溶解循环
DNA损伤
生物
细胞生长
DNA修复
细胞周期
细胞周期检查点
癌症研究
DNA
DNA复制
雷达51
细胞
细胞生物学
病毒
病毒学
遗传学
作者
Andrea Arena,Maria Saveria Gilardini Montani,Maria Anele Romeo,Rossella Benedetti,Aurelia Gaeta,Mara Cirone
标识
DOI:10.1016/j.bbamcr.2021.119168
摘要
The induction of DNA damage together with the interference with DNA repair represents a promising strategy in cancer treatment. Here we show that the PARP-1/2/3 inhibitor AZD2461 in combination with the CHK1 inhibitor UCN-01 altered the DNA damage response and reduced cell proliferation in PEL cells, an aggressive B cell lymphoma highly resistant to chemotherapies. AZD2461/UCN-01 combination activated p53/p21 and downregulated c-Myc in these cells, leading to a reduced expression level of RAD51, molecule involved in DNA repair. The effect of AZD2461/UCN-01 on c-Myc and p53/p21 was inter-dependent and, besides impairing cell proliferation, contributed to the activation of the replicative cycle of KSHV, carried in a latent state in PEL cells. Finally, we found that the pharmacological or genetic inhibition of p21 counteracted the viral lytic cycle activation and further reduced PEL cell proliferation, suggesting that it could induce a double beneficial effect in this setting. This study unveils that, therapeutic approaches, based on the induction of DNA damage and the reduction of DNA repair, could be used to successfully treat this malignant lymphoma.
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