An HDAC/PI3K Inhibitor Shows Potential as a Senolytic Drug
Researchers are discovering new senolytic drugs at a fairly steady pace. These compounds can selectively destroy senescent cells, though their efficacy varies widely, both generally and by origin and tissue of senescent cell. It requires the destruction of a sizable fraction of the burden of senescent cells in aged tissues to produce the rapid, sizable rejuvenation observed in mice treated with the best of the senolytics discovered to date. Senolytics that clear only a small fraction of lingering senescent cells are far less interesting.
The study noted here is an example of the sort of early stage discovery taking place in this part of the field, with researchers presenting in vitro data only on their drug of interest. Animal data arrives later, if at all: evidence of efficacy in destroying senescent cells in a cell culture often fails to translate to efficacy in destroying senescent cells in a living mammal.
The accumulation of senescent cells has an important role in the phenotypical changes observed in ageing and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated.
Given the involvement of histone deacetylases (HDACs and the PI3K pathway in senescence, we hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53. Consistent with this, CUDC-907 showed senolytic properties in different cell models of stress-induced senescence.
Our results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, our results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved.