Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner

Probst, Brandon L.; Liu, L.; Ramesh, Vani; Li, L.; Sun, Haiying; Minna, John D.; Wang, L.

doi:10.1038/cdd.2010.44

Cited by 94 publications

(80 citation statements)

References 24 publications

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“…36,37 Consistent with these previous findings, we observed no significant induction of cell death or change in the Rip1 activation within SM-treated TNFR1/2 À / À macrophages. Interestingly, TNFR1/2 À / À macrophages showed elevated basal levels of Rip kinases, suggesting that the receptor may also have a role in the degradation of Rips.…”

Section: Discussionsupporting

confidence: 92%

cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

et al. 2012

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Cellular inhibitor of apoptosis proteins (cIAPs) have emerged as important anti-cell death mediators, particularly in cancer. Although they are known to be expressed in immune tissue, their specific immune function remains unclear. We observed that degradation of cIAPs with SMAC mimetic (SM) results in death of primary bone-marrow-derived macrophages. SM-induced death of macrophages occurred by programmed necrosis (necroptosis), which was dependent on TNF receptor expression. Consistent with necroptosis, SM-induced death of macrophages was abrogated by inhibition of receptor interacting protein 1 (Rip1) kinase signaling or by receptor interacting protein 3 (Rip3) knockdown. SM-induced necroptosis was also dependent on inhibition of SM-induced apoptosis due to the expression of the endogenous caspase inhibitor, xIAP. We found that cIAPs limit Rip3, and to a lesser extent Rip1, expression via post-transcriptional mechanisms, leading to inhibition of the Rip1-Rip3 death complex (necrosome). Reduced cIAP activity in vivo, via SM treatment or specific knockout of either cIAP, resulted in elevated macrophage cell death and compromised control of an intracellular bacterium, Listeria monocytogenes. These results show that cIAPs have an important role in limiting programmed necrosis of macrophages, which facilitates effective control of a pathogen.

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Section: Discussionsupporting

confidence: 92%

cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

et al. 2012

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“…By comparison, TNFa turned out to be dispensable for BV6-and g-irradiation-induced apoptosis because Enbrel, a TNFa blocking antibody, did not prevent cell death induction. TNFa has previously been implicated to mediate cell death induced by single agent treatment with Smac mimetic (10)(11)(12) or by combinations of Smac mimetic with chemotherapeutics (29,30). This suggests that the involvement of TNFa in Smac mimetic-induced apoptosis is context dependent.…”

Section: Discussionmentioning

confidence: 98%

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

Berger

Jennewein²,

Marschall³

et al. 2011

Molecular Cancer Therapeutics

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Evasion of apoptosis contributes to radioresistance of glioblastoma, calling for novel strategies to overcome apoptosis resistance. In this study, we investigated the potential of the small molecule Smac mimetic BV6 to modulate radiosensitivity of glioblastoma cells. Here, we identify a novel proapoptotic function of NF-kB in g-irradiation-induced apoptosis of glioblastoma cells by showing, for the first time, that NF-kB is critically required for Smac mimetic-mediated radiosensitization. BV6 significantly increases g-irradiation-triggered apoptosis in several glioblastoma cell lines in a dose-and time-dependent manner. Calculation of combination index (CI) reveals that the interaction of BV6 and g-irradiation is highly synergistic (CI < 0.3). Molecular studies show that BV6 stimulates NF-kB activation, which is critical for radiosensitization, because genetic inhibition of NF-kB by overexpression of the dominant-negative superrepressor IkBa-SR significantly decreases BV6-and g-irradiation-induced apoptosis. Also, the BV6-mediated enhancement of g-irradiation-triggered caspase activation, drop of mitochondrial membrane potential, and cytochrome c release is abolished in cells overexpressing IkBa-SR. Similarly, NF-kB inhibition by ectopic expression of a kinase dead mutant of IKKb prevents the BV6-mediated sensitization for g-irradiation. The clinical relevance is underscored by experiments with primary tumor samples showing that BV6 sensitizes primary cultured glioma cells as well as glioblastoma-initiating cancer stem cells derived from surgical specimens for g-irradiation. In conclusion, we identify NF-kB as a critical mediator of Smac mimetic-conferred radiosensitization of glioblastoma cells. These results have important implications for the development of Smac mimetic-based combination protocols for radiosensitization of glioblastoma. Mol Cancer Ther; 10(10); 1867-75. Ó2011 AACR.

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“…The combination of Smac activation with classical anticancer drugs seems to be a rational therapeutic approach (15,16). Overexpression of Smac and chemically synthesized Smac mimetics can enhance apoptosis induced by chemotherapy and radiotherapy in several types of tumor cells (12,13,(17)(18)(19)(20)(21). Smac expression has been detected in a variety of normal and tumor tissues, but the expression varies among different tumor types (22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma

Zhou

Huang

et al. 2011

Clinical Cancer Research

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Purpose: Second mitochondria-derived activator of caspase (Smac) regulates chemotherapy-induced apoptosis. Smac mimetics have been tested in clinical trials as chemosensitizers. We determined the role of Smac in modulating the chemosensitivity of esophageal squamous cell carcinoma (ESCC).Experimental Design: Smac expression was evaluated in tissues from ESCC patients with differential chemotherapeutic responses. The effects of Smac knockdown and Smac mimetics on the chemosensitivity of ESCC cells and the molecular mechanisms by which Smac and Smac mimetics modulate chemosensitivity were determined. The therapeutic responses of ESCC cells with different Smac statuses were compared using xenograft models.Results: We found that Smac was significantly downregulated in most ESCC samples (36.8%, 25/68, P ¼ 0.001), and Smac expression differed significantly (P < 0.05) between chemosensitive and chemoresistant tumors. The associations of tested factors and their responses were examined using logistic regression analysis. In ESCC cells treated with cisplatin, a common chemotherapeutic drug, Smac and cytochrome c were released from mitochondria, and caspase-3 and caspase-9 were activated.

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Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner

Cited by 94 publications

References 24 publications

cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

Role of Smac in Determining the Chemotherapeutic Response of Esophageal Squamous Cell Carcinoma

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