For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.

Targeting apoptosis in cancer therapy

Apoptosis, or programmed cell death, plays a pivotal role in the elimination of unwanted, damaged, or infected cells in multicellular organisms and also in diverse biological processes, including development, cell differentiation, and proliferation. Apoptosis is a highly regulated form of cell death, and dysregulation of apoptosis results in pathological conditions including cancer, autoimmune and neurodegenerative diseases. The Bcl-2 family proteins are key regulators of apoptosis, which include both anti- and pro-apoptotic proteins, and a slight change in the dynamic balance of these proteins may result either in inhibition or promotion of cell death. Execution of apoptosis by various stimuli is initiated by activating either intrinsic or extrinsic pathways which lead to a series of downstream cascade of events, releasing of various apoptotic mediators from mitochondria and activation of caspases, important for the cell fate. In view of recent research advances about underlying mechanism of apoptosis, this review highlights the basics concept of apoptosis and its regulation by Bcl-2 family of protein. Furthermore, this review discusses the interplay of various apoptotic mediators and caspases to decide the fate of the cell. We expect that this review will add to the pool of basic information necessary to understand the mechanism of apoptosis which may implicate in designing better strategy to develop biomedical therapy to control apoptosis.

Role of Bcl-2 family proteins and caspases in the regulation of apoptosis.

Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells

A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.

Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins.

Although the presence of a BH4 domain distinguishes the antiapoptotic protein Bcl-2 from its proapoptotic relatives, little is known about its function. BH4 deletion converts Bcl-2 into a proapoptotic protein, whereas a TAT-BH4 fusion peptide inhibits apoptosis and improves survival in models of disease due to accelerated apoptosis. Thus, the BH4 domain has antiapoptotic activity independent of full-length Bcl-2. Here we report that the BH4 domain mediates interaction of Bcl-2 with the inositol 1,4,5-trisphosphate (IP3) receptor, an IP3-gated Ca 2+ channel on the endoplasmic reticulum (ER). BH4 peptide binds to the regulatory and coupling domain of the IP3 receptor and inhibits IP3-dependent channel opening, Ca 2+ release from the ER, and Ca 2+ -mediated apoptosis. A peptide inhibitor of Bcl-2-IP3 receptor interaction prevents these BH4-mediated effects. By inhibiting proapoptotic Ca 2+ signals at their point of origin, the Bcl-2 BH4 domain has the facility to block diverse pathways through which Ca 2+ induces apoptosis.

https://www.pnas.org/content/pnas/106/34/14397.full.pdf

The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor

Promises and challenges of targeting Bcl-2 anti-apoptotic proteins for cancer therapy.

Cancer cells with elevated levels of Bcl-2 and the related anti-apoptotic proteins Bcl-x(L), Mcl-1 and Bcl-W are broadly resistant to standard anticancer drugs and other therapeutic modalities. Antisense oligodeoxynucleotides and, more recently, small-molecule ligands for Bcl-2 and Bcl-x(L), sensitize cancer cells to cytotoxic therapies. In some cases, Bcl-2-targeted therapies can function as single therapeutic agents to kill tumor cells, suggesting that Bcl-2 has an important role in the critical functions of cancer cells. The molecular mechanisms of Bcl-2 are not completely understood, therefore, the validation of cytotoxic mechanisms related to Bcl-2 as well as the identification of surrogate markers for Bcl-2 function are significant obstacles for drug development. Despite these problems, two Bcl-2 small-molecule inhibitors are currently undergoing phase I/II clinical trials and several other compounds are in preclinical development. Ongoing studies with these investigational drugs should provide new insights into optimal strategies to disrupt Bcl-2 survival functions to selectively kill cancer cells.

Pam S. Schwartz

Papers

Promises and challenges of targeting Bcl-2 anti-apoptotic proteins for cancer therapy.

Small-molecule inhibitors of Bcl-2.