Abstract
Deregulated cellular apoptosis is a hallmark of cancer and chemotherapy resistance. The B-cell lymphoma 2 (BCL-2) protein family members are sentinel molecules that regulate the mitochondrial apoptosis machinery and arbitrate cell fate through a delicate balance between pro- and anti-apoptotic factors. The recognition of the anti-apoptotic BCL2 gene as an oncogenic driver in hematological malignancies has directed attention toward unraveling the biological significance of each of the BCL-2 superfamily members in cancer progression and garnered interest in the targeting of apoptosis in cancer therapy. Accordingly, the approval of venetoclax (ABT-199), a small molecule BCL-2 inhibitor, in patients with chronic lymphocytic leukemia and acute myeloid leukemia has become the proverbial torchbearer for novel candidate drug approaches selectively targeting the BCL-2 superfamily. Despite the inspiring advances in this field, much remains to be learned regarding the optimal therapeutic context for BCL-2 targeting. Functional assays, such as through BH3 profiling, may facilitate prediction of treatment response, development of drug resistance and shed light on rational combinations of BCL-2 inhibitors with other branches of cancer therapy. This review summarizes the pathological roles of the BCL-2 family members in cancer, discusses the current landscape of their targeting in clinical practice, and highlights the potential for future therapeutic inroads in this important area.
Highlights
Apoptosis from the Chemotherapy LensChemotherapy resistance in cancer has been attributed to multiple mechanisms, which often act in concert [1,2]
In diffuse large B-cell lymphoma (DLBCL), concomitant overexpression of B-cell lymphoma 2 (BCL-2) and MYC is classified as a “double-hit” DLBCL, which is associated with a dismal prognosis, high risk for relapse, resistance to standard chemotherapy and justifies upfront escalation to more intensive treatment
A mild to moderate increase in intracellular superoxide anion has been shown to impact the phosphorylation status of BCL-2, at S70 via the generation of peroxynitrite. This involves peroxynitrite mediated nitrative modification of the regulatory subunit B56δ of the protein phosphatase 2A (PP2A), which prevents holoenzyme assembly and results in the sustained S70 phosphorylation of BCL-2 to stabilize its anti-apoptotic activity [35]. These findings provide evidence for an intricate crosstalk between BCL-2 and cellular redox metabolism, thereby delineating a novel facet in the biology of this death regulatory protein with potential therapeutic implications
Summary
Chemotherapy resistance in cancer has been attributed to multiple mechanisms, which often act in concert [1,2]. This repertoire includes altering drug transport through influx/efflux pumps such as ATP-binding cassette transporters [3] and P-glycoprotein overexpression [1]. Dysregulation of drug-induced autophagy and apoptosis has been recognized as a key mechanism of carcinogenesis and chemotherapy resistance, whereby the surviving cancer cell continues to accumulate oncogenic mutations which further propagate tumor progression [6]. We discuss the roles of the BCL-2 superfamily in carcinogenesis and treatment resistance, and review the successes and failures of strategies targeting the BCL-2 family members in cancer therapy
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