MCL-1 Inhibition by Selective BH3 Mimetics Disrupts Mitochondrial Dynamics Causing Loss of Viability and Functionality of Human Cardiomyocytes

Rasmussen, Megan L.; Taneja, Nilay; Neininger, Abigail C.; Wang, Lili; Robertson, Gabriella L.; Riffle, Stellan; Shi, Linzheng; Knollmann, Björn C.; Burnette, Dylan T.; Gama, Vivian

doi:10.1016/j.isci.2020.101015

Cited by 53 publications

(46 citation statements)

References 64 publications

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“…Milani and coworkers showed that several BH3 mimetics (ABT-199, A1331852, A1210477) induced mitochondrial fission and apoptosis in a Drp1-dependent manner (Milani et al 2019 , 2017 ). Appropriately, the treatment of human cardiomyocytes with the MCL-1 inhibitor S63845 resulted in Drp1-dependent mitochondrial fragmentation (Rasmussen et al 2020 ). Conversely, Drp1 siRNA or the negative mutant Drp1 K38A did not affect the ability of the BI97CIqa and BI112D1, derivatives of GP, to induce mitochondrial fragmentation in the non-small cell lung cancer cell line H23 (Varadarajan et al 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro

et al. 2021

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A major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melanoma cells and the underlying biochemical mechanisms. To prevent undesired side effects due to toxicity on normal (healthy) cells, concentrations only toxic for tumor cells have been elaborated. Viability assays were performed to determine the cytotoxicity of GP in A375 melanoma and normal (healthy) cells. For the majority of experiments, a concentration of 2.5 µM GP was used resulting in a ROS-independent but caspase-dependent cell death of A375 melanoma cells. At this level, GP was non-toxic for normal human epidermal melanocytes. GP has a very short half-life, however, it was demonstrated that only the “parent” compound and not decomposition products are responsible for the cytotoxic effect in A375 melanoma cells. GP significantly decreased mitochondrial membrane potential accompanied by a Drp1-dependent loss of mitochondrial integrity (fragmentation) in tumor cells. Taken together, GP induced a ROS-independent intrinsic apoptosis leading to the conclusion that within a specific concentration range, GP may work as effective anticancer drug without harmful side effects.

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Section: Discussionmentioning

confidence: 99%

The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro

et al. 2021

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“…MCL1 is highly expressed in the myocardium and is crucial for mitochondrial homeostasis and the induction of autophagy in cardiomyocytes 141 . Deficiency of MCL1 in murine hearts leads to rapid and fatal cardiomyopathy 28 , 29 , and inhibition of MCL1 in human cardiomyocytes results in a severe contractile defect 142 . Furthermore, deletion of MCL1 triggers the loss of hematopoietic stem cells, lymphocytes, and neutrophils 138 , 143 – 145 .…”

Section: Targeting Mcl1 In Cancer Treatmentmentioning

confidence: 99%

Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

Luo

Liu

2020

Cell Death Dis

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MCL1 is an important antiapoptotic member of the BCL-2 family that is distinguishable from other family members based on its relatively short half-life. Emerging studies have revealed the crucial role of MCL1 in the chemoresistance of cancer cells. The antiapoptotic function of MCL1 makes it a popular therapeutic target, although specific inhibitors have begun to emerge only recently. Notably, emerging studies have reported that several E3 ligases and deubiquitinases modulate MCL1 stability, providing an alternate means of targeting MCL1 activity. In addition, the emergence and development of proteolysis-targeting chimeras, the function of which is based on ubiquitination-mediated degradation, has shown great potential. In this review, we provide an overview of the studies investigating the ubiquitination and deubiquitination of MCL1, summarize the latest evidence regarding the development of therapeutic strategies targeting MCL1 in cancer treatment, and discuss the promising future of targeting MCL1 via the ubiquitin–proteasome system in clinical practice.

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“…The Axion Biosystems analyzer was used to measure contractility and impedance in hiCMs as described previously (Rasmussen et al, 2020). Recordings were taken for 5 min at baseline and after 2 hr of drug treatment.…”

Section: Methodsmentioning

confidence: 99%

“…The Axion Biosystems analyzer was used to measure contractility and impedance in hiCMs as described previously (Rasmussen et al, 2020).…”

Section: Impedance Assaysmentioning

confidence: 99%

Inhibition of focal adhesion kinase increases myofibril viscosity in cardiac myocytes

et al. 2020

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The coordinated generation of mechanical forces by cardiac myocytes is required for proper heart function. Myofibrils are the functional contractile units of force production within individual cardiac myocytes. At the molecular level, myosin motors form cross-bridges with actin filaments and use ATP to convert chemical energy into mechanical forces. The energetic efficiency of the cross-bridge cycle is influenced by the viscous damping of myofibril contraction. The viscoelastic response of myofibrils is an emergent property of their individual mechanical components. Previous studies have implicated titin-actin interactions, cell-ECM adhesion, and microtubules as regulators of the viscoelastic response of myofibrils. Here we probed the viscoelastic response of myofibrils using laser-assisted dissection. As a proof-of-concept, we found actomyosin contractility was required to endow myofibrils with their viscoelastic response, with blebbistatin treatment resulting in decreased myofibril tension and viscous damping. Focal adhesion kinase (FAK) is a key regulator of cell-ECM adhesion, microtubule stability, and myofibril assembly. We found inhibition of FAK signaling altered the viscoelastic properties of myofibrils. Specifically, inhibition of FAK resulted in increased viscous damping of myofibril retraction following laser ablation. This damping was not associated with acute changes in the electrophysiological properties of cardiac myocytes. These results implicate FAK as a regulator of mechanical properties of myofibrils.

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MCL-1 Inhibition by Selective BH3 Mimetics Disrupts Mitochondrial Dynamics Causing Loss of Viability and Functionality of Human Cardiomyocytes

Cited by 53 publications

References 64 publications

The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro

The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro

Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

Inhibition of focal adhesion kinase increases myofibril viscosity in cardiac myocytes

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