Differing Mechanisms of Death Induction by Fluorinated Taxane SB-T-12854 in Breast Cancer Cells

Jelínek, Michael; Kábelová, Adéla; Šrámek, Jiří; Seitz, Joshua D.; Ojima, Iwao; Kovář, Jan

doi:10.21873/anticanres.11488

Cited by 3 publications

(2 citation statements)

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“…Therefore, it is possible that presence of ERα may amplify p53 stability and increased activation of p53 may sensitize cells to apoptotic signaling in BOK-silenced MCF7 cells. Furthermore, differences in expression of Bcl-2 family proteins and lack of functional caspase-3 in MCF7 cells [ 27 ] may also contribute to reduce long-term viability of BOK-silenced MCF7 cells compared to MDA-MB-231 or MDA-MB-468 cells. Nevertheless, depletion of both BOK and Mcl-1 rescued the effect of Mcl-1 silencing on long-term viability of MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cells (Figure 5D ).…”

Section: Resultsmentioning

confidence: 99%

Novel post-transcriptional and post-translational regulation of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 determine the fate of breast cancer cells to survive or die

et al. 2017

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Deregulation of apoptosis is central to cancer progression and a major obstacle to effective treatment. The Bcl-2 gene family members play important roles in the regulation of apoptosis and are frequently altered in cancers. One such member is pro-apoptotic protein Bcl-2-related Ovarian Killer (BOK). Despite its critical role in apoptosis, the regulation of BOK expression is poorly understood in cancers. Here, we discovered that miR-296-5p regulates BOK expression by binding to its 3’-UTR in breast cancers. Interestingly, miR-296-5p also regulates the expression of anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1), which is highly expressed in breast cancers. Our results reveal that Mcl-1 and BOK constitute a regulatory feedback loop as ectopic BOK expression induces Mcl-1, whereas silencing of Mcl-1 results in reduced BOK levels in breast cancer cells. In addition, we show that silencing of Mcl-1 but not BOK reduced the long-term growth of breast cancer cells. Silencing of both Mcl-1 and BOK rescued the effect of Mcl-1 silencing on breast cancer cell growth, suggesting that BOK is important for attenuating cell growth in the absence of Mcl-1. Depletion of BOK suppressed caspase-3 activation in the presence of paclitaxel and in turn protected cells from paclitaxel-induced apoptosis. Furthermore, we demonstrate that glycogen synthase kinase (GSK3) α/β interacts with BOK and regulates its level post-translationally in breast cancer cells. Taken together, our results suggest that fine tuning of the levels of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 may decide the fate of cancer cells to either undergo apoptosis or proliferation.

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Section: Resultsmentioning

confidence: 99%

Novel post-transcriptional and post-translational regulation of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 determine the fate of breast cancer cells to survive or die

et al. 2017

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“…It has been indicated that next-generation taxoids, exhibiting high potencies against CSCs, suppress the expression of “stemness genes”, promoting differentiation of the treated CSCs (Figure ), which may provide a new mechanism of action for taxoid anticancer agents for which the major MOA is the blocking of cell mitosis at the G2/M stage, leading to the activation of caspases and then apoptosis. ,,− …”

Section: Newer Insights Into the Mechanism Of Actionmentioning

confidence: 99%

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

et al. 2018

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Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3′ positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation taxoids. Discussed herein are SAR studies on different types of taxoids, a common pharmacophore proposal for microtubule-stabilizing anticancer agents and its interesting history, the identification of the paclitaxel binding site and its bioactive conformation, characteristics of the next-generation taxoids in cancer cell biology, including new aspects of their mechanism of action, and the highly efficacious tumor-targeted drug delivery of potent next-generation taxoids.

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Microtubule-targeting agents and their impact on cancer treatment

Čermák

Dostal

Jelínek

et al. 2020

European Journal of Cell Biology

173

120

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Differing Mechanisms of Death Induction by Fluorinated Taxane SB-T-12854 in Breast Cancer Cells

Abstract: Cell death induced by SB-T-12854, in the tested breast cancer cells, differs regarding activation of caspases, changes in levels of pro-apoptotic and anti-apoptotic proteins of the Bcl-2 family and activation of the mitochondrial apoptotic pathway.

Cited by 3 publications

References 43 publications

Novel post-transcriptional and post-translational regulation of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 determine the fate of breast cancer cells to survive or die

Novel post-transcriptional and post-translational regulation of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 determine the fate of breast cancer cells to survive or die

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

Microtubule-targeting agents and their impact on cancer treatment

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