Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy

Abstract

According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. The identification of novel targets for cancer treatment is an area of intense work that has led Bcl-2 over-expression to be proposed as one of the hallmarks of cancer and Bcl-2 inhibition as a promising strategy for cancer treatment. In this review, we describe the different pathways related to programmed cell death, the role of Bcl-2 family members in apoptosis resistance to anti-cancer treatments, and the potential utility of Bcl-2 inhibitors to overcome resistance to chemo- and immunotherapy.

Immunotherapy: A Challenge of Breast Cancer Treatment

“…These findings have been the basis for the development of different modalities of anticancer immunotherapy, including tumor-targeting immunotherapies, oncolytic viruses, anticancer vaccines, or adoptive cell immunotherapies [24] that are designed to target tumor cells and work with the immune system at different levels ( Figure 2). As a result of the great success achieved in different studies and trials that demonstrate the efficacy of immunotherapies not only against primary tumors, but also preventing metastasis and recurrence [25], cancer immunotherapy has become the fourth pillar of cancer care, complementing surgery, cytotoxic therapy, and radiotherapy [26].…”

“…Another major impediment to immunotherapy success in breast cancer patients is the selection of apoptosis-resistant cells, which constitutes one of the hallmarks of cancer [17]. Since both chemo-and immunotherapies directly or indirectly activate the cellular apoptosis machinery, tumor sensitivity to anti-cancer treatments will significantly depend on the level of expression of anti-apoptotic proteins [24] in general and, more specifically, on the existence of a pro-survival profile characterized by an increased ratio between anti-/pro-apoptotic proteins [24,90,91].…”

“…Provided that antiapoptotic proteins such as clusterin (APO-J) [91,92], BCL-2, BMF [24] as well as different pro-survival kinases [8] are frequently altered in metastatic breast cancer, the use of profiling techniques or systematic mapping of anti-apoptotic gene dependencies would be justified in order to effectively select those patients that could better benefit from combined treatments of protein inhibitors and immunotherapy. In this regard, different studies have already evidenced the need to use therapies with a combination of inhibitors targeting different anti-apoptotic proteins in order to achieve better clinical benefits and avoid the activation of alternate pro-survival pathways [8,23,24].…”

BCL-2 antagonism sensitizes cytotoxic T cell–resistant HIV reservoirs to elimination ex vivo

“…In the oncology setting, the prosurvival BCL-2 family proteins have been identified as key factors in the resistance of many tumor cells to death (35)(36)(37)(38). BCL-2 antagonists, such as , have been developed as cancer therapies that aim to directly promote the apoptosis of tumor cells, which often overexpress BCL-2 (35)(36)(37)(38)(39)(40). By adding ABT-199 to our kick-and-kill cocultures, we were able to achieve the reductions in ex vivo HIV reservoirs that we have been unable to achieve with CTL and LRAs alone.…”

Anti-tumour effects of red blood cell membrane-camouflaged black phosphorous quantum dots combined with chemotherapy and anti-inflammatory therapy

“…As shown in Figure 5(C,D), DOX caused an upregulation of protein expression of Bax and Bcl-2 by 33% and 39%, respectively. It is well documented that upregulating anti-apoptotic protein Bcl-2 is a common mechanism in tumours to evade apoptosis [31]. With the combination of anti-inflammatory ingredient, KIR, the protein expression of Bax further increased by 85%, while Bcl-2 protein expression was significantly decreased by 63%.…”