Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer

Abstract

The dynamic interplay between pro-death and pro-survival Bcl-2 family proteins is responsible for a cell’s fate. Due to the recognized relevance of this family in cancer progression and response to therapy, different efforts have made in recent years in order to develop small molecules able to target anti-apoptotic proteins such as Bcl-2, Bcl-xL and Mcl-1. The limitations of the first Bcl-2 family targeted drugs, regarding on-target and off-target toxicities, have been overcome with the development of venetoclax (ABT-199), the first BH3 mimetic inhibitor approved by the FDA. The purpose of this review is to discuss the state-of-the-art in the development of drugs targeting Bcl-2 anti-apoptotic proteins and to highlight the potential of their application as single agents or in combination for improving anti-cancer therapy, focusing in particular on solid tumors.

BCL2L10 Is Overexpressed in Melanoma Downstream of STAT3 and Promotes Cisplatin and ABT-737 Resistance

“…Otherwise, these therapeutic attempts are bound to fail, as happened with the therapies targeting BCL2 or BCL2/Bcl-xL in tumors rich in MCL1 [ 48 , 49 , 50 , 51 ]. The surveying of anti-apoptotic Bcl-2 proteins in different tumor types led to a focus on the members more frequently expressed: BCL2, Bcl-xL, and MCL1 [ 11 , 52 ]. In contrast, our knowledge of the function of the other three members of the family (Bcl-w, Bfl-1, and BCL2L10) has lagged behind.…”

“…Given its important role in cancer progression, anti-apoptotic members of the Bcl-2 family have been studied as therapeutic targets in cancer, first by using antisense oligonucleotides against BCL2 and Bcl-xL, and more recently by using the small molecule compounds called BH3-mimetics since they emulate the function of the BH3-only proteins. Currently, several BH3-mimetics are being evaluated as single agents or combined with other compounds in clinical trials for a wide number of tumor types, including melanoma [ 11 ].…”

Molecular stratification by BCL2A1 and AIM2 provides additional prognostic value in penile squamous cell carcinoma

“…Regarding the molecular mechanism, the knockdown of AIM2 significantly decreased BCL2A1 expression via the NF-κB pathway, suggesting that BCL2A1 is a dominant downstream oncogene that is not only regulated by AIM2 but also independently influences the progression of PSCC. Therefore, selective BCL2 inhibitors, such as venetoclax, which has been shown to be effective against hematological malignancies 45 , might be an option for targeted treatment, particularly for patients with BCL2A1-positive PSCC. In addition, the MAPK pathway plays a crucial role in cell proliferation, differentiation, and apoptosis in various tumors 46 .…”

Regulation of Apoptosis by the Bcl-2 Family of Proteins: Field on a Brink

“…The current Special Issue of Cells , “Regulation of Apoptosis by the Bcl-2 Family of Proteins”, gives a sense of the recent advances in all aspects of apoptotic regulation, ranging from in vitro biophysical characterization, through in vivo cellular studies, to preclinical and clinical studies of cancer treatments. The contributions to this Special Issue include three original articles, employing sophisticated techniques to gain important insights into the mechanisms of apoptotic regulation [ 1 , 2 , 3 ]; a thought-provoking perspective article [ 4 ] and two conceptual reviews, discussing state-of-the-art developments in drugs targeting anti-apoptotic Bcl-2 proteins [ 5 , 6 ]. Despite the collection of articles not encompassing all aspects of apoptosis, the following two general themes can be clearly identified.…”

“…Inhibiting the inhibitor has been the main approach in the development of cancer therapeutics targeting the Bcl-2 family. Two reviews describe current progress with applications of BH3 mimetic inhibitors, such as a drug recently approved by the FDA, venetoclax (ABT-199), which restores apoptosis and primes malignant cells for death [ 5 , 6 ]. Another important aspect of the functioning of the Bcl-2 proteins is the involvement of family members in various cellular processes and interactions, not directly related to MOMP.…”