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During the last two decades, the study of Mcl-1, an anti-apoptotic member of the Bcl-2 family, attracted researchers due to its important role in cancer cell survival and tumor development. The significance of Mcl-1 protein in resistance to chemotherapeutics makes it an attractive target in cancer therapy. Here, we discuss the diverse possibilities for indirect Mcl-1 inhibition through its downregulation, for example, via targeting for proteasomal degradation or blockage of translation and transcription. We also provide an overview of the direct blocking of protein-protein interactions with pro-apoptotic Bcl-2 family proteins, including examples of the most promising regulators of Mcl-1 and selective BH3-mimetics, which at present are under clinical evaluation. Moreover, several approaches for the co-targeting of Mcl-1 and other proteins (e.g., CDKs) are also presented. In addition, we highlight the broad spectrum of problems that accompanied the discovery and development of effective Mcl-1 inhibitors., (© 2020 Elsevier Inc. All rights reserved.)

Among cell death regulators, members of the Bcl-2 family are of interest because they are highly conserved across species and represent promising targets for anticancer therapy. This family and its associated proteins include more than 25 members, with either anti- or proapoptotic functions. Although the overall regulation of apoptosis by Bcl-2 family proteins is now well understood, targeted therapy requires careful consideration of individual members of the family and their crosstalk. One of the most studied representatives of the Bcl-2 family is antiapoptotic Mcl-1. After 25 years of investigations, a large amount of data regarding Mcl-1's regulation and functions has been compiled. In this review, we summarize current knowledge about Mcl-1, focusing on molecular aspects relevant to Mcl-1-targeted therapies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background The development of approaches that increase therapeutic effects of anti-cancer drugs is one of the most important tasks of oncology. Caloric restriction in vivo or serum deprivation (SD) in vitro has been shown to be an effective tool for sensitizing cancer cells to chemotherapeutic drugs. However, the detailed mechanisms underlying the enhancement of apoptosis in cancer cells by SD remain to be elucidated. Methods Flow cytometry, caspase activity assay and western blotting were used for cell death rate evaluation. Western blotting, gel-filtration, siRNA approach and qRT-PCR were used to elucidate the mechanism underlying cell death potentiation upon SD. Results We demonstrated that SD sensitizes cancer cells to treatment with chemotherapeutic agent cisplatin. This effect is independent on activation of caspases-2 and -8, apical caspases triggering apoptosis in response to genotoxic stress. SD potentiates cell death via downregulation of the anti-apoptotic protein Mcl-1. In fact, SD reduces the Mcl-1 mRNA level, which consequently decreases the Mcl-1 protein level and renders cells more susceptible to apoptosis induction via the formation of apoptosome. Conclusions Mcl-1 protein is an important regulator of sensitivity of cancer cells to apoptotic stimuli upon SD. General significance This study identifies Mcl-1 as a new target for the sensitization of human cancer cells to cell death by SD, which is of great significance for the development of efficient anti-cancer therapies. [ABSTRACT FROM AUTHOR]