Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition

Song, Ting; Chai, Gaobo; Liu, Yubo; Xie, Mingzhou; Chen, Qingbin; Yu, Xiaoyan; Sheng, Hwai-Ping; Zhang, Zhichao

doi:10.1016/j.ejps.2015.01.003

Cited by 12 publications

(6 citation statements)

References 29 publications

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“…Herein, we show that Mcl-1 is downregulated in sensitive 5637 cells, but not in resistant HT1197 cells in response to paclitaxel and that Mcl-1 is overexpressed in many muscle-invasive bladder carcinomas. The relevance of Mcl-1 as a biomarker of aggressiveness is well described in several malignancies, and its overexpression has also been related to the resistance of several BH3 mimetics [28,29,30]. We found that combinations of obatoclax and paclitaxel were able to induce apoptotic cell death in resistant HT1197 cells, as well as in other models of paclitaxel resistance such as HT1376 and MDA-MB-231 cells.…”

Section: Discussionmentioning

confidence: 64%

Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

Jiménez-Guerrero

Gasca

Flores

et al. 2018

Cancers

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Paclitaxel is a treatment option for advanced or metastatic bladder cancer after the failure of first-line cisplatin and gemcitabine, although resistance limits its clinical benefits. Mcl-1 is an anti-apoptotic protein that promotes resistance to paclitaxel in different tumors. Obatoclax, a BH3 mimetic of the Bcl-2 family of proteins, antagonizes Mcl-1 and hence may reverse paclitaxel resistance in Mcl-1-overexpressing tumors. In this study, paclitaxel-sensitive 5637 and -resistant HT1197 bladder cancer cells were treated with paclitaxel, obatoclax, or combinations of both. Apoptosis, cell cycle, and autophagy were measured by Western blot, flow cytometry, and fluorescence microscopy. Moreover, Mcl-1 expression was analyzed by immunohistochemistry in bladder carcinoma tissues. Our results confirmed that paclitaxel alone induced Mcl-1 downregulation and apoptosis in 5637, but not in HT1197 cells; however, combinations of obatoclax and paclitaxel sensitized HT1197 cells to the treatment. In obatoclax-treated 5637 and obatoclax + paclitaxel-treated HT1197 cells, the blockade of the autophagic flux correlated with apoptosis and was associated with caspase-dependent cleavage of beclin-1. Obatoclax alone delayed the cell cycle in 5637, but not in HT1197 cells, whereas combinations of both retarded the cell cycle and reduced mitotic slippage. In conclusion, obatoclax sensitizes HT1197 cells to paclitaxel-induced apoptosis through the blockade of the autophagic flux and effects on the cell cycle. Furthermore, Mcl-1 is overexpressed in many invasive bladder carcinomas, and it is related to tumor progression, so Mcl-1 expression may be of predictive value in bladder cancer.

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Section: Discussionmentioning

confidence: 64%

Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

Jiménez-Guerrero

Gasca

Flores

et al. 2018

Cancers

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“…Overexpression of Bcl-2 provides a survival advantage to cancer cells in response to a wide range of apoptotic stimuli through the inhibition of mitochondrial cytochrome c release (26). Inhibition of Mcl-1 is associated with synergistic upregulation of Bim by the displacement of Bak from Mcl-1 (73). Moreover, blocking Mcl-1-mediated suppression of Bid-induced Bax activation in vitro can activate cell death pathways (42).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cDNA microarrays may aid in establishing and improving gene expression patterns capable of predicting individual responses to therapy. The results of several recent studies have shown a synergistic effect of apoptosis inhibitors with clinically used cytostatics which enhanced their cytotoxicity (42,43,73,83). The concept is that the combination of apoptotic Bcl-2 inhibitors with a chemotherapeutic agent such as temozolomide, which is routinely used in clinical practice, may provide a better clinical effect.…”

