Development of Mcl-1 inhibitors for cancer therapy

Negi, Arvind S.; Murphy, Paul V.

doi:10.1016/j.ejmech.2020.113038

Cited by 63 publications

(44 citation statements)

References 159 publications

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“…1 C and D and S1). Mcl-1 is an anti-apoptotic protein that, functionally like Bcl-2 and Bcl-X L , negatively regulates intrinsic apoptotic pathway [ 23 , 24 ]. We also checked Mcl-1 levels in these cell lines and found that APG-1252-M1-senstive cell lines tended to have lower levels of Mcl-1 than those insensitive to APG-1252-M1, showing a significant negative correlation between Mcl-1 abundance and cell response to APG-1252-M1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

et al. 2022

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“…Another alternative could be to target both Mcl-1 and BCL2A1 activities using peptide inhibitors or small molecules such as selective BH3-mimetics. While many Mcl-1 inhibitors have been generated, few are under clinical development, and none have yet been approved for clinical use (60,61). Concerning BCL2A1, very few peptide inhibitors or small molecules are in development, though some have been tested in vitro and in vivo in animal models; no clinical development was reported (62).…”

Section: Discussionmentioning

confidence: 99%

Neutralizing Anti-IL-17A Antibody Demonstrates Preclinical Activity Enhanced by Vinblastine in Langerhans Cell Histiocytosis

et al. 2022

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Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterised by the accumulation into granulomas of apoptosis-resistant pathological dendritic cells (LCH-DCs). LCH outcome ranges from self-resolving to fatal. Having previously shown that, (i) monocyte-derived DCs (Mo-DCs) from LCH patients differentiate into abnormal and pro-inflammatory IL-17A-producing DCs, and (ii) recombinant IL-17A induces survival and chemoresistance of healthy Mo-DCs, we investigated the link between IL-17A and resistance to apoptosis of LCH-DCs. In LCH granulomas, we uncovered the strong expression of BCL2A1 (alias BFL1), an anti-apoptotic BCL2 family member. In vitro, intracellular IL-17A expression was correlated with BCL2A1 expression and survival of Mo-DCs from LCH patients. Based on the chemotherapeutic drugs routinely used as first or second line LCH therapy, we treated these cells with vinblastine, or cytarabine and cladribine. Our preclinical results indicate that high doses of these drugs decreased the expression of Mcl-1, the main anti-apoptotic BCL2 family member for myeloid cells, and killed Mo-DCs from LCH patients ex vivo, without affecting BCL2A1 expression. Conversely, neutralizing anti-IL-17A antibodies decreased BCL2A1 expression, the downregulation of which lowered the survival rate of Mo-DCs from LCH patients. Interestingly, the in vitro combination of low-dose vinblastine with neutralizing anti-IL-17A antibodies killed Mo-DCs from LCH patients. In conclusion, we show that BCL2A1 expression induced by IL-17A links the inflammatory environment to the unusual pro-survival gene activation in LCH-DCs. Finally, these preclinical data support that targeting both Mcl-1 and BCL2A1 with low-dose vinblastine and anti-IL-17A biotherapy may represent a synergistic combination for managing recurrent or severe forms of LCH.

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“…To further confirm whether LCT-3d treatment activated mitochondrial pathway, we detected mitochondria-related proteins in gastric cancer cells. Bcl-2 family proteins are the major regulators and effectors of the mitochondrial apoptotic pathway, which include anti-apoptotic proteins such as Bcl-2 and pro-apoptotic proteins such as Bax (26)(27)(28)(29). The oligomerization of Bax and Bak proteins promote the increase of the mitochondrial membrane permeability, which leading to the release of cytochrome c into the cytosol, subsequently cell apoptosis occurred through Caspase cascade.…”

Section: Discussionmentioning

confidence: 99%

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells

Wang

Wu²,

Yu³

et al. 2021

Front. Oncol.

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Gastric cancer is a global health problem. In this study, we investigate the role of a novel Indole derivative, named LCT-3d, in inhibiting the growth of gastric cancer cells by MTT assay. The Western blotting results showed that LCT-3d modulated the mitochondrial-related proteins and Cleaved-Caspases 3/9, to induce cell apoptosis. The up-regulation of Death receptor 5 (DR5) in MGC803 cells was observed with LCT-3d treatment. Knockdown of DR5 on MGC803 cells partially reversed the LCT-3d-induced mitochondrial apoptosis. The level of Reactive Oxygen Species (ROS) in MGC803 cells was increased with LCT-3d treatment and could be blocked with the pretreatment of the ROS inhibitor N-Acetylcysteine (NAC). The results demonstrate that the elevating ROS can up-regulate the expression of DR5, resulting in apoptosis via mitochondrial pathway. Although the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway served an important role in protecting gastric cancer cells against the injury of ROS, it can’t reverse LCT-3d-induced cell apoptosis. Taken together, our study showed that LCT-3d induced apoptosis via DR5-mediated mitochondrial apoptotic pathway in gastric cancer cells. LCT-3d could be a novel lead compound for development of anti-cancer activity in gastric cancer.

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Development of Mcl-1 inhibitors for cancer therapy

Cited by 63 publications

References 159 publications

Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

Neutralizing Anti-IL-17A Antibody Demonstrates Preclinical Activity Enhanced by Vinblastine in Langerhans Cell Histiocytosis

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells

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