Targeting Bcl-2 Family Proteins: What, Where, When?

Proteins of the Bcl-2 family are known as regulators of apoptosis, one of the most studied forms of programmed cell death. The Bcl-2 protein family is represented by both pro- and antiapoptotic members. Antiapoptotic proteins are often exploited by tumor cells to avoid their death, thus playing an important role in carcinogenesis and in acquisition of resistance to various therapeutic agents. Therefore, antiapoptotic proteins represent attractive targets for cancer therapy. A detailed investigation of interactions between Bcl-2 family proteins resulted in the development of highly selective inhibitors of individual antiapoptotic members. These agents are currently being actively studied at the preclinical and clinical stages and represent a promising therapeutic strategy, which is highlighted by approval of venetoclax, a selective inhibitor of Bcl-2, for medical use. Meanwhile, inhibition of antiapoptotic Bcl-2 family proteins has significant therapeutic potential that is yet to be revealed. In the coming era of precision medicine, a detailed study of the mechanisms responsible for the sensitivity or resistance of tumor cells to various therapeutic agents, as well as the search for the most effective combinations, is of great importance. Here, we discuss mechanisms of how the Bcl-2 family proteins function, principles of their inhibition by small molecules, success of this approach in cancer therapy, and, eventually, biochemical features that can be exploited to improve the use of Bcl-2 family inhibitors as anticancer drugs.

Nutrient Deprivation Promotes MCL-1 Degradation in an Autophagy-Independent Manner.

The antiapoptotic protein Mcl-1, which is an attractive target for cancer treatment, is degraded under nutrient deprivation conditions in different types of cancer. This process sensitizes cancer cells to chemotherapy. It has been found that nutrient deprivation leads to suppression of Mcl-1 synthesis; however, the mechanisms of Mcl-1 degradation under such conditions remain to be elucidated. In this study, we have investigated the contribution of autophagy and proteasomal degradation to the regulation of the level of Mcl-1 protein under nutrient deprivation conditions. We found that these circumstances cause a decrease in the level of Mcl-1 in cancer cells in a macroautophagy-independent manner via proteasomal degradation.

[Nutrient restriction in combinatory therapy of tumors].

The main objective of anticancer treatment is the elimination of degenerated cells by the induction of programmed cell death. Various chemotherapy drugs and radiation are able to activate cell death mechanisms in tumors. However, unfortunately, monotherapy will always be insufficiently effective because of the variety and virulence of tumors, as well as their ability to develop resistance to drugs. Moreover, monotherapy might constrain many negative side effects. Therefore, the combination of different approaches and/or drugs will increase the efficiency of treatment. One such promising approach is the combination of nutrient restriction (NR) and various chemotherapeutic drugs. This approach may not only affect the autophagy but also influence apoptotic cell death. This review is focused on the potential of NR use in anticancer therapy, as well as the molecular mechanisms underlying this approach.