ABT-737 ameliorates docetaxel resistance in triple negative breast cancer cell line

Hwang, Eun Ju; Hwang, Seong Hye; Kim, Jong-Jin; Park, Jin Hyun; Oh, Sohee; Kim, Young A; Hwang, Kihwan

doi:10.4174/astr.2018.95.5.240

Cited by 15 publications

(12 citation statements)

References 31 publications

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“…Our results showed no difference in PARP cleavage between vector and BAD cells in response to docetaxel, suggesting that BAD did not specifically stimulate PARP-mediated necroptosis. Inhibiting apoptotic caspases with zVAD-FMK alone did not inhibit docetaxel-induced cell death, similar to previous reports by others with MDA-MB-231 cells 49 . Therefore, apoptosis is not a major cell death pathway for docetaxel in these triple-negative breast carcinoma cells.…”

Section: Discussionsupporting

confidence: 91%

BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis

Mann

Yang

Montpetit

et al. 2020

Sci Rep

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Breast cancer patients are commonly treated with taxane (e.g. docetaxel) chemotherapy, despite poor outcomes and eventual disease relapse. We previously identified the Bcl-2-associated death promoter (BAD) as a prognostic indicator of good outcome in taxane-treated breast cancer patients. We also demonstrated that BAD expression in human breast carcinoma cells generated larger tumors in mouse xenograft models. These paradoxical results suggest that BAD-expressing tumors are differentially sensitive to taxane treatment. We validated this here and show that docetaxel therapy preferentially reduced growth of BAD-expressing xenograft tumors. We next explored the cellular mechanism whereby BAD sensitizes cells to docetaxel. taxanes are microtubule inhibiting agents that cause cell cycle arrest in mitosis whereupon the cells either die in mitosis or aberrantly exit (mitotic slippage) and survive as polyploid cells. In response to docetaxel, BAD-expressing cells had lengthened mitotic arrest with a higher proportion of cells undergoing death in mitosis with decreased mitotic slippage. Death in mitosis was non-apoptotic and not dependent on Bcl-XL interaction or caspase activation. Instead, cell death was necroptotic, and dependent on RoS. these results suggest that BAD is prognostic for favourable outcome in response to taxane chemotherapy by enhancing necroptotic cell death and inhibiting the production of potentially chemoresistant polyploid cells. Triple-negative breast cancer patients receive taxane chemotherapy, such as docetaxel (Taxotere ®), as standard first-line treatment despite an overall poor prognosis, high rate of relapse, and adverse effects 1. While multiple causes of cellular taxane resistance are known, these have not yet provided clinical markers to guide taxane therapy decisions 2-4. Understanding the molecular mechanisms that mediate outcome to taxane therapy may identify predictive biomarkers and novel therapeutic targets. The Bcl-2 family member BAD (Bcl-2-associated death promoter) is a prognostic indicator for good clinical outcome of taxane-treated breast cancer patients 5. BAD modulates breast cancer cell proliferation and tumor progression by regulating cell cycle progression 6,7. Thus, understanding how BAD better predicts patient outcome could aid in understanding docetaxel chemoresistance. Taxanes are anti-mitotic drugs that perturb microtubule dynamics, leading to chronic activation of the spindle assembly checkpoint and inhibition of the anaphase promoting complex that delays the degradation of cyclin B1 and inhibits mitotic exit 8. Ideally, this aberrant mitotic arrest initiates cell death in mitosis by facilitating the accumulation of a caspase-dependent death signal 9. Often, however, cells degrade sufficient cyclin B1 prior to full activation of apoptotic caspases, and cells slip out of mitosis in the absence of cytokinesis and enter G1 as polyploid cells. These polyploid cells have differential fates of G1 arrest, post-mitotic death, or continued cell cycle progression 10,11. The su...

