More on PI3K Inhibitors as Senolytic Drugs

Senolytic drugs selectively clear senescent cells from aged tissues. They are variably effective in different stages of cellular senescence, origins of cellular senescence, and tissue types, as senescent cells vary widely in the details of their biochemistry. We might expect a near future clinical marketplace to feature a dozen or more senolytic therapies, each of which is tailored to specific circumstances and age-related conditions. One of the interesting use cases is to destroy the senescent cancer cells that remain in the body after chemotherapy and other forms of cancer treatment. This will likely require somewhat different senolytics from those used to clear cells that become senescent in other contexts. As an example of this sort of research, scientists here explore the senolytic abilities of PI3K inhibitor drugs in cancer cells.

The targeted elimination of radiotherapy-induced or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells.

Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib)) and PI3K class delta (with CAL-101 (Idelalisib)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21WAF1/CIP1 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.


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