Molinaro Caroline, Wambang Nathalie, Bousquet Till, Vercoutter-Edouart Anne-Sophie, Pélinski Lydie, Cailliau Katia, Martoriati Alain
Univ. Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France.
AGAT Laboratories, Intertek, Montréal, QC, Canada.
Front Oncol. 2022 Feb 24;12:837373. doi: 10.3389/fonc.2022.837373. eCollection 2022.
Topoisomerases, targets of inhibitors used in chemotherapy, induce DNA breaks accumulation leading to cancer cell death. A newly synthesized copper(II) indenoisoquinoline complex WN197 exhibits a cytotoxic effect below 0.5 µM, on MDA-MB-231, HeLa, and HT-29 cells. At low doses, WN197 inhibits topoisomerase I. At higher doses, it inhibits topoisomerase IIα and IIβ, and displays DNA intercalation properties. DNA damage is detected by the presence of γH2AX. The activation of the DNA Damage Response (DDR) occurs through the phosphorylation of ATM/ATR, Chk1/2 kinases, and the increase of p21, a p53 target. WN197 induces a G2 phase arrest characterized by the unphosphorylated form of histone H3, the accumulation of phosphorylated Cdk1, and an association of Cdc25C with 14.3.3. Cancer cells die by autophagy with Beclin-1 accumulation, LC3-II formation, p62 degradation, and RAPTOR phosphorylation in the mTOR complex. Finally, WN197 by inhibiting topoisomerase I at low concentration with high efficiency is a promising agent for the development of future DNA damaging chemotherapies.
拓扑异构酶是化疗中所用抑制剂的作用靶点，可诱导DNA断裂积累，从而导致癌细胞死亡。一种新合成的铜（II）茚并异喹啉配合物WN197在低于0.5µM的浓度下对MDA-MB-231、HeLa和HT-29细胞表现出细胞毒性作用。在低剂量时，WN197抑制拓扑异构酶I。在高剂量时，它抑制拓扑异构酶IIα和IIβ，并表现出DNA嵌入特性。通过γH2AX的存在检测DNA损伤。DNA损伤反应（DDR）的激活通过ATM/ATR、Chk1/2激酶的磷酸化以及p53靶点p21的增加而发生。WN197诱导G2期阻滞，其特征为组蛋白H3的未磷酸化形式、磷酸化Cdk1的积累以及Cdc25C与14.3.3的结合。癌细胞通过自噬死亡，伴有Beclin-1积累、LC3-II形成、p62降解以及mTOR复合物中RAPTOR磷酸化。最后，WN197通过高效低浓度抑制拓扑异构酶I，是未来开发DNA损伤化疗药物的一种有前景的试剂。
