MCL-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin resistant ovarian carcinoma cells

Simonin, Karin; Dufort, Sandrine; Brotin, Émilie; Denoyelle, Christophe; Dutoit, Soizic; Goux, Didier; Gauduchon, Pascal; Poulain, Laurent

doi:10.1016/s1359-6349(08)71491-5

Cited by 11 publications

(17 citation statements)

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“…Consistent with this, a combination chemogene regimen including siMcl1 was reported to enhance the chemosensitivity of pancreatic carcinoma to gemcitabine (18). Moreover, co-treatment with siMcl1 was shown to increase the chemosensitivity of cisplatin-resistant ovarian carcinoma cells (2).…”

Section: Introductionmentioning

confidence: 61%

“…Mcl1 has been reported to be involved in the growth of tumor cells and to reduce sensitivity to apoptosis (17). Apoptosis-inducing effects have reported for siMcl1 in ovarian carcinoma cells (2), and for antisense Mcl1 oligonucleotides in non-small cell lung cancer cells (17). Moreover, siMcl1 has been shown to enhance the chemosensitivity of pancreatic carcinoma cells to gemcitabine (25).…”

Section: Discussionmentioning

confidence: 99%

“…Several groups have reported significant improvement with combination cancer therapies employing potential anticancer siRNAs and chemical drugs (1)(2)(3). In these studies, anticancer siRNAs and chemical drugs have typically been administered as separate formulations.…”

Section: Introductionmentioning

confidence: 99%

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Section: Introductionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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“…Bcl-2 and Bcl-xl, two key anti-apoptotic Bcl-2 family proteins, preserve mitochondrial integrity and prevent Cyt.c efflux from triggering apoptosis [29,30]. HA14-1, an inhibitor of Bcl-2 and Bcl-xl, has been demonstrated to enhance cell apoptosis via preventing Bcl-2/ Bcl-xl interaction with Bax [45,53]. Our previous study demonstrated that pretreatment with HA14-1 significantly increased the cytotoxicity of treatment with DHA alone or the combined treatment with DHA and gemcitabine in lung cancer cells [13].…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

et al. 2015

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This report is designed to dissect the detail molecular mechanism by which dihydroartemisinin (DHA), a derivative of artemisinin, induces apoptosis in human hepatocellular carcinoma (HCC) cells. DHA induced a loss of the mitochondrial transmemberane potential (ΔΨm), release of cytochrome c, activation of caspases, and externalization of phosphatidylserine indicative of apoptosis induction. Compared with the modest inhibitory effects of silencing Bax, silencing Bak largely prevented DHA-induced ΔΨm collapse and apoptosis though DHA induced a commensurable activation of Bax and Bak, demonstrating a key role of the Bak-mediated intrinsic apoptosis pathway. DHA did not induce Bid cleavage and translocation from cytoplasm to mitochondria and had little effects on the expressions of Puma and Noxa, but did increase Bim and Bak expressions and decrease Mcl-1 expression. Furthermore, the cytotoxicity of DHA was remarkably reduced by silencing Bim, and modestly but significantly reduced by silencing Puma or Noxa. Silencing Bim or Noxa preferentially reduced DHA-induced Bak activation, while silencing Puma preferentially reduced DHA-induced Bax activation, demonstrating that Bim and to a lesser extent Noxa act as upstream mediators to trigger the Bak-mediated intrinsic apoptosis pathway. In addition, silencing Mcl-1 enhanced DHA-induced Bak activation and apoptosis. Taken together, our data demonstrate a crucial role of Bim in preferentially regulating the Bak/Mcl-1 rheostat to mediate DHA-induced apoptosis in HCC cells.

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“…26,27 As we previously demonstrated, platinum compound-based chemotherapy is also able to decrease Mcl-1 protein levels as well as to induce BH3-only proteins in ovarian carcinoma, leading to a sensitization to ABT-737. 21,22 However, the difficult application of such strategies in clinical practice, in part due to cumulative toxicities (conventional chemotherapies) or to in vivo inefficiency (siRNA, gene therapy), incites researchers to identify specific and potent Mcl-1 inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-x_L-Targeting Strategies

et al. 2015

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Apoptosis control defects such as the deregulation of Bcl-2 family member expression are frequently involved in chemoresistance. In ovarian carcinoma, we previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect cancer cells against apoptosis and their concomitant inhibition leads to massive apoptosis even in the absence of chemotherapy. Whereas Bcl-xL inhibitors are now available, Mcl-1 inhibition, required to sensitize cells to Bcl-xL-targeting strategies, remains problematic. In this context, we designed and synthesized oligopyridines potentially targeting the Mcl-1 hydrophobic pocket, evaluated their capacity to inhibit Mcl-1 in live cells, and implemented a functional screening assay to evaluate their ability to sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies. We established structure-activity relationships and focused our attention on MR29072, named Pyridoclax. Surface plasmon resonance assay demonstrated that pyridoclax directly binds to Mcl-1. Without cytotoxic activity when administered as a single agent, pyridoclax induced apoptosis in combination with Bcl-xL-targeting siRNA or with ABT-737 in ovarian, lung, and mesothelioma cancer cells.

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MCL-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin resistant ovarian carcinoma cells

Cited by 11 publications

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Cationic Liposomal Co-delivery of Small Interfering RNA and a MEK Inhibitor for Enhanced Anticancer Efficacy

Cationic Liposomal Co-delivery of Small Interfering RNA and a MEK Inhibitor for Enhanced Anticancer Efficacy

Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-x_L-Targeting Strategies

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MCL-1 is an important determinant of the apoptotic response to the BH3-mimetic molecule HA14-1 in cisplatin resistant ovarian carcinoma cells

Cited by 11 publications

References 0 publications

Cationic Liposomal Co-delivery of Small Interfering RNA and a MEK Inhibitor for Enhanced Anticancer Efficacy

Cationic Liposomal Co-delivery of Small Interfering RNA and a MEK Inhibitor for Enhanced Anticancer Efficacy

Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-xL-Targeting Strategies

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Product

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First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-x_L-Targeting Strategies