Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

Abstract

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal β-galactosidase (SA-β-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-β-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells).Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclaxinduced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

“…There have been recent attempts to increase the specificity of Navitoclax to senescent cells by combining the drug with galactose. As senescent cells have higher levels of the galactosidase enzyme (SA β-galactosidase), the release of active Navitoclax is targeted to the senescent cells, potentially reducing platelet toxicity [ 93 ]. There are currently a few early phase clinical trials in progress, but unless the toxicity issue can be addressed it may not have a role in routine oncology practice.…”

Transient metabolic improvement in obese mice treated with navitoclax or dasatinib/quercetin

“…The description of the first senolytic treatments by the combination of dasatinib with quercetin in vitro [17], or the inhibitor of the Bcl-2 family of antiapoptotic proteins navitoclax [18], was followed by many other new, and still less studied senolytic compounds [19][20][21]. In general, senolytics have been used in mouse models to alleviate senescence-related diseases [16,[22][23][24] The use of senolytic compounds has been previously reported for the treatment of type 2 diabetes in mouse models. In particular, the combination of dasatinib and quercetin was used to alleviate metabolic dysfunction in diet-induced obese mice, attaining a reduction in the senescence markers SA-βGal and Cdkn2a-p16, and improved glucose and insulin tolerance tests [25].…”

Emerging use of senolytics and senomorphics against aging and chronic diseases

“…84 Cytotoxic drugs have also been targeted to senescent cells by conjugation with galactose or galacto-oligosaccharides. [85][86][87] In addition, local senolytic delivery to target organs, such as the articulations of osteoarthritic patients may also attenuate systemic side effects.…”