Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

Abstract

Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues.

Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells

“…Thus, senescent cancer cell can be perceived as potentially dangerous, cancer dormant cell that might, under certain circumstances, lead to tumor recurrence. Fortunately, senescent cells might be selectively eliminated by compounds called senolytics, which target prosurvival as well as antiapoptotic pathways active in senescent cells [ 54 , 55 , 56 ]. So far, a number of studies have shown that senolytics are effective in treatment of age-related diseases.…”

Nutraceutical Approaches of Autophagy and Neuroinflammation in Alzheimer’s Disease: A Systematic Review

“…After activation of senescence, senescent cells need to be cleared from the organism, so that they do not accumulate. This can be achieved by either selectively destroying those (as done by senolytic drugs) or inhibiting their function (senostatic drugs) [ 25 ].…”

“…In recent years, it has achieved the image of a functional food and is promoted to prolong lifespan and counter various effects of aging. Apart from its antioxidant abilities, fisetin has been studied for its wide ranging effects on a number of key pathways involved in cell cycle regulation, apoptosis, the suppression of inflammation, angiogenesis, and metastasis [ 25 ]. In vivo, fisetin has been found to enhance long-term memory in non-AD mice (orally administered, 10–25 mg/kg) [ 70 ].…”

“…Senolytic flavonoids such as quercitin and fisetin act in part by inhibiting BCL-2 family members such as BCL-xL as well as HIF-1a and other senescent cell anti- apoptotic pathway (SCAP) network components. In comparison to other flavonoids, fisetin is twice as potent as quercetin in its senolytic properties [ 25 , 28 ].…”

Senescent Cells: A Potential Target for New Cancer Therapies in Older Oncologic Patients

“…Senolytic drugs might improve physical function and survival at old age as well [ 6 ]. Wyld et al describe navitoclax, fisetin, dasatinib/quercetin, Hsp90 inhibitors, and metformin as potential senolytic and senostatic drugs [ 7 ]. Also, panobinostat, authophagy modulators, and cardiac glycosides are discussed by Saleh et al as potential senotherapies [ 3 ].…”