Mcl-1 Inhibitors as a Novel Class of Senolytic
Researchers working with prostate cancer cells here show that senescent cancer cells depend upon Mcl-1 to prevent programmed cell death, a novel target with existing drugs that may prove useful as general purpose senolytics, able to clear senescent cells from tissues. Cancers are highly varied, and this would have to be tested against the more usual types of senescent cell present in the aged body. Even if only applicable in the context of some cancers, however, this is still a useful discovery. Cancer survivors have a significantly reduced life expectancy in large part because they suffer a greatly increased burden of cellular senescence, and thus chronic inflammation, disruption of normal tissue function, and so forth. Efficient removal of those senescent cells would be beneficial.
Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype (SASP), and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy.
Most of the currently available senotherapies for cancers are still restricted to Bcl-2 targeting. Here, we describe a population of senescent prostate cancer tumor cells that do not rely on Bcl-2 to survive. This population of cells upregulates Mcl-1 and after treatment with the Bcl-2 inhibitor Navitoclax, remains still capable to promote tumorigenesis through the SASP. Thus, regardless of senescence heterogeneity, our analysis identified Mcl-1 as a ubiquitous target to effectively remove senescent tumor cells.
We show that the efficacy of Docetaxel treatment, a standard of therapy for metastatic prostate cancer patients, can be enhanced by the concomitant administration of Mcl-1 inhibitors both in vitro and in vivo. Furthermore, treatment with different Mcl-1 inhibitors resulted in the effective removal of senescent tumor cells and the complete abrogation of the bystander migratory phenotype, orchestrated by the SASP on non-senescent tumor cells, both in transgenic and xenograft models. Moreover, this combination of compounds was superior in terms of efficacy to the combination of Docetaxel with Navitoclax.
In sum, senescent cells are highly heterogenous, but ultimately rely on a common pro-survival factor, Mcl-1. Importantly, this study endorses Mcl-1 inhibitors as a class of highly effective senolytics. Interestingly, a previous study on breast cancer showed that the senolytic sensitivity of Navitoclax is controlled by NOXA, an inhibitor of Mcl-1. While senescent cells with a high level of NOXA respond to Navitoclax, cells with a low level are resistant to Navitoclax and respond to Mcl-1 inhibitor, thereby validating our results in a different system.
"Niclosamide is an FDA-approved drug that has been used for anti-tapeworm infections for approximately 50 years7. In recent years, niclosamide was found a potential anticancer drug against various cancers including human lung cancer8,9, ovarian cancer10, prostate cancer11,12, head and neck cancer13, osteosarcoma14 and breast cancer15,16 both in vivo and in vitro."
"In summary, our results show that niclosamide inhibited cell growth and enhanced drug sensitivity of HCC cells by suppressing the STAT3 signaling pathway and blocking the anti-apoptotic function of Mcl-1 and survivin in HCC cells. Niclosamide may be developed into a single and combined anticancer drug against HCC"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277621
A really interesting paper, and a nice way of showing the heterogeneity of senescent cells (analogous to cancer heterogeneity).
Mcl-1 inhibitors have had unacceptable cardiotoxicity, perhaps due to cardiomyocyte dependence on Mcl-1 for survival (e.g. https://jhoonline.biomedcentral.com/articles/10.1186/s13045-021-01079-1); the bigger picture of pursuing combinatorial senolytic therapy seems quite promising, though.