Targeting the Bcl-2 family for cancer therapy

Abstract

Introduction Programmed cell death is well-orchestrated process regulated by multiple pro-apoptotic and anti-apoptotic genes, particularly those of the Bcl-2 gene family. These genes are well documented in cancer with aberrant expression being strongly associated with resistance to chemotherapy and radiation. Areas covered This review focuses on the resistance induced by the Bcl-2 family of anti-apoptotic proteins and current therapeutic interventions currently in preclinical or clinical trials that target this pathway. Major resistance mechanisms that are regulated by Bcl-2 family proteins and potential strategies to circumvent resistance are also examined. Although antisense and gene therapy strategies are used to nullify Bcl-2 family proteins, recent approaches use small molecule inhibitors and peptides. Structural similarity of the Bcl-2 family of proteins greatly favors development of inhibitors that target the BH3 domain, called BH3 mimetics. Expert opinion Strategies to specifically identify and inhibit critical determinants that promote therapy-resistance and tumor progression represent viable approaches for developing effective cancer therapies. From a clinical perspective, pretreatment with novel, potent Bcl-2 inhibitors either alone or in combination with conventional therapies hold significant promise for providing beneficial clinical outcomes. Identifying small molecule inhibitors with broader and higher affinities for inhibiting all of the Bcl-2 pro-survival proteins will facilitate development of superior cancer therapies.

Members of the microRNA-200 family are promising therapeutic targets in cancer

“…Therefore, decreased tumor blood supply combined with lower chemotherapy drug delivery may reduce the sensitivity of cancer cells to chemotherapy, resulting in the development of chemoresistance. The B-cell lymphoma 2 (Bcl-2) protein family is associated with multi-drug resistance (53). One of the most important and common features of tumor cells is resistance to apoptosis signaling, which generates multi-drug resistance (53).…”

“…The B-cell lymphoma 2 (Bcl-2) protein family is associated with multi-drug resistance (53). One of the most important and common features of tumor cells is resistance to apoptosis signaling, which generates multi-drug resistance (53). The miR-200 family is able to reduce resistance to apoptosis and drugs in cancer cells by targeting Bcl-2 (54).…”

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“…Cancerous cells undergo uninterrupted mitosis as they are capable of evading the Apoptotic machineries. BCL-2 family proteins play a major role in the regulation of apoptosis 44 . Amphipathic α-helical BH3 segment is a -death domain‖ which mediates the interaction between BCL-2 members.…”

The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer

“…Many of these approaches have mechanistic potential to enhance radiation induced lethal damage within the tumour cell and are presented in table 1 [21][22][23][24][25][26][27][28]. It should be noted that a number of studies examining the combination of novel or targeted agents with radiotherapy in NSCLC are underway [29].…”