Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative–(BMS 247550) and Apo-2L/TRAIL–induced apoptosis

Guo, Fei; Nimmanapalli, Ramadevi; Paranawithana, Shanthi R.; Wittman, Sylvie; Griffin, David Ray; Bali, Purva; O'Bryan, Erica; Fumero, C.; Wang, Hong Gang; Bhalla, Kapil N.

doi:10.1182/blood.v99.9.3419

Cited by 160 publications

(100 citation statements)

References 48 publications

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“…Notably, knockdown of XIAP by shRNA or overexpression of Smac alone without concomitant g-irradiation had no effect on spontaneous apoptosis of PaTuII pancreatic carcinoma cells (Figure 2). This is in line with results reported by our group and other investigators that silencing of XIAP or overexpression of Smac did not trigger apoptosis in the absence of an additional apoptotic stimulus in many cancer cells including pancreatic carcinoma (Holcik et al, 2000;Guo et al, 2002;Fulda et al, 2002;Cummins et al, 2004;Giagkousiklidis et al, 2005;Vogler et al, 2005Vogler et al, , 2007 To double confirm the sensitization effect of XIAP antagonism for g-irradiation-induced apoptosis, we used annexin-V staining as a second method to determine apoptotic cell death (van Engeland et al, 1998). Downregulation of XIAP by shRNA significantly enhanced g-irradiation-induced exposure of phosphatidylserine on the plasma membrane compared to nonsense shRNA, as shown by the increase in annexin-V positive cells ( Figure 2c).…”

Section: Xiap Targeting and G-irradiation Cooperate To Induce Apoptossupporting

confidence: 93%

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

et al. 2007

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Resistance of pancreatic cancer to current treatments including radiotherapy remains a major challenge in oncology and may be caused by defects in apoptosis programs. Since 'inhibitor of apoptosis proteins' (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could tackle a key resistance mechanism. Here, we report that targeting X-linked inhibitor of apoptosis (XIAP) by RNA-interference-mediated knockdown or overexpression of second mitochondria-derived activator of caspase significantly enhanced apoptosis and markedly reduced clonogenic growth of pancreatic carcinoma cells upon c-irradiation. Analysis of signaling pathways revealed that antagonizing XIAP increased activation of caspase-2, -3, -8 and -9 and loss of mitochondrial membrane potential upon c-irradiation. Interestingly, inhibition of caspases also reduced the cooperative effect of XIAP targeting and c-irradiation to trigger mitochondrial perturbations, suggesting that XIAP controls a feedback mitochondrial amplification loop by regulating caspase activity. Importantly, our data demonstrate for the first time that small molecule XIAP inhibitors sensitized pancreatic carcinoma cells for c-irradiation-induced apoptosis, whereas they had no effect on c-irradiation-mediated apoptosis of non-malignant fibroblasts indicating some tumor specificity. In conclusion, targeting XIAP, for example by small molecules, is a promising novel approach to enhance radiosensitivity of pancreatic cancer that warrants further investigation.

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Section: Xiap Targeting and G-irradiation Cooperate To Induce Apoptossupporting

confidence: 93%

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

et al. 2007

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“…For example, Smac agonists or ectopic overexpression of Smac peptide may enhance drug-induced cytotoxicity, as recently reported (Guo et al, 2002;Ng et al, 2002). The observation that inhibition of SOD induces apoptosis of MM cells further suggests that the combination of SOD inhibitor (2ME2) with modalities that produce free radicals may enhance anti-MM activity.…”

Section: ) (D) Effects Of 2me2 and Dex On Omentioning

confidence: 83%

Superoxide-dependent and -independent mitochondrial signaling during apoptosis in multiple myeloma cells

Chauhan

Sattler

et al. 2003

Oncogene

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Superoxide (O 2 À ) radicals have been linked to apoptosis. Here, we show that 2-methoxyestradiol (2ME2)-induced apoptosis in multiple myeloma (MM) cells is associated with O 2 À generation, whereas dexamethasone (Dex)-induced apoptosis occurs without concurrent increase in O 2 À . In contrast, both these agents decrease mitochondrial transmembrane potential (Dw m ). Treatment of MM cells with an antioxidant N-acetyl-l-cysteine blocks 2ME2, but not Dex-induced apoptosis as well as release of mitochondrial proteins cytochrome c (cyto c) and Smac. Taken together, these results demonstrate that there are at least two distinct apoptotic pathways: one dependent on O 2 À , which is induced by 2ME2 and is associated with release of cyto c and Smac; and the other an independent of O 2 À , which is triggered by Dex and associated with Smac release.

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“…Jurkat T cells overexpressing Smac have been shown to be more sensitive to epothilone B and TRAIL treatment (Guo et al, 2002). Earlier studies have shown that resistance to TRAIL in HCT116 Bax-null cells can be reversed by overexpression of Smac (Deng et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative–(BMS 247550) and Apo-2L/TRAIL–induced apoptosis

Cited by 160 publications

References 48 publications

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

Superoxide-dependent and -independent mitochondrial signaling during apoptosis in multiple myeloma cells

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

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