that Livin cleavage will become a highly potent proapoptotic agent in the future. In this article, we review the current understanding of the versatile roles of Livin in the apoptotic cascade and exploit the promising approach to interfere with Livin as a novel strategy for cancer therapy. [Mol Cancer Ther 2008;7(12):3661 -9]

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“…By binding to XIAP and cIAPs, Smac can release the inhibition of caspase or lead to the degradation of cIAPs, which in turn activates the apoptosis process in cells (26,27). Therefore, regarding the potency of Smac to revert the antiapoptotic process of cancer cells, several Smac mimetics have been designed and synthesized as antitumor drugs in recent years (28)(29)(30)(31). These compounds can induce cIAP1/2 degradation and prevent XIAP from binding to caspases, which induce the apoptosis of tumor cells with little effect on normal cells (27,32).…”

Section: Introductionmentioning

confidence: 99%

Smac Mimetics in Combination with TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma

Wu¹,

Wang²,

Zhao³

et al. 2013

Molecular Cancer Therapeutics

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Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stem cells (CSC) have been shown with resistance against therapies and thus considered as the initiator of recurrence and metastasis in tumors, where the antiapoptotic property of CSCs play an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis. Here, the effects of Smac mimetics on the CSCs of nasopharyngeal carcinoma were studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 as models. We found that one of the clones, S18, had CSC-like properties and IAPs were overexpressed. The combination of Smac mimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colonyand sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stem cells, and this combination treatment should be considered as a promising strategy for the treatment of nasopharyngeal carcinoma. Mol Cancer Ther; 12(9); 1728-37. Ó2013 AACR.

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Design, Synthesis, and Biological Activity of a Potent Smac Mimetic That Sensitizes Cancer Cells to Apoptosis by Antagonizing IAPs

Cited by 167 publications

References 43 publications

Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation

Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation

Challenge and promise: roles for Livin in progression and therapy of cancer

Smac Mimetics in Combination with TRAIL Selectively Target Cancer Stem Cells in Nasopharyngeal Carcinoma

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