Caspase-dependent Mcl-1 cleavage and effect of Mcl-1 phosphorylation in ABT-737-induced apoptosis in human acute lymphoblastic leukemia cell lines

Ryu, Yongku; Hall, Connor P.; Reynolds, C. Patrick; Kang, Min H.

doi:10.1177/1535370214538745

Cited by 13 publications

(8 citation statements)

References 53 publications

(126 reference statements)

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“…Bim) other than the proteins assessed in this study may affect ABT-737 in vitro responsiveness. In agreement with published data [ 57 , 58 ], we demonstrated that increasing concentrations of ABT-737 further decreased Bcl-xL and Mcl-1 expression only in MOLT-4, a sensitive cell line, inducing significant cell growth reduction and apoptosis at nanomolar concentration. By contrast, protein levels were not affected in CEM S cells, a resistant cell model, showing no significant changes of apoptosis induction even at micromolar doses.…”

Section: Discussionsupporting

confidence: 93%

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

et al. 2015

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Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL.

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Section: Discussionsupporting

confidence: 93%

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

et al. 2015

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“…This is because MCL-1 is one of the substrates of caspase 3. (39)(40)(41) The observed increase in caspase activation and cleavage of key apoptotic substrates reinforces the notion that co-targeting BCL-xL and BCL-2 for degradation induces a robust pro-apoptotic response in SCLC cells, ultimately leading to reduced cell viability.…”

Section: Discussionsupporting

confidence: 73%

PROTAC-mediated dual degradation of BCL-xL and BCL-2 is a highly effective therapeutic strategy in small-cell lung cancer

Khan,

Cao,

Wiegand

et al. 2024

Preprint

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BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216+venetoclax to reduce the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b leads to significant tumor growth delay similar to the DT2216+venetoclax combination in H146 xenografts by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. 753b at this dosage was well tolerated in mice without induction of severe thrombocytopenia as seen with navitoclax nor induced significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients warranting clinical trials in future.

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“…Another splicing factor, SRSF1, was not affected (data not shown). Because Mcl-1 can also be cleaved by caspases to generate a smaller protein fragment, ABT-737-treated cells were used as a positive control for caspase-mediated Mcl-1 cleavage (43). ABT-737 treatment resulted in the expected smaller fragment of approximately 22 kDa that was abrogated by co-treatment with caspase inhibitor Z-VAD-FMK.…”

Section: Saclac Alters the Ratio Of Pro-survival To Pro-apoptotic MCLmentioning

confidence: 99%

Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia

Pearson

Tan

Sharma

et al. 2020

Molecular Cancer Research

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Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. The 5-year survival rate is approximately 25%, and recent therapeutic developments have yielded little survival benefit. Therefore, there is an urgent need to identify novel therapeutic targets. We previously demonstrated that acid ceramidase (ASAH1, referred to as AC) is upregulated in AML and high AC activity correlates with poor patient survival. Here, we characterized a novel AC inhibitor, SACLAC, that significantly reduced the viability of AML cells with an EC50 of approximately 3 μmol/L across 30 human AML cell lines. Treatment of AML cell lines with SACLAC effectively blocked AC activity and induced a decrease in sphingosine 1-phosphate and a 2.5-fold increase in total ceramide levels. Mechanistically, we showed that SACLAC treatment led to reduced levels of splicing factor SF3B1 and alternative MCL-1 mRNA splicing in multiple human AML cell lines. This increased proapoptotic MCL-1S levels and contributed to SACLAC-induced apoptosis in AML cells. The apoptotic effects of SACLAC were attenuated by SF3B1 or MCL-1 overexpression and by selective knockdown of MCL-1S. Furthermore, AC knockdown and exogenous C16-ceramide supplementation induced similar changes in SF3B1 level and MCL-1S/L ratio. Finally, we demonstrated that SACLAC treatment leads to a 37% to 75% reduction in leukemic burden in two human AML xenograft mouse models. Implications: These data further emphasize AC as a therapeutic target in AML and define SACLAC as a potent inhibitor to be further optimized for future clinical development.

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Caspase-dependent Mcl-1 cleavage and effect of Mcl-1 phosphorylation in ABT-737-induced apoptosis in human acute lymphoblastic leukemia cell lines

Cited by 13 publications

References 53 publications

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

PROTAC-mediated dual degradation of BCL-xL and BCL-2 is a highly effective therapeutic strategy in small-cell lung cancer

Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia

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