Combination Therapy of Navitoclax with Chemotherapeutic Agents in Solid Tumors and Blood Cancer: A Review of Current Evidence

Abstract

Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

“…Cellular sensitivity to BH-3 mimetics is dictated not only by the presence of anti-apoptotic BCL-2 family proteins, but also by the activities of pro-apoptotic BCL-2 family proteins [ 46 ]. Although the dependency on BCL-xL is often caused by alterations in the expression of other BCL-2 family proteins, such as MCL-1 and NOXA [ 24 , 47 , 48 ], the combination of everolimus and gemcitabine in malignant meningioma cells did not consistently alter the expression of these proteins in the present study. Further studies are needed to elucidate the mechanisms underlying the increases in BCL-xL dependency induced by this combination in malignant meningioma cells.…”

Navitoclax Enhances the Therapeutic Effects of PLK1 Targeting on Lung Cancer Cells in 2D and 3D Culture Systems

“…Navitoclax, as a single agent, has demonstrated limited outcomes in clinical trials on particular cancer types, namely acute lymphocytic leukemia (ALL) and advanced small cell lung cancer (SCLC), probably due to different expression levels of the BCL-2 family proteins, being thrombocytopenia and neutropenia the most adverse events [48,49]. Compared to its potent antitumor efficacy in preclinical studies, the efficacy of BI2536 as a single agent in clinical studies was moderate, namely in patients with NSCLC, advanced exocrine adenocarcinoma of the pancreas, and different types of lymphoma [14,50,51].…”

Bcl-xL activity influences outcome of the mitotic arrest

“…These observations corroborate with previous reports on navitoclax ( Chen et al, 2011 ; Shi et al, 2011 ; Tan et al, 2011 ; Bah et al, 2014 ). However, navitoclax is not specific–it also inhibits Bcl-2 ( Shi et al, 2011 ) and induces significant side-effects in humans killing proliferating hematopoietic cells ( Gandhi et al, 2011 ; Gupta et al, 2021 ; Nor Hisam et al, 2021 ). Our data show that nanomolar concentrations of A-1155643 and A-13331852 have the same efficacy as navitoclax on cultured cancer cells inducing DiM in highly resistant A549 and PC-3 cells.…”