In addition to Bcl-2, navitoclax also inhibits the relatedBcl-xL andBcl-w proteins.[3] Because navitoclax inhibits Bcl-xL, it reducesplatelet lifespan, causingthrombocytopenia, and this makes it dose-limiting.[4][5] A 2020 article published inAging Cell details the synthesis of Nav-Gal (navitoclax-galactose), a novelprodrug via galacto-conjugation of navitoclax and its superiority. The prodrug reduces thrombocytopenia in treated mice at therapeutically effective doses, as well as apoptosis of platelets in human blood samples treatedex vivo. Nav-Gal is efficient for selective senolysis and is passively taken up by both non-senescent and senescent cells.[6]
Inanimal studies, navitoclax was found to be asenolytic agent, inducingapoptosis insenescent, but not non-senescent cells.[7] Oral administration of navitoclax (ABT-263) to either sublethally irradiated or normally aged mice reduced senescent cells, including senescentbone marrowhematopoietic stem cells and senescent muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice.[8]
On September 19, 2018, an article was published inNature about using navitoclax to kill senescentglial cells in mice. The drug had a protective effect against memory loss in mice genetically engineered tosimulateAlzheimer's disease.[9]
On December 3, 2024, an article was published inAging detailing a study investigating the effects of topical navitoclax (ABT-263) on aged mouse skin. It examined whether eliminating senescent cells could improvewound healing. In the study, 24-month-old mice were treated with topical navitoclax (ABT-263) for five days. The treatment reduced the expression of senescence markersp16 andp21 and decreased the number ofSA-β-gal– and p21-positive cells compared withDMSO controls. Navitoclax (ABT-263) application also induced a transient inflammatory response andmacrophage infiltration. Bulk RNA sequencing revealed upregulation of genes involved in wound-healing pathways, includinginflammation,angiogenesis,collagen synthesis, andextracellular matrix remodeling. Mice pre-treated with navitoclax (ABT-263) exhibited faster wound closure, suggesting that topical senolytic treatment may enhance skin repair by reducing senescent cell burden.[10]
Additionally, an ongoing global multi-center,randomized,open-label, phase 3 study evaluating efficacy and safety of navitoclax in combination withruxolitinib versus best available therapy in adult patients with relapsed/refractorymyelofibrosis was initiated on 31 August 2020. The study is expected to conclude in 2026.[17]
Not directly related to cancer, rather as a therapy forscleroderma, navitoclax appeared to reduce existingfibrosis through inducing apoptosis ofmyofibroblasts.[18] Further research is required to elucidate the exact mechanisms and confirm studies.
^Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. (March 2015). "Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy".Science Translational Medicine.7 (279): 279ra40.doi:10.1126/scitranslmed.aaa4642.PMID25787766.S2CID206686917.
^Tolcher, Anthony (2015). "Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with in patients with advanced solid tumors. Cancer Chemother Pharmacol".Cancer Chemotherapy and Pharmacology.76 (5):1025–1032.doi:10.1007/s00280-015-2883-8.PMID26420235.S2CID23878408.
