Search

DNA repair allows the survival of cancer cells. Therefore, the development of DNA repair inhibitors is a critical need for sensitizing cancers to chemoradiation. Sae2CtIP has specific functions in initiating DNA end resection, as well as coordinating cell cycle checkpoints, and it also greatly interacts with the DDR at different levels. In this study, we demonstrated that corylin, a potential sensitizer, causes deficiencies in DNA repair and DNA damage checkpoints in yeast cells. More specifically, corylin increases DNA damage sensitivity through the Sae2-dependent pathway and impairs the activation of Mec1-Ddc2, Rad53-p and γ-H2A. In breast cancer cells, corylin increases apoptosis and reduces proliferation following Dox treatment by inhibiting CtIP. Xenograft assays showed that treatment with corylin combined with Dox significantly reduced tumor growth in vivo. Our findings herein delineate the mechanisms of action of corylin in regulating DNA repair and indicate that corylin has potential long-term clinical utility as a DDR inhibitor. [Display omitted] • Corylin inhibits DNA repair and DNA damage checkpoints in the SSA system. • Corylin increases DNA damage sensitivity through the Sae2CtIP-dependent pathway. • The combination of corylin and Doxorubicin significantly suppressed tumor growth. [ABSTRACT FROM AUTHOR]

[Display omitted] • 37 β -carboline derivatives were synthesized, with monomer M3 and dimer D4 possessing the selective activity and higher cytotoxicity in tumor cells than in normal cells. • The antitumor mechanism of M3 and D4 was explored, identifying CDK2 and DNA as potential key targets. • M3 and D4 interacts with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes. • M3 , as a dual-pocket inhibitor of CDK2, is a promising framework for the rational design of next-generation CDK2 inhibitors. β -Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized β -carbolines exert excellent antitumor activity. In the present research, 37 β -carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. β -Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC 50 = 1.44 ± 1.10 μM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC 50 = 2.84 ± 0.73 μM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3 -treated A549 cells and D4 -treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis. [ABSTRACT FROM AUTHOR]