B-cell lymphoma 2 (BCL-2) family proteins primarily work as a programmed cell death regulator, whereby multiple interactions between them determine cell survival. This explains the two major classes of BCL-2 proteins which are anti-apoptotic and pro-apoptotic proteins. The anti-apoptotic proteins are attractive targets for BCL-2 family inhibitors, which result in the augmentation of the intrinsic apoptotic pathway. BCL-2 family inhibitors have been studied extensively for novel targeted therapies in various cancer types, fibrotic diseases, aging-related as well as autoimmune diseases. Navitoclax is one of them and it has been discovered to have a high affinity toward BCL-2 anti-apoptotic proteins, including BCL-2, BCL-W and B-cell lymphoma-extra-large. Navitoclax has been demonstrated as a single agent or in combination with other drugs to successfully ameliorate tumor progression and fibrosis development. To date, navitoclax has entered phase I and phase II clinical studies. Navitoclax alone potently treats small cell lung cancer and acute lymphocytic leukemia, whilst in combination therapy for solid tumors, it enhances the therapeutic effect of other chemotherapeutic agents. A low platelet count has always associated with single navitoclax treatments, though this effect is tolerable. Moreover, the efficacy of navitoclax is determined by the expression of several BCL-2 family members. Here, we elucidate the complex mechanisms of navitoclax as a pro-apoptotic agent, and review the early and current clinical studies of navitoclax alone as well as with other drugs. Additionally, some suggestions on the development of navitoclax clinical studies are presented in the future prospects section.

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.

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Navitoclax is an effective pro-apoptotic agent against cancer cells. Uncontrolled cell survival is a hallmark of pathological angiogenesis in cancer and could promote plaque instability that contributes to atherosclerosis progression owing to intraplaque neovascularization. Cancer cell inhibition by navitoclax can restrain metastasis; therefore, it is possible to reduce endothelial cells survival and is expected to confer a novel therapeutic strategy for advanced atherosclerosis in regards to plaque instability. However, regulation of endothelial cell activity by navitoclax is yet to be examined. This study will analyze navitoclax efficacy in modulating human umbilical vein endothelial cells (HUVEC) viability, proliferation, migration and angiogenesis. Navitoclax concentrations ranging from 0.2 to 3.0µM at four-time points; 18-, 24-, 48- and 72-hours were used for MTT assay. The IC50 value for 18-hours post-treatment was undefined due to low efficacy at a limited time. While for 24-, 48- and 72-hours, the IC50 values were 0.91µM, 0.72µM, and 0.12µM, respectively. Navitoclax potency to inhibit HUVEC viability increased as the treatment time elevated. 0.9µM navitoclax for 24 hours treatment was selected for subsequent experiments. Next, 25 ng/ml IL-3 was used to induce the in-vitro angiogenesis model within 6 hours. Expectedly, navitoclax reduced the tube formation and migration of HUVEC induced by IL-3 in consistent with CXCL-8 released and MMP-3 expression in the cell. However, HUVEC proliferative activity was not affected by navitoclax treatment, as well as the BCL-2 gene expression. Therefore, an anti-angiogenic effect of navitoclax on HUVEC by preventing the cell motility through CXCL-8 and MMP-3 mechanism is determined.