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.

Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition

“…We see that inhibition of BCR-ABL1, FLT3-ITD, or RAF1 causes cell cycle arrest in the G1 phase and that hydroxyurea causes S phase arrest. In contrast to TKi and hydroxyurea, navitoclax has no impact on cell cycle regulation, which is coherent with the expectation that inactivation of BCL-XL and further BCL2 proteins by this drug does not alter cell cycle progression [36]. Nonetheless, administration of navitoclax to hydroxyurea-treated cells was linked to a reduction in the S and G2/M phase cell populations.…”

“…These data made us hypothesize that inhibition of BCL-XL could sensitize K562 cells to hydroxyurea. To test this, we inactivated BCL-XL with the clinically tested drug navitoclax [36] in hydroxyurea-treated K562 cells. Flow cytometry revealed that navitoclax plus hydroxyurea caused apoptosis and DNA fragmentation in K562 cells (Figure 3b,c).…”

Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

“…Similar to D+Q, ABT-263 was successful in eliminating senescent cell populations in several disease models including aging-associated bone loss [87], radiation-induced lung fibrosis [88], lung emphysema [89], uterine leiomyoma [90], tau-dependent neurodegenerative disease [91], radiation-induced neurodegeneration [92], myocardial infarction (including ischemia-reperfusion injury) [93,94], heart failure [95], pulmonary hypertension [96], insulin resistance [97], osteoarthritis [98,99], synthetic implant-mediated fibrosis [100], and Duchenne muscular dystrophy [101]. ABT-263 is currently a cornerstone in preclinical studies of senolysis and remains a promising drug for use against both liquid and solid tumors [102][103][104].…”

Circular RNA: A novel type of biomarker for glioma (Review)

“…Apoptosis is mainly modulated via the caspase family of proteases and the B-cell lymphoma 2 (Bcl-2) family of intracellular proteins. Previous studies have demonstrated that circRNAs are pivotal modulators of a number of cell processes in glioma, including apoptosis ( 88 , 89 ). circRNAs can alter the extrinsic and intrinsic apoptotic pathways in several ways, resulting in a decrease in apoptosis or development of apoptosis resistance; these involve the injured death receptor pathway, alteration of the balance between anti-apoptotic and pro-apoptotic proteins of the Bcl-2 family, reduced caspase function and impaired p53 function ( 90 , 91 ).…”