Abstract
Current understanding points to unrepairable chromosomal damage as the critical determinant of accelerated senescence in cancer cells treated with radiation or chemotherapy. Nonetheless, the potent senescence inducer etoposide not only targets topoisomerase II to induce DNA damage but also produces abundant free radicals, increasing cellular reactive oxygen species (ROS). Toward examining roles for DNA damage and oxidative stress in therapy-induced senescence, we developed a quantitative flow cytometric senescence assay and screened 36 redox-active agents as enhancers of an otherwise ineffective dose of radiation. While senescence failed to correlate with total ROS, the radiation enhancers, etoposide and the other effective topoisomerase inhibitors each produced high levels of lipid peroxidation. The reactive aldehyde 4-hydroxy-2-nonenal, a lipid peroxidation end product, was sufficient to induce senescence in irradiated cells. In turn, sequestering aldehydes with hydralazine blocked effects of etoposide and other senescence inducers. These results suggest that lipid peroxidation potentiates DNA damage from radiation and chemotherapy to drive therapy-induced senescence.
Highlights
Accelerated senescence (AS) is considered a form of premature cellular aging characterized by irreversible proliferative arrest accompanied by characteristic changes in gene expression, metabolism and cell morphology
Median fluorescence intensities for duplicate microwell samples were calculated and averaged, and SA-β-Gal and AF measurements were expressed as S:B ratios comparing the lipid peroxidation (LPO) is correlated with the extent of AS induced by IR and topoisomerase inhibitors To better understand potential links between redox-modulating compounds, topoisomerase inhibitors and senescence, we further examined the cellular reactive oxygen species (ROS) levels detected with the violet probe Calcein Violet at 450 nm (CV450) in the cytometric screen (Figure 3a)
A role for free radicals is still recognized in cell senescence, this is typically ascribed to induction of single- and double-strand DNA breaks
Summary
Accelerated senescence (AS) is considered a form of premature cellular aging characterized by irreversible proliferative arrest accompanied by characteristic changes in gene expression, metabolism and cell morphology. Even though cancer cells resist RS due to re-expression of telomerase, significant levels of unrepairable DNA damage can successfully induce AS in these cells.[4] Laboratory and clinical evidence show that conventional cancer treatments including chemotherapy and radiation induce AS in tumors,[5,6] a process termed therapy-induced senescence (TIS). The aldehydescavenging compound hydralazine HCl (HYD)[21,22] prevented senescence induction by etoposide and other topoisomerase inhibitors, including camptothecin and doxorubicin. These findings provide insight into a new mechanism underlying cellular senescence, and may provide a mechanistic basis by which etoposide and other agents can efficiently promote TIS
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