Apoptosis’ activation associated to BH3 only domain and BCL-2 homology domain proteins: new way to design anti-cancer drugs

Abstract

Cancer is one of the leading health problems we face today. A possible way to develop specific treatments is through the identification and understanding of proteins responsible for the regulation of apoptosis. Apoptosis is a cell suicide that is critically important for organ development and tissue turnover.1 The BCL-2 homology domain (BHD) and BH3-only domain (BOD) are pro-apoptotic proteins that mediate mitochondrial damage, inducing intrinsic pathway cell death. This review wants to explain how BOD and BHD proteins trigger mitochondrial events associated to apoptosis to develop treatments that can promote apoptosis in cancer cells.

Characterization of BCL-XL, MCL-1, and BAX Protein Expression in Response to Neoadjuvant Chemotherapy in Breast Cancer

“…43 While some proapoptotic proteins take the form of amphipathic α-helices, conserved in only 1 domain, α-helices interact with BCL homology domains of the active site, leading to the formation of BAX/BAK interaction and mitochondrial permeabilization. 43 Normally, pro-cell death proteins are in an inactive state. 41 When a cell is challenged with a stressful stimulus, the expression of BCL homology domain proteins such as BAX and BAK is increased.…”

“…41 When a cell is challenged with a stressful stimulus, the expression of BCL homology domain proteins such as BAX and BAK is increased. 42,43 Then, BAX and BAK, dimerize and are inserted into the mitochondrial membrane, resulting in increased permeability of the mitochondrial membrane and releasing cytochrome c protein from the mitochondria. 14 On the other hand, BCL-2 and BCL-X L maintain the mitochondrial impermeability to cytochrome c by binding to BAX and preventing it from penetrating through the mitochondrial membrane.…”

“…Pro-cell death proteins comprise 2 subgroups, BCL homology domains (ie, BAK, BAX, Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1 or NOXA proteins), and p53 upregulated modulator of apoptosis (PUMA) and BH3-only domain (ie, BIM and BID) 42 . Both pro-cell death proteins (particularly BCL homology domains) and anti-cell death proteins share four similar structural domains and soluble C-terminal regions 43 . While some pro-apoptotic proteins take the form of amphipathic α-helices, conserved in only 1 domain, α-helices interact with BCL homology domains of the active site, leading to the formation of BAX/BAK interaction and mitochondrial permeabilization 43 .…”

“…Both pro-cell death proteins (particularly BCL homology domains) and anti-cell death proteins share four similar structural domains and soluble C-terminal regions 43 . While some pro-apoptotic proteins take the form of amphipathic α-helices, conserved in only 1 domain, α-helices interact with BCL homology domains of the active site, leading to the formation of BAX/BAK interaction and mitochondrial permeabilization 43 . Normally, pro-cell death proteins are in an inactive state 41 .…”

Key genes and drug delivery systems to improve the efficiency of chemotherapy

“…The cellular outcome of undergoing intrinsic apoptosis or surviving depends on the balance and interaction between the pro- and anti-apoptotic proteins inside the cell. These Bcl-2 proteins show four homologous domains in their sequence (BH1, BH2, BH3, and BH4) and are called BCL-2 homology motifs [ 63 , 64 ] , except the BH3-only proteins; Bim, Bid, and Bad. Genetic alterations associated with cancer and tumor growth often affect programmed cell death regulation in a way that favors cell proliferation [ 65 ] .…”