Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Cell Biol Int. 2020 Aug;44(8):1640-1650. doi: 10.1002/cbin.11357. Epub 2020 Apr 28.
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.
龙吉酯是一种具有药理作用的天然化合物，因其具有抗癌特性而受到关注。然而，其抗癌作用的确切机制仍不清楚。在本研究中，我们使用淋巴母细胞 TK6 细胞系来确定龙吉酯的 DNA 损伤和修复机制。结果表明，龙吉酯诱导 DNA 双链断裂（DSBs）。我们还发现，缺乏与拓扑异构酶 1（TOP1）相关的酪氨酸-DNA 磷酸二酯酶 1（TDP1）和与拓扑异构酶 2（TOP2）相关的酪氨酸-DNA 磷酸二酯酶 2（TDP2）的细胞对龙吉酯更为敏感。龙吉酯诱导 TOP1-DNA 断裂复合物（TOP1cc）和 TOP2-DNA 断裂复合物（TOP2cc）的形成。与野生型（WT）细胞相比，当比较 γ-H2AX 焦点的积累和染色体畸变（CA）的数量时，TDP1 和 TDP2 细胞的敏感性与增加的 DNA 损伤相关。我们的结果提供了龙吉酯在 TK6 细胞中诱导 DNA 损伤的证据，并表明龙吉酯诱导的损伤与异常拓扑异构酶活性有关。我们得出结论，TDP1 和 TDP2 在龙吉酯的抗癌作用中发挥重要作用。
