Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane

Wolf, Philipp; Schoeniger, Axel; Edlich, Frank

doi:10.1016/j.bbamcr.2022.119317

Cited by 79 publications

(37 citation statements)

References 168 publications

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“…While hematologic cancer cell lines were on average more sensitive to ANJ810 treatment than solid tumor cells, sensitivity to ANJ810 was observed across tumor indications, and we propose the ratio of BCL-xL to BAK mRNA as a potential biomarker for patient stratification in ongoing and future MCL1 inhibitor trials. This biomarker profile is in line with earlier studies and resonates with the understanding that BCL-xL can compensate for MCL1 loss, while BAK is a pro-apoptotic protein required to induce the intrinsic apoptotic pathway [46][47][48] .…”

Section: Discussionsupporting

confidence: 88%

ANJ810 is a novel highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

Rauh¹,

Wei

Serrano‐Wu³

et al. 2023

Preprint

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MCL1 is an anti-apoptotic protein that is frequently amplified in cancer and confers resistance to current standard of care. Therefore, MCL1 is an attractive anti-cancer target. Here we describe ANJ810 as a novel, potent, and selective MCL1 inhibitor and its key design principle of a rapid systemic clearance to potentially minimize AUC-driven toxicities associated with MCL1 inhibition. ANJ810 induced rapid cell killing within 4 hours in vitro but in the same 4-hour window had no impact on cell viability or troponin I release in hiPSC-derived cardiomyocytes, even at supra-pharmacologic concentrations. In vivo ANJ810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of ANJ810 in plasma. In totality our data support the hypothesis that short-term inhibition of MCL1 with ANJ810 can induce cell apoptosis in tumor cells while maintaining an acceptable safety profile. We therefore intend to advance ANJ810 to clinical trials.

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Section: Discussionsupporting

confidence: 88%

ANJ810 is a novel highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

Rauh¹,

Wei

Serrano‐Wu³

et al. 2023

Preprint

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“…Bcl-2 blocks cytochrome c and apoptosis-inducing factor release ( 59 ). Bax, conversely, increases the permeability of the outer mitochondrial membrane and promotes the release of apoptotic factors ( 60 – 62 ). From the results in Figure 4 , MLZD alleviates mitochondrial-associated apoptosis and regulates the expression of apoptosis-related proteins to near-physiological levels.…”

Section: Discussionmentioning

confidence: 99%

Modified Linggui Zhugan Decoction protects against ventricular remodeling through ameliorating mitochondrial damage in post-myocardial infarction rats

Xiang

Zhao

et al. 2023

Front. Cardiovasc. Med.

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IntroductionModified Linggui Zhugan Decoction (MLZD) is a Traditional Chinese Medicine prescription developed from Linggui Zhugan Decoction (LZD) that has been used for the clinical treatment of ischemic cardiovascular diseases. However, the cardioprotective mechanism of MLZD against post-myocardial infarction (MI) ventricular remodeling remains unclear.MethodsWe explored the effects of MLZD on ventricular remodeling and their underlying mechanisms, respectively, in SD rats with MI models and in H9c2 cardiomyocytes with oxygen-glucose deprivation (OGD) models. The cardiac structure and function of rats were measured by echocardiography, HE staining, and Masson staining. Apoptosis, inflammation, mitochondrial structure and function, and sirtuin 3 (SIRT3) expression were additionally examined.ResultsMLZD treatment significantly ameliorated cardiac structure and function, and thus reversed ventricular remodeling, compared with the control. Further research showed that MLZD ameliorated mitochondrial structural disruption, protected against mitochondrial dynamics disorder, restored impaired mitochondrial function, inhibited inflammation, and thus inhibited apoptosis. Moreover, the decreased expression level of SIRT3 was enhanced after MLZD treatment. The protective effects of MLZD on SIRT3 and mitochondria, nevertheless, were blocked by 3-TYP, a selective inhibitor of SIRT3.DiscussionThese findings together revealed that MLZD could improve the ventricular remodeling of MI rats by ameliorating mitochondrial damage and its associated apoptosis, which might exert protective effects by targeting SIRT3.

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“…As a complex regulator, apoptosis plays an important role in maintaining development and homeostasis ( 40 ). The apoptosis mechanism imbalance is associated with various diseases; the most concerning is carcinogenesis and malignant tumor occurrence and development ( 34 ).…”

Section: The Carcinogenic Effect Of Mfap2 and Its Mechanismsmentioning

confidence: 99%

The role of microfibrillar‐associated protein 2 in cancer

Wang

Bai

et al. 2022

Front. Oncol.

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Microfibrillar-associated protein 2 (MFAP2), a component of the extracellular matrix, is important in controlling growth factor signal transduction. Recent studies have shown that MFAP2, an effective prognostic molecule for various tumors, is associated with tumor occurrence and development and may be involved in remodeling the extracellular matrix and regulating proliferation, apoptosis, invasion, tumor cell metastasis, and tumor angiogenesis. However, MFAP2’s specific mechanism in these tumor processes remains unclear. This article reviewed the possible mechanism of MFAP2 in tumorigenesis and progression and provided a reference for the clinical prognosis of patients with cancer and new therapeutic target discovery.

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Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane

Cited by 79 publications

References 168 publications

ANJ810 is a novel highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

ANJ810 is a novel highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

Modified Linggui Zhugan Decoction protects against ventricular remodeling through ameliorating mitochondrial damage in post-myocardial infarction rats

The role of microfibrillar‐associated protein 2 in cancer

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