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Section: Discussionsupporting

confidence: 91%

BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis

Mann

Yang

Montpetit

et al. 2020

Sci Rep

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“…Because patients with TNBC usually exhibit poor overall survival to chemotherapy, and because LISCH7 deregulation has been implicated in increased resistance to chemotherapy in lung cancer cells, 26 we then evaluated the effect of LISCH7 knockdown on sensitivity to DOC, a first-line chemotherapy medication used to treat TNBC. 16 Naïve and scrambled shRNA-transfected cells both demonstrated DOC-elicited suppression of cellular proliferation in a dose-dependent manner, whereas LISCH7-depleted cells were noticeably more responsive to DOC inhibition ( Figure 2D). Such growth inhibition effect by LISCH7 knockdown was also observed, at the in vivo level, in DOC-treated xenograft models using different transfected cells (Figure 2E).…”

Section: Lisch7 Overexpression Significantly Potentiates Tnbc Progrmentioning

confidence: 94%

“…Cell viability was then assessed using the Cell Viability Assay Kit (Abcam, Shanghai), and cell viability (%) was expressed as a percentage of viable cell proportion for treated sample compared to that of untreated control. 16…”

Section: Cell Proliferation and Viabilitymentioning

confidence: 99%

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple‐negative breast cancer

Tang

Zhou

Liu

et al. 2020

J of Cellular Biochemistry

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As an aggressive breast cancer (BCa) subtype, triple‐negative breast cancer (TNBC) responses poorly to chemotherapy and endocrine therapy, and usually has a worse prognosis. This is largely due to the lack of specific therapeutic targets, laying claim to an imperious demand to clarify the key signaling pathways potentiating TNBC progression. Herein, we report that expression levels of the liver‐specific bHLH‐Zip transcription factor (LISCH7), a recently identified key player in cancerous progression, preferentially enriched in TNBC in comparison with other BCa subtypes, and this upregulation was observed to be correlated to a poor survival outcome in patients with TNBC. Ablation of LISCH7 in TNBC cells impaired cell proliferation, reduced cell invasiveness, and enhanced sensitivity to the first‐line chemotherapeutic drug docetaxel at both in vitro and in vivo levels. Importantly, concurrent induction of TGFB1, the gene encoding transforming growth factor‐β1 (TGF‐β1), an essential multipluripotent regulator of TNBC, was accompanied with these alterations in cancerous properties. We further showed that LISCH7 could directly bind to the TGFB1 promoter and stimulate TGFB1 transcription in TNBC cells. The recruitment of LISCH7 onto the TGFB1 chromatin and transactivation of TGFB1 were substantially augmented by treatment with the exogenous TGF‐β1 in a time‐ and dose‐dependent manner. Collectively, these findings suggest that LISCH7 and TGF‐β1 form a reciprocal positive regulatory loop and cooperatively regulate cancerous progression in TNBC cells. Thus, simultaneous inhibition of both LISCH7 and TGF‐β1 signaling may represent a more effective approach to counteract advanced TNBC.

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“…ABT-737 can induce intrinsic apoptosis pathway and reduce cell viability through Bax and Bak [4]. Cancer cells expressing high Bcl-2 levels are sensitive to ABT-737 treatment [2,5,6], and ABT-737 combines with cytotoxic drugs against solid tumors and hematological malignancy and overcome cancer cell resistance [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Accumulating evidence suggests that the ratio between pro-apoptotic and anti-apoptotic Bcl-2 proteins determines the susceptibility of cancer cells, and cell apoptosis may be induced by inhibiting Bcl-2 [2,3,[16][17][18]. A synergistic therapeutic effect on triple-negative breast cancer cell line MDA-MB-231 that overexpresses Bcl-2 can be achieved by combining ABT-737 with docetaxel [10]. In the present study, we investigated a novel treatment strategy that enhances the unique pathways of ABT-737 other than Bax and Bak to determine novel pathways and augment their effects that kill cancer cells in uterine cervixes.…”

Section: Introductionmentioning

confidence: 99%

The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death

Hsin

Chou

Hung

et al. 2019

Cancers

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ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.

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ABT-737 ameliorates docetaxel resistance in triple negative breast cancer cell line

Cited by 15 publications

References 31 publications

BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis

BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple‐negative breast cancer

The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death

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