Critical roles of tyrosyl‐DNA phosphodiesterases in cell tolerance to carnosol‐induced DNA damage

Abstract

Carnosol is a natural compound with pharmacological action due to its anti‐cancer properties. However, the precise mechanism for its anti‐carcinogenic effect remains elusive. In this study, we used lymphoblastoid TK6 cell lines to identify the DNA damage and repair mechanisms of carnosol. Our results showed that carnosol induced DNA double‐strand breaks (DSBs). We also found that cells lacking tyrosyl‐DNA phosphodiesterase 1 (TDP1), an enzyme related to topoisomerase 1 (TOP1), and tyrosyl‐DNA phosphodiesterase 2 (TDP2), an enzyme related to topoisomerase 2 (TOP2), were supersensitive to carnosol. Carnosol was found to induce the formation of the TOP1‐DNA cleavage complex (TOP1cc) and TOP2‐DNA cleavage complex (TOP2cc). When comparing the accumulation of γ‐H2AX foci and the number of chromosomal aberrations (CAs) with wild‐type (WT) cells, the susceptivity of the TDP1−/− and TDP2−/− cells were associated with an increased DNA damage. Our results provided evidence of carnosol inducing DNA lesions in TK6 cells and demonstrated that the damage induced by carnosol was associated with abnormal topoisomerase activity. We conclude that TDP1 and TDP2 play important roles in the anti‐cancer effect of carnosol.

Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases

“…Interestingly, carnosol has also been described as one of the compounds with the best induction of HO-1/low cytotoxicity profile in BV2 microglial cells in vitro (121). Nevertheless, a recent study has indicated that carnosol induces DNA damage, although this activity is associated with abnormal topoisomerase activity in lymphoblastoid TK6 cells (122). Importantly, these compounds have the lowest cytotoxicity when compared to other compounds such as allyl isothiocyanate (ITC) or caffeic acid phenethyl ester (CAPE) (121).…”

Targeting DNA repair pathways: mechanisms and potential applications in cancer therapy

“…Carnosol is a natural compound that has anticancer activity; however, the mechanism of its anticancer effects remains unclear. More recently, carnosol was found to induce the formation of both TOP1cc and TOP2cc (Feng et al 2020). 4-Nitroquinoline-1-oxide (4NQO), a compound that has been shown to be hypersensitive to BLMdeficient cells, induces higher levels of Top1cc formation in BLM-deficient cells than it does in BLM-complemented cells (Miao et al 2006).…”