It is well known that chemotherapy and radiotherapy accelerate the aging process in cancer survivors. In fact, the incidence of age-associated diseases in cancer survivors is comparable to rates in the elderly.1 Anti-cancer agents damage DNA in both tumor cells and healthy tissue. This onslaught of DNA damage (known as genotoxic stress) overwhelms cellular repair capacity and activates a complex cascade of signaling pathways that can drive damaged cells toward apoptosis or senescence. Apoptosis and cellular senescence are failsafe mechanisms designed to limit the propagation of a damaged genome.2 Senescence, therefore, can be thought of as a built-in tumor suppression program that is triggered by cellular stress. Unfortunately, senescent cells tend to remain senescent, causing chronic inflammation, and inducing senescence in adjacent cells. The overall impact is that senescent cells promote aging and the development of age-associated health conditions, including cancer.3
Efforts to prevent senescence resulting from cancer treatment have led to the emerging field of senolytic drug development. The goal of potential senolytic drugs is to induce apoptosis in tumor cells or inhibit expression of the senescence-associated secretory phenotype (SASP). The SASP is characterized by complex cellular changes that upregulate the secretion of signaling molecules such as inflammatory cytokines, growth factors, and chemokines. Certain drugs have been approved for use in conjunction with chemotherapy or radiation to induce apoptosis in senescent tumor cells.4
Other substances are being studied experimentally for their potential anti-cancer activity. Standouts in this latter category include the flavonoids quercetin and fisetin. Both quercetin5
and fisetin6,7 have been studied pre-clinically for their ability to therapeutically target cellular senescence, in other words, induce apoptosis in senescent cells and spare healthy cells. In vitro studies of the senolytic properties of fisetin, which is closely related to quercetin but has a shorter half-life, have found that it has antiproliferative and proapoptotic effects.8
Some senolytic drugs, such as navitoclax, target a specific regulator protein within a network of anti-apoptotic pathways, to block an enzyme that prevents apoptosis.9 By contrast, the mechanism of action for both quercetin and fisetin appears to involve direct cytotoxic activity, which means they target senescent cells rather than anti-apoptotic pathways. As a result, they do not cause adverse effects. By contrast, navitoclax affects non-senescent cells such as platelets, which happen to express the same anti-apoptotic regulator protein it is designed to target, thereby causing thrombocytopenia.10
Pre-clinical studies have helped scientific understanding of cellular senescence grow significantly in the last few years. Hopefully, future clinical trials will shed light on how effective senotherapeutics can be in promoting healthy aging, increasing healthy lifespan, and improving long-term health outcomes for cancer survivors.
References
- https://www.jci.org/articles/view/158452
- https://pubmed.ncbi.nlm.nih.gov/33512317/
- https://pubmed.ncbi.nlm.nih.gov/30474843/
- https://www.sciencedirect.com/science/article/pii/S240580332030159X
- https://pubmed.ncbi.nlm.nih.gov/25754370/
- https://pubmed.ncbi.nlm.nih.gov/28273655/
- https://pubmed.ncbi.nlm.nih.gov/21922137/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9782831/
- https://pubmed.ncbi.nlm.nih.gov/26711051/
- https://pubmed.ncbi.nlm.nih.gov/33741395/