Targeting Mcl-1 and Other Bcl-2 Family Member Proteins in Cancer Therapy

Publication date: Available online 19 October 2018Source: Pharmacology & TherapeuticsAuthor(s): Ryuji Yamaguchi, Lydia Lartigue, Guy PerkinsAbstractRegulation of both the extrinsic and the mitochondria-dependent intrinsic apoptotic pathways plays a key role in the development of the hematopoietic system, for sustaining cell survival during generation of various cell types, in eliminating cells with dual identities such as CD4/CD8 double-positive cells1,2, for sustaining cells during the rapid clonal expansion phase3, as well as eliminating cells during the contraction phase4. The anti-apoptotic protein Mcl-1 is necessary for sustaining hematopoietic stem cells (HPS)5,6. The anti-apoptotic factors Mcl-1, Bcl-2, and Bcl-xL were also found to be over-expressed in acute myeloid leukemia (AML)7 and acute lymphocytic leukemia (ALL)8, suggesting that dis-regulated apoptotic processes could be a factor in the instigation of leukemia and/or its relapse. Molecules targeting these proteins were used as single agents to treat leukemia. However, by using a set of recently developed specific molecule inhibitors targeting anti-apoptotic proteins, distinct roles are being discovered for these anti-apoptotic proteins during hematopoietic and tumor development. Furthermore, using these inhibitors in proper combinations can effectively induce apoptosis in various solid tumors, even though each agent on its own cannot induce apoptosis in them. These new findings suggest that inhibiting anti-apop...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research