A team of researchers have explained in Aging how multiple compounds that target the BCL-2 protein family are considerably more effective against senescent cells than each compound by itself [1].
The limitations of existing senolytics
The researchers begin their paper with a familiar discussion of senescent cells and their dangers, citing a 2019 paper outlining their effects on a panoply of age-related diseases [2]. The paper then discusses methods of eliminating these cells, focusing on the BCL-2 family of proteins, which prevent senescent cells from eliminating themselves: they are anti-apoptotic. ABT-737 and its more orally bioavailable cousin, ABT-263 (navitoclax), target some, but not all, of these proteins [3] by mimicking proteins that promote apoptosis..
However, navitoclax diminishes the number of blood platelets (thrombocytopenia), making it dangerous to use at high doses [4]. It also does not target the full BCL-2 family of proteins, most notably MCL-1. Therefore, the researchers sought to determine if navitoclax could be made more effective when taken in combination with an MCL-1 inhibitor.
Many doses, many tests
To begin their experiment, the researchers used homoharringtonine (HHT), a non-specific MCL-1 inhibitor, in conjunction with navitoclax and ABT-737 on a wide variety of senescent cells. These included multiple quiescent and proliferating cells along with cells that were driven senescent through chemicals, radiation, and cancer-related gene expression.
HHT is a cellular killer (a cytotoxin). Worse, it preferentially kills proliferating, rather than senescent, cells. However, moderate doses of HHT in conjunction with navitoclax had a synergistic effect, significantly increasing the ability of navitoclax to preferentially kill senescent, rather than proliferating, cells.
With these results in hand, the researchers moved on to a less dangerous MCL-1 inhibitor: MIK665. This is a drug that has been studied as a potential cancer treatment [5] but, on its own, is not effective as a senolytic. However, when testing it in conjunction with the BCL-2 inhibitors, the researchers were able to find doses that significantly increased the ability of navitoclax to preferentially remove senescent cells, regardless of whether that senescence was induced by radiation or drugs.
The team then examined three other inhibitors: ABT-199 (venetoclax), which only targets BCL-2 itself, A1331852, which targets BCL-XL, and S63845, another inhibitor of MCL-1. Similar results were found here as well: each of the first two compounds was found to work in synergy with the third, providing much more senolytic power than either has by itself.
Further analysis confirmed the researchers’ results, showing that cells that are resistant to BCL-2 inhibitors exhibit increased amounts of MCL-1. The researchers note that senescent cells are naturally heterogenous in this way, showing that it is necessary to defeat all of the potential methods of self-preservation in order to completely remove a population of senescent cells.
Conclusion
This is a cellular in vitro study that was not conducted in an animal model; therefore, it has yet to be seen whether or not its findings will be found to hold true in mice, let alone people. However, these findings are particularly promising, and such experiments are certainly worth conducting. It may be that such a combination, or even a more detailed combination with a broader range of targets, will succeed where previous senolytic therapies have failed.
Literature
[1] Rysanek, D., Vasicova, P., Kolla, J. N., Sedlak, D., Andera, L., Bartek, J., & Hodny, Z. Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells. Aging, 14(undefined).
[2] Myrianthopoulos, V., Evangelou, K., Vasileiou, P. V., Cooks, T., Vassilakopoulos, T. P., Pangalis, G. A., … & Gorgoulis, V. G. (2019). Senescence and senotherapeutics: a new field in cancer therapy. Pharmacology & therapeutics, 193, 31-49.
[3] Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., … & Elmore, S. W. (2008). ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer research, 68(9), 3421-3428.
[4] Knight, T., Luedtke, D., Edwards, H., Taub, J. W., & Ge, Y. (2019). A delicate balance–The BCL-2 family and its role in apoptosis, oncogenesis, and cancer therapeutics. Biochemical pharmacology, 162, 250-261.
[5] Wei, A. H., Roberts, A. W., Spencer, A., Rosenberg, A. S., Siegel, D., Walter, R. B., … & Stein, A. (2020). Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood reviews, 44, 100672.
