Spermidine antagonizes the anti-cancer effect of cold atmospheric plasma and induces transit G0/G1 cell cycle arrest of triple negative breast cancers

Cancer remains as a global health threat, with the incidence of breast cancers keep increasing. Dis-regulated redox homeostasis has been considered with essential roles for tumor initiation and progression. Using triple negative breast cancers, the most malignant subtype of breast cancers, as the tumor model, we explored the roles of the anti-oxidant spermidine, the pro-oxidative tool cold atmospheric plasma (CAP), and their combined use in cancer growth, anti-oxidative ability and cell cycle. We also characterized the important roles of FTO in driving the redox modulatory functionalities of spermidine and CAP-activated medium (PAM) as well as their demonstrated synergy on breast cancer cells. We found that spermidine reversed the anti-cancer effect of PAM and stimulated outrageous progression of transformed cells to the level exceeding that treated with spermidine alone, and combined launch of spermidine and PAM enabled cancer cells with elevated anti-oxidant ability and enhanced survival in response to instant redox perturbation via transient stalk at the G0/G1 stage. We, in addition, identified the vital role of FTO in mediating the observed effect of spermidine, PAM and their synergy, on triple negative breast cancer cells. Our results reported the antagonism between PAM and anti-oxidants as represented by spermidine for cancer treatment, and implicated the differential responses of healthy and diseased individuals to anti-oxidants for improved design on redox-based anti-cancer regimen.