Clinical Review: Navitoclax as a Pro-Apoptotic and Anti-Fibrotic Agent

Abstract

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.

Keywords: B-cell lymphoma; anti-cancer agent; apoptosis; cancer; fibrosis; navitoclax (ABT-263).

FIGURE 1

BCL-2 family protein members. The BCL-2 family members are comprised of anti-apoptotic and pro-apoptotic proteins. Pro-apoptotic proteins are further categorized into three groups according to their functions: (A) Pro-apoptotic effectors = executioner proteins (B) Proapoptotic activators = BH3-only activators (C) Proapoptotic sensitizers = BH3-only sensitizers. BCL-2, B-cell lymphoma 2; BCL-X_L, B-cell lymphoma-extra-large; MCL-1, Myeloid cell leukemia; A1, BCL-2 related protein A1. Adapted from Shamas-Din et al. (2013).

FIGURE 2

Summary of B-cell lymphoma 2 (BCL-2) family proteins mechanism of actions. Initiation of death signal is through the binding of BH3-only proapoptotic proteins either into the hydrophobic groove of antiapoptotic BCL-2 family or executioner proteins, leading to executioner proteins activation and oligomerization. This results in mitochondrial outer membrane permeabilization, cytochrome c release and activation of caspase activity. Eventually, cell death is observed. However, cell apoptosis is inhibited by anti-apoptotic proteins through the suppression of executioner proteins activities and blocking cytochrome c released.

FIGURE 3

Apoptotic mechanism of navitoclax on tumor cells. Left: Classical apoptotic pathway of B-cell lymphoma 2 (BCL-2) family proteins. Right: Potentiation of apoptotic activity in the presence of navitoclax. Navitoclax affinity on antiapoptotic BCL-2 proteins are varied. MOMP, mitochondrial outer membrane permeabilization.

FIGURE 4

Mechanism of B-cell lymphoma-extra-large (BCL-X_L) inhibitor in diminishing liver fibrosis. PSC, Primary sclerosing cholangitis; PDGF, Platelet-derived growth factor; ECM, extracellular matrix.