Mcl-1 as a “barrier” in cancer treatment: Can we target it now?

Pervushin, Nikolay V.; Senichkin, Viacheslav V; Zhivotovsky, Boris; Kopeina, Gelina S.

doi:10.1016/bs.ircmb.2020.01.002

Cited by 12 publications

(26 citation statements)

References 141 publications

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“…Our studies of in vitro EC and VSMC toxicity to cancer therapeutics also revealed a high sensitivity to BH3 mimetics, especially those inhibiting BCL-X L and MCL-1. While BCL-2 inhibitors have thus far had the most clinical success among the BH3 mimetics (mainly targeting hematological cancers including chronic lymphocytic and acute myelogenous leukemias) ( 46 , 47 ), there are currently a multitude of clinical trials ongoing with BCL-X L and MCL-1 inhibitors for treatment of various hematological and solid cancers ( 48 , 49 ). Several preclinical studies are also advocating the combination of BH3 mimetics with different BCL-2 family targets to increase antitumor effects or combining these agents with other apoptosis-inducing therapies ( 14 , 48 ).…”

Section: Discussionmentioning

confidence: 99%

“…While BCL-2 inhibitors have thus far had the most clinical success among the BH3 mimetics (mainly targeting hematological cancers including chronic lymphocytic and acute myelogenous leukemias) ( 46 , 47 ), there are currently a multitude of clinical trials ongoing with BCL-X L and MCL-1 inhibitors for treatment of various hematological and solid cancers ( 48 , 49 ). Several preclinical studies are also advocating the combination of BH3 mimetics with different BCL-2 family targets to increase antitumor effects or combining these agents with other apoptosis-inducing therapies ( 14 , 48 ). While some of these studies report tolerable in vivo toxicity experiments, most are only performed on a short-term basis and do not take into account the long latency period frequently associated with CV toxicity ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

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Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy–induced toxicities

et al. 2022

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Although major organ toxicities frequently arise in patients treated with cytotoxic or targeted cancer therapies, the mechanisms that drive them are poorly understood. Here, we report that vascular endothelial cells (ECs) are more highly primed for apoptosis than parenchymal cells across many adult tissues. Consequently, ECs readily undergo apoptosis in response to many commonly used anticancer agents including cytotoxic and targeted drugs and are more sensitive to ionizing radiation and BH3 mimetics than parenchymal cells in vivo. Further, using differentiated isogenic human induced pluripotent stem cell models of ECs and vascular smooth muscle cells (VSMCs), we find that these vascular cells exhibit distinct drug toxicity patterns, which are linked to divergent therapy–induced vascular toxicities in patients. Collectively, our results demonstrate that vascular cells are highly sensitive to apoptosis-inducing stress across life span and may represent a “weakest link” vulnerability in multiple tissues for development of toxicities.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy–induced toxicities

et al. 2022

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“…Similar to BH3-only proteins, several BH3 mimetics (e.g., obatoclax and gossypol) interact with various Bcl-2 family proteins. These compounds are widely used in vitro but have not been shown to be effective in clinical trials [ 23 ]. BH3 mimetics to individual anti-apoptotic proteins were more successful, and the most important breakthrough was the approval of venetoclax, a selective Bcl-2 inhibitor, for the treatment of patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) (for the latter, in combination with azacitidine, decitabine, or low-dose cytarabine) [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to venetoclax, BH3 mimetics to other Bcl-2 family members have been studied only in preclinical or early phase clinical trials [ 24 ]. For a long time, there were no selective and highly active inhibitors of Mcl-1 [ 23 ]. However, in the recent five years, a number of BH3 mimetics to Mcl-1, such as A1210477 [ 25 ], S63845 [ 26 ], AZD-5991 [ 27 ], AMG-176 [ 28 ], and VU661013 [ 29 ], have been described.…”

Section: Introductionmentioning

confidence: 99%

“…However, in the recent five years, a number of BH3 mimetics to Mcl-1, such as A1210477 [ 25 ], S63845 [ 26 ], AZD-5991 [ 27 ], AMG-176 [ 28 ], and VU661013 [ 29 ], have been described. Several of them have been included in clinical trials for the treatment of patients with hematological diseases, both as single agents or in combination with venetoclax [ 23 ]. Hence, studying BH3 mimetics to Mcl-1 is of great importance in the context of their possible use as anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

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Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors

Senichkin

Pervushin

Zamaraev

et al. 2021

Cancers

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BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependent mechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance to Mcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissues from patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increased Bak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrated dramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL and Mcl-1 might lead to a release of Bak, which cannot be neutralized by other anti-apoptotic proteins. Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition.

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The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy

Basu

2022

Pharmacology & Therapeutics

103

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Mcl-1 as a “barrier” in cancer treatment: Can we target it now?

Cited by 12 publications

References 141 publications

Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy–induced toxicities

Heightened apoptotic priming of vascular cells across tissues and life span predisposes them to cancer therapy–induced toxicities

Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors

The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy

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