Targeting Cell Death in Tumors by Activating Caspases

MacKenzie, S.H.; Clark, A. Clay

doi:10.2174/156800908783769391

Cited by 86 publications

(38 citation statements)

References 104 publications

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“…Most drug compounds reportedly induce apoptosis through intrinsic death signaling pathways. Caspase-3 is regarded as a member of the apoptosis executioner caspases and cleaves many key proteins in apoptosis [40]. We found that CXCR4 knockdown can increase the activation of caspase-3 and induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin

Liang

Peng

et al. 2014

Oncotarget

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Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer for which there is no effective treatment. Previously, we and others demonstrated that CXCR4 surface expression is an independent prognostic factor for disease relapse and survival in breast cancer. In this study, we investigated the effects of CXCR4 gene silencing on cisplatin chemosensitivity in human triple-negative breast cancer cell lines. We found that CXCR4 silencing significantly inhibited cell growth, decreased colony formation, and enhanced cisplatin sensitivity while overexpression of CXCR4 rendered cells more resistant to cisplatin. Moreover, the percentage of apoptosis and cell cycle arrest at the G2/M phase of cisplatin-treated CXCR4 knockdown cells was significantly higher than control cells. Furthermore, we demonstrated CXCR4 knockdown cells showed lower levels of mutant p53 and Bcl-2 protein than the control group, while also having higher levels of caspase-3 and Bax. However overexpression of CXCR4 had the reverse effect. In vivo experiments confirmed that downregulation of CXCR4 enhanced cisplatin anticancer activity in tumor-bearing mice, and that this enhanced anticancer activity is attributable to tumor cell apoptosis. Thus, this study indicates that CXCR4 can modulate cisplatin sensitivity in TNBC cells and suggests that CXCR4 may be a therapeutic target for TNBC.

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Section: Discussionmentioning

confidence: 99%

Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin

Liang

Peng

et al. 2014

Oncotarget

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“…It is well established that activated caspases are the critical components of the execution phase of cell death in most forms of apoptosis. Therefore, factors affecting caspase activation might be important determinants of drug sensitivity [21]. We found that cell death was prevented by the pancaspase inhibitor Z-VAD, suggesting that MMPT induces caspase-dependent apoptosis in H1792 cells.…”

Section: Discussionmentioning

confidence: 87%

MMPT: a thiazolidin compound inhibits the growth of lung cancer H1792 cells via Fas-mediated and caspase-dependent apoptosis pathway

Zhao

Sun

et al. 2009

Invest New Drugs

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MMPT, a thiazolidin compound, was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. However, the related mechanism has yet not been revealed. In this study, we investigated the cellular and molecular events underlying the antitumor function of this compound in human lung adenocarcinoma H1792 cells, focusing on the early cytotoxic effect. Treatment of H1792 cancer cells with MMPT (0.1-100 microM for 24-72 h) resulted in a growth inhibition in a dose and time-dependent manner, determined by MTT assay. This effect was accompanied by apoptosis, evidenced by Nucleosome ELISA, H33258 stained assay, and Sub-G1 analysis. Our data showed that MMPT caused activation of caspase-3, caspase-6 and caspase-8, but not caspase-9. The finding that MMPT induced apoptosis through a membrane-mediated mechanism was supported by the up-regulated expression of Fas (CD95/APO-1), and Fas ligand. Overall, our results demonstrated that MMPT induced growth inhibition of H1792 cells through a Fas-mediated and caspase-dependent apoptosis pathway, which suggested that MMPT might be used as a Fas/FasL and caspases promoter to initiate lung cancer cell apoptosis.

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“…In vitro studies also demonstrated that large numbers of BCL1 cells suppress the growth of CD8 + T cells in a contact-dependent manner. Since BCL1 tumor cells express Fas-Ligand, binding to Fas on target cells likely initiates caspase-mediated apoptosis [35]. Our co-culture assays showed that high ratios of BCL1 tumor cells were needed to induce caspase-3 activation in CD8 + T cells suggesting that prolonged or repeated contact between BCL1 tumor cells and cytotoxic T cells might be required to kill the latter.…”

Section: Discussionmentioning

confidence: 93%

“…Caspase-3 is a member of the family of effector caspases and its active form triggers the apoptosis pathway. Caspase-3 activation can be initiated in target cells by the binding of Fas-ligand (FasL) to its surface receptor, CD95 (Fas), which leads to subsequent activation of the caspase-3-mediated apoptosis [35]. Since BCL1 tumor cells express FasL (data not shown), we questioned whether tumor cell-mediated inhibition of CD8 + T cells was induced via the FasL-mediated caspase cascade.…”

Section: Resultsmentioning

confidence: 99%

The Role of Regulatory B Cell-Like Malignant Cells and Treg Cells in the Mouse Model of BCL1 Tumor Dormancy

2016

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Cancer dormancy is a clinical state in which residual tumor cells persist for long periods of time but do not cause detectable disease. In the mouse B cell lymphoma model (BCL1), dormancy can be induced and maintained by immunizing mice with a soluble form of the IgM expressed on the surface of the tumor cells. Immunization induces an anti-idiotype antibody response that maintains dormancy. Mice with dormant tumor have low numbers of BCL1 cells in their spleens that divide and are killed at the same rate. When the anti-Id antibodies wane, the tumor cells grow rapidly and kill the host. Spleens from tumor-bearing mice contain both effector (CD4+ and CD8+) and regulatory T cells (Tregs). In other tumor models, it has been reported that Tregs promote tumor progression by preventing effector cells from killing the tumor. In this report, we demonstrate that the tumor site with rapidly dividing BCL1 cells has fewer Tregs than the tumor site harboring dormant BCL1 cells. In both cases, the Tregs were equally suppressive in vitro. In spleens from mice with actively growing tumor, CD8+ but not CD4+ T cells were virtually absent. In vitro analysis demonstrated a tumor-mediated elimination of CD8+ T cells that was contact dependent and involved the caspase-3 pathway. Most importantly, we found that the BCL1 cells expressed characteristics of B10 regulatory B cells, i.e., they were CD1dhiCD5+ and secreted high levels of IL-10. These BCL1 tumor cells can inhibit anti-tumor immune responses by depleting CD8+ effector T cells.

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Targeting Cell Death in Tumors by Activating Caspases

Cited by 86 publications

References 104 publications

Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin

Silencing of CXCR4 sensitizes triple-negative breast cancer cells to cisplatin

MMPT: a thiazolidin compound inhibits the growth of lung cancer H1792 cells via Fas-mediated and caspase-dependent apoptosis pathway

The Role of Regulatory B Cell-Like Malignant Cells and Treg Cells in the Mouse Model of BCL1 Tumor Dormancy

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