The BCL-2 protein family, BH3-mimetics and cancer therapy

Abstract

Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy

“…The latter, is an interesting observation that can be explained as an unsuccessful attempt of cells after the removal of carboranes form the culture to overcome the agent-triggered cell-cycle arrest mediated by p53/p21. Importantly enough, through these opposing molecular pathways impinging on to either proliferation and survival, or growth arrest and apoptosis [45][46][47], the treatment of glioblastoma U87 MG cultures with carboranes leads to a such functional balance in gene expression that permanently leads them to inability for cell cycling and division. Overall, these bifunctional acting Upper panels: The EGFR neg primary GBM CSCs, which grow in culture as monolayers, were treated at specified concentrations of BOR2, BOR3 and BOR4 for 48 h. Cell proliferation was assessed by the MTT assay, as described under A significance level of p < 0.05 denoted significance.…”

Biphasic regulation of InsP 3 receptor gating by dual Ca 2+ release channel BH3-like domains mediates Bcl-x L control of cell viability

“…Notable in this regard is the Bcl-2 protein family. Proapoptotic Bcl-2-related proteins Bax and Bak initiate cytochrome C release from mitochondria in response to diverse apoptotic stimuli, whereas antiapoptotic Bcl-2-related proteins, including Bcl-2 and Bcl-x L , antagonize Bax/Bak by forming heterodimers that prevent their oligomerization and apoptosis initiation (22,23). Heterodimerization is mediated by interactions of proapoptotic Bcl-2 homology 3 (BH3) domains with a hydrophobic groove on the surface of antiapoptotic Bcl-2 proteins (23) that is a therapeutic target in diseases, including cancer (22).…”

“…Proapoptotic Bcl-2-related proteins Bax and Bak initiate cytochrome C release from mitochondria in response to diverse apoptotic stimuli, whereas antiapoptotic Bcl-2-related proteins, including Bcl-2 and Bcl-x L , antagonize Bax/Bak by forming heterodimers that prevent their oligomerization and apoptosis initiation (22,23). Heterodimerization is mediated by interactions of proapoptotic Bcl-2 homology 3 (BH3) domains with a hydrophobic groove on the surface of antiapoptotic Bcl-2 proteins (23) that is a therapeutic target in diseases, including cancer (22). Whereas a central feature of molecular models of apoptosis is the control of outer mitochondrial membrane permeability by Bcl-2-related proteins, a substantial body of evidence has demonstrated that these proteins localize to the ER (24,25), bind to InsP 3 Rs (26)(27)(28)(29)(30)(31)(32) and, by modulating InsP 3 R-mediated Ca 2+ release, regulate ERmediated cell death and survival (15,27,(32)(33)(34).…”

K9(C4H4FN2O2)2Nd(PW11O39)2·25H2O induces apoptosis in human lung cancer A549 cells

“…The use of chemotherapy for the clinical management of lung cancer causes notable side effects (18,19); therefore, new effective drugs to treat lung cancer are required. Previous studies have shown that polyoxometalates exert their antitumor properties by regulating cell invasion, proliferation and migration in a variety of malignancies such as breast, kidney, lung, ovary, pancreas and prostate cancer (17).…”