Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors: Figure 1.

Gores, Gregory J.; Kaufmann, Scott H.

doi:10.1101/gad.186189.111

Cited by 78 publications

(72 citation statements)

References 45 publications

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“…4,6 Second, the observation that antiapoptotic BCL2 family members preferentially impact BH3-only tolerance provides an explanation for the ability of a short-lived BCL2 family member like MCL1 to modulate apoptosis so effectively. 4,55 Third, the observation that individual antiapoptotic BCL2 paralogs affect tolerances of various BH3-only proteins somewhat differently (Figure 4e) provides additional support for the notion that antiapoptotic BCL2 family members have somewhat specialized functions (e.g., Noxa binding preferentially to MCL1 over BCL2) 29,37 rather than being equivalent. Finally, our observation that apoptotic tolerances are affected more by overexpression of antiapoptotic BCL2 family members than by downregulation of BH3-only family members also provides a potential biochemical explanation for the observation that amplification of the BCLX and MCL1 genes is much more common than mutation or deletion of genes encoding BH3-only proteins during cancer development.…”

Section: Discussionmentioning

confidence: 71%

Measurement of BH3-only protein tolerance

et al. 2017

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The BCL2 family of proteins regulates cellular life and death decisions. Among BCL2 family members, BH3-only proteins have critical roles by neutralizing antiapoptotic family members, as well as directly activating BAX and BAK. Despite widespread occurrence of BH3-only protein upregulation in response to various stresses, this process is rarely quantified. Moreover, it is unclear whether all BH3-only proteins are equipotent at inducing cell death. Here we show that BH3-only proteins increase as much as 15-to 20-fold after various treatments and define a parameter, termed BH3-only tolerance, which measures how many copies of a particular BH3-only protein can be expressed before the majority of cells in a population undergo apoptosis. We not only assess the relative contributions of anti-and proapoptotic BCL2 family members to BH3-only tolerance, but also illustrate how the study of this parameter can be used to understand cellular sensitivity to anticancer drugs and new combinations. These observations provide a new quantitative framework for assessing apoptotic susceptibility under various conditions.

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Section: Discussionmentioning

confidence: 71%

Measurement of BH3-only protein tolerance

et al. 2017

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“…MCL-1 is a short-lived protein with a complex regulation, including transcriptional and translational control, as well as the involvement of different E3 ligases and deubiquitinating enzymes. 13,31 It may also be regulated by its interaction with some BH3-only proteins, particularly NOXA. 32 We therefore exposed H1299 cells to TW-37 in the presence of ABT-737, which resulted in the induction of NOXA but not BIM or PUMA (Figure 6c and data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…The BCL-2-specific inhibitors, ABT-263 and ABT-199, are ineffective against other anti-apoptotic BCL-2 family members, such as MCL-1 and BCL2A1, which are often associated with chemoresistance. 7,[12][13][14] Many attempts have been made to inhibit MCL-1 by alteration of its transcriptional, translational or post-translational regulatory mechanisms. 12,13,31 In this study, we have evaluated the specificity of putative MCL-1 inhibitors to inhibit MCL-1.…”

Section: Discussionmentioning

confidence: 99%

“…7,[12][13][14] Many attempts have been made to inhibit MCL-1 by alteration of its transcriptional, translational or post-translational regulatory mechanisms. 12,13,31 In this study, we have evaluated the specificity of putative MCL-1 inhibitors to inhibit MCL-1. Although MCL-1 is structurally similar to other BCL-2 family members, there are differences in its BH3-binding grove, resulting in a lower affinity of commonly available BCL-2 antagonists.…”

Section: Discussionmentioning

confidence: 99%

“…Of the different BCL-2 family members, MCL-1 is commonly amplified in human tumours and is often associated with tumour relapse and chemoresistance, particularly to ABT-737 and ABT-263. 7,[11][12][13][14] These findings highlight an urgent need to find either specific MCL-1 inhibitors or pan-BCL-2 family inhibitors, which could be valuable in treating resistant tumours.…”

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Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-X L but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak-and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2-or BCL-X L -dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

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Apoptosis and Necrosis in the Liver

Guicciardi

Malhi

Mott

et al. 2013

Comprehensive Physiology

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324

248

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Because of its unique function and anatomical location, the liver is exposed to a multitude of toxins and xenobiotics, including medications and alcohol, as well as to infection by hepatotropic viruses, and therefore, is highly susceptible to tissue injury. Cell death in the liver occurs mainly by apoptosis or necrosis, with apoptosis also being the physiologic route to eliminate damaged or infected cells and to maintain tissue homeostasis. Liver cells, especially hepatocytes and cholangiocytes, are particularly susceptible to death receptor-mediated apoptosis, given the ubiquitous expression of the death receptors in the organ. In a quite unique way, death receptor-induced apoptosis in these cells is mediated by both mitochondrial and lysosomal permeabilization. Signaling between the endoplasmic reticulum and the mitochondria promotes hepatocyte apoptosis in response to excessive free fatty acid generation during the metabolic syndrome. These cell death pathways are partially regulated by microRNAs. Necrosis in the liver is generally associated with acute injury (i.e., ischemia/reperfusion injury) and has been long considered an unregulated process. Recently, a new form of “programmed” necrosis (named necroptosis) has been described: the role of necroptosis in the liver has yet to be explored. However, the minimal expression of a key player in this process in the liver suggests this form of cell death may be uncommon in liver diseases. Because apoptosis is a key feature of so many diseases of the liver, therapeutic modulation of liver cell death holds promise. An updated overview of these concepts is given in this article.

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Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors: Figure 1.

Cited by 78 publications

References 45 publications

Measurement of BH3-only protein tolerance

Measurement of BH3-only protein tolerance

Evaluation and critical assessment of putative MCL-1 inhibitors

Apoptosis and Necrosis in the Liver

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