Therapy-induced senescence in normal fibroblasts promotes in vitro tumour cell growth and invasiveness: study of the role of Quercetin in modulating these processes.

Aging is a complex biological phenomenon representing the major risk factor for developing agerelated diseases, such as cardiovascular pathologies, neurodegenerative diseases, and cancer. Geroscience, the new vision of gerontology, identifies cellular senescence as an interconnected biological process that characterises aging and age-related diseases. Therefore, many strategies have been employed in the last years to reduce the harmful effects of senescence, such as senolytic drugs that selectively kill senescent cells, or senomorphic ones that interfere with the production of the senescence-associated secretory phenotype (SASP) factors. Here we show that a pre-treatment with Quercetin, a bioactive flavonoid present in many fruits and vegetables, increasing cellular antioxidant defence, can reduce Doxorubicin (Doxo)-induced cellular senescence in human normal WI-38 fibroblasts. Moreover, exerting an excellent senomorphic action, Quercetin reduces the SASP and consequently reduces the pro-tumour effects of conditioned medium (CM) from Doxo-induced senescent fibroblasts on Osteosarcoma cells. Furthermore, we also analyse the effect of Quercetin after the induction of senescence to investigate its senolytic activity, and we show that it can reduce the number of Doxo-induced senescent fibroblasts without affecting the proliferating ones, even if more investigations about the mechanism of action are necessary. Finally, our data show that, also in this condition, the treatment with Quercetin can cancel the pro-tumour effects of Doxo-induced senescent fibroblasts CM on U2OS cells. Overall, our findings demonstrate that Quercetin is an excellent senomorphic agent and a potential senolytic substance that can protect normal fibroblasts against the off-target induction of senescence by the chemotherapy drug Doxorubicin, and it can potentially eliminate the formed senescent cells, reducing their pro-tumour and deleterious effects on Osteosarcoma cells.