X-linked Inhibitor of Apoptosis: A Chemoresistance Factor or a Hollow Promise

Kashkar, Hamid

doi:10.1158/1078-0432.ccr-10-1664

Cited by 82 publications

(56 citation statements)

References 63 publications

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“…It has been reported that XIAP is the only IAP protein that can directly bind to and inhibit caspases (20,24,25); cIAP1/2 are two paralogs of XIAP (22,23). In this study, we found that Smac mimetics, especially when used in combination with TRAIL, can induce the degradation of cIAP1 and XIAP.…”

Section: Discussionmentioning

confidence: 48%

“…4D). It has been reported that XIAP is the only IAP protein that can bind directly to and inhibit caspases, indicating that XIAP must play a critical role in the apoptosis pathway (20,24,25). The cIAP1 and cIAP2 proteins are two XIAP paralogs that may also play important role in apoptosis (22,23).…”

Section: Smac Mimetics In Combination With Trail Can Induce Iap Degramentioning

confidence: 99%

“…Among the 8 proteins in the family, namely survivin, IAP-like protein (ILP2), melanoma IAP (ML-IAP), X-linked IAP (XIAP), cellular IAP1 (cIAP1), cellular IAP2 (cIAP2), neuronal apoptotic inhibitor protein (NAIP), and BIR-containing ubiquitin conjugating enzyme (BRUCE), XIAP is the most well-characterized one, and cIAP1 and cIAP2 are the 2 closest XIAP paralogs (22,23). Moreover, XIAP is the only IAP protein that binds directly to caspases and inhibits their activities, which result in promoting resistance to apoptosis in cancer cells (20,24,25). In contrast, the cIAPs can bind to caspases without inhibiting their activities (23).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 48%

Section: Smac Mimetics In Combination With Trail Can Induce Iap Degramentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…There is growing evidence showing the correlation between XIAP overexpression and malignant cancer aggression (4), drug resistance (26), and poor clinical prognosis in many malignancies (27). Poorly differentiated carcinomas also display significantly higher levels of XIAP expression than well differentiated carcinomas (28).…”

Section: Discussionmentioning

confidence: 99%

The Chinese Herb Isolate Isorhapontigenin Induces Apoptosis in Human Cancer Cells by Down-regulating Overexpression of Antiapoptotic Protein XIAP

Fang

Hou

et al. 2012

Journal of Biological Chemistry

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Background:The anti-cancer activity and mechanisms of isorhapontigenin (ISO) have never been explored. Results: ISO exhibited an anti-cancer activity accompanied by apoptotic induction and XIAP down-regulation through attenuation of SP1 expression. Conclusion: ISO is an active anti-cancer compound by inducing apoptosis via down-regulation of SP1/XIAP pathway. Significance: Current studies identify a new promising active compound for therapy of human cancers with XIAP overexpression.

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“…From western blot analysis, marked increases in cleaved-PARP and caspase-3 were observed in HO-8910 cells following dasatinib and CA-4 combination treatment. IAPs also play an important role during the apoptotic process; XIAP is the best known member of this family, and correlates with resistance to chemotherapy (36). Our data showed that the synergistic effect on apoptosis obtained with the dasatinib/CA-4 co-treatment was accompanied by a large decrease in antiapoptotic XIAP protein.…”

Section: Discussionmentioning

confidence: 58%

Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo

Zhang

Zhou

et al. 2013

Oncology Reports

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Abstract. The present study showed that the combination of dasatinib and combretastatin A-4 (CA-4) exhibited synergistic cytotoxicity in multiple types of cancer, including ovarian, hepatocellular, lung and prostate carcinoma. The enhanced apoptosis induced by dasatinib plus CA-4 was accompanied by a greater extent of mitochondrial depolarization, caspase-3 activation and PARP cleavage in HO-8910 cells. Furthermore, elevated expression of Mcl-1 led to a reduced apoptosis induced by dasatinib plus CA-4, highlighting that downregulated Mcl-1 was necessary for the potentiating effect of dasatinib to CA-4-triggered apoptosis. A clear increase in γ-H2AX expression was observed in the dasatinib + CA-4 group compared with the mono-treatment groups, indicating that dasatinib plus CA-4 may induce double-strand breaks (DSBs) in HO-8910 cells. Moreover, the increased anticancer efficacy of dasatinib combined with CA-4 was further validated in a human HO-8910 ovarian cancer xenograft model in nude mice. Our study is the first to show that the combination of dasatinib with CA-4 could be a novel and promising therapeutic approach for the treatment of cancer. IntroductionCombretastatin A-4 (CA-4), a natural product isolated from the bark of a south african tree combretum caffrum, is a highly effective antiangiogenic agent that causes vascular shutdown, leading to tumor death (1). CA-4 phosphate (CA-4P), a water soluble pro-drug of CA-4, is rapidly dephosphorylated to the active compound CA-4 and shows reversible binding kinetics to tubulin, leading to disruption of microtubular structures (2,3). Although CA-4P is being studied in clinical trials as a vascular disrupting agent, cardiovascular toxicity and neurotoxicity are dose limiting for CA-4P (4,5). These severe side-effects currently represent the main obstacles to broad clinical application of CA-4P (2). Thus, it is important to develop new antitumor combination therapy with lower concentrations of CA-4 and more specificity for tumor endothelial cells than normal endothelial cells to avoid cardiac toxicity from endothelial damage.Tyrosine kinase inhibitors (TKIs) are rapidly being integrated into the management of a variety of malignant diseases (6). Dasatinib, a novel orally bioactive TKI currently used to treat patients with hematologic and solid malignancies, correlated with a combined targeting of PDGFR-β and VEGFR/c-Src signaling pathways (7-9). The Src kinases have multiple substrates that lead to diverse biological effects in cancer cells, including changes in proliferation, motility, invasion, survival and angiogenesis (10). Dasatinib suppresses tumor angiogenesis, invasion, and metastasis by inhibiting Src expression (11). Cardiovascular and hematologic toxicity are dose limiting for dasatinib; thus, it is necessary to develop new anticancer combination therapy with lower concentrations of dasatinib to avoid these major side-effects (12). Dasatinib has shown synergistic anticancer activity in combination with chemotherapeutic agents including paclitaxel, ixabepil...

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X-linked Inhibitor of Apoptosis: A Chemoresistance Factor or a Hollow Promise

Cited by 82 publications

References 63 publications

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

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

The Chinese Herb Isolate Isorhapontigenin Induces Apoptosis in Human Cancer Cells by Down-regulating Overexpression of Antiapoptotic Protein XIAP

Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo

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