An Example to Illustrate Why Navitoclax is Not a Suitable Clinical Senolytic Drug
Senolytic therapies are those that selectively destroy senescent cells. Cells that become senescent grow in size, cease to replicate, and generate a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). Senescence occurs at the Hayflick limit on cellular replication, or in response to cell damage and a toxic local environment. The SASP provokes the immune system into an inflammatory state, disrupts tissue structure and function, and encourages nearby cells to also become senescent. It is useful in the short term, in the context of wound healing and cancer suppression for example, but when present for the long-term, the SASP is an important cause of degenerative aging. A significant fraction of aging and age-related disease is driven by the accumulation of senescent cells throughout the body, and hence the research community is quite interested in finding ways to get rid of these errant cells.
The earliest discovered senolytic small molecule drugs are chemotherapeutics. It is fair to say that they are selective for senescent cells, but in some cases far from selective enough. They kill a lot of non-senescent cells and, further, cause all sorts of problematic and potentially serious side-effects. In addition, drugs such as the small molecules targeting Bcl-2 family proteins, particularly navitoclax, tend to require a few weeks of dosing at chemotherapeutic levels to generate senolytic effects. This is as opposed to the few doses or intermittent doses of the arguably more effective senolytic chemotherapeutic dasatinib. Less of a chemotherapeutic drug is almost always a good thing.
The open access paper I'll point out today provides an additional incentive to avoid navitoclax as a senolytic treatment. It does indeed kill senescent cells in aged tissues, but it is just too toxic, with too many harmful side-effects, for use in the clinic. This is the case, at least, without the use of one or more of the clever adaptations to limit its harms that have been proposed of late. Whether or not these approaches make it into clinical use is somewhat hit and miss, however, given that there are many other alternative senolytic therapies presently under development.
Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice.
This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its in vivo effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice.
Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (-60.1% females, -45.6% males), and bone marrow stromal cells (BMSC) derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (-88% females, -83% males). Moreover, in vitro administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated in vivo. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures.
Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax's potential (or risk) as a therapeutic agent for combating age-related musculoskeletal dysfunction and bone loss.