Section: Discussionmentioning

confidence: 99%

Microfluidic profiling of apoptosis-related genes after treatment with BH3-mimetic agents in astrocyte and glioblastoma cell lines

et al. 2016

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Glioblastoma (GB) is the most frequent and biologically the most aggressive primary brain tumor in adults. Standard treatment for newly diagnosed GB consists of surgical resection, radiotherapy and chemotherapy. Resistance to therapy is a major obstacle, even with optimal treatment with a survival median of only 12-15 months. The heterogeneity and treatment response of GB makes this tumor type a challenging area of research. The aim of our study was to study the response of normal human astrocyte (HA) and human GB (T98G) cell lines to apoptosis inhibitors in vitro. ABT-737 is an inhibitor of anti-apoptotic proteins Bcl-2, Bcl-xL, Bcl-w, while MIM-1 is an Mcl-1 protein inhibitor. The viability of the cells was assayed biochemically using the cytotoxic methyl thiazolyl tetrazolium (MTT) assay. Changes in the expression of apoptosis-associated genes (n=93) in two human brain cell lines after treatment with the apoptosis inhibitors ABT-737 and MIM-1 (individually), between the apoptosis inhibitor treated group and the control group, were determined using a commercially pre-designed microfluidic array. Significant changes in apoptotic gene expression with more than a 2.0-fold difference in their expression levels were obtained in both cell lines; the most altered genes were in the HA cell line after MIM-1 treatment (n=42). These results contribute to the importance of apoptosis in normal and cancerous brain tissues and provide information on the effect of apoptosis inhibitors on cell viability and gene expression. Despite extensive investigations, a cure for GB is currently not available. The identification of an apoptotic gene panel and determining the sensitivity of normal and GB brain cells to individual apoptosis inhibitors could help to improve clinical practice and increase our understanding of brain tumor cell metabolism and apoptosis inhibitors in GB cells and astrocytes. Recognizing expression changes in pro-apoptotic and anti-apoptotic genes could contribute to the development of new treatments.

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“…Forkhead box transcription factor 1 might be a new therapeutic target in docetaxel-resistant gastric cancer (Li et al, 2013). However, recent evidence has demonstrated that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead (Weaver, 2014; Zhang et al, 2014; Song et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A Bayesian Network Meta-Analysis for Identifying the Optimal Taxane-Based Chemotherapy Regimens for Treating Gastric Cancer

Zhang

Duan

et al. 2019

Front. Pharmacol.

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Background: Several taxane-based chemotherapy regimens are effective in the treatment of gastric cancer; nevertheless, their comparative efficacy and safety remain disputed. This network meta-analysis (NMA) was designed to compare the efficacy and safety of different taxane-based chemotherapy regimens against gastric cancer. Methods: A comprehensive search was conducted to identify all relevant randomized controlled trials (RCTs) in multiple electronic databases. A Bayesian NMA was performed to combine the direct and indirect evidence and estimate the comparative efficacy and safety of different taxane-based chemotherapy regimens simultaneously by utilizing WinBUGS 1.4.3 and Stata 13.1 software. The efficacy outcomes included overall survival rate (OS), progression-free survival (PFS), and overall response rate (ORR), and the safety outcomes were adverse reactions (ADRs), namely, neutropenia, leucopenia, vomiting, and fatigue. Results: A total of 37 RCTs were identified involving 7,178 patients with gastric cancer, and 10 taxane-based chemotherapy regimens (RT, T, TC, TCF, TF, TO, TOF, mTCF, mTF, and mTOF) were collected in gastric cancer therapy. According to the results of cluster analysis, compared with other taxane-based chemotherapy regimens, the regimens of TOF, mTCF, and TF were associated with the most favorable clinical efficacy in improving OS, PFS, and ORR. On the other hand, the regimens of T and mTF had the potential to be the most tolerable and acceptable therapeutic alternative in terms of ADRs. Conclusions: The current NMA provides the evidence that the combination of taxanes (paclitaxel or docetaxel) and fluorouracil is associated with the most preferable and beneficial option for patients with gastric cancer, although additional results from multicenter trials and high-quality studies will be pivotal for supporting our findings.

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Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition

Cited by 12 publications

References 29 publications

Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

Microfluidic profiling of apoptosis-related genes after treatment with BH3-mimetic agents in astrocyte and glioblastoma cell lines

A Bayesian Network Meta-Analysis for Identifying the Optimal Taxane-Based Chemotherapy Regimens for Treating Gastric Cancer

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