Small molecule 2,3-DCPE induces S phase arrest by activating the ATM/ATR-Chk1-Cdc25A signaling pathway in DLD-1 colon cancer cells

In our previous study, it was reported that 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE) induces apoptosis and cell cycle arrest. The current study aimed to investigate the molecular mechanism involved in 2,3-DCPE-induced S phase arrest. The results demonstrated that 2,3-DCPE upregulated phosphorylated (p-)H2A histone family member X, a biomarker of DNA damage, in the DLD-1 colon cancer cell line. Western blotting revealed that 2,3-DCPE increased the checkpoint kinase (Chk)1 (Ser317 and Ser345) level and decreased the expression of M-phase inducer phosphatase 1 (Cdc25A) in a time-dependent manner. Subsequently, the results demonstrated that the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) inhibitors wortmannin and caffeine had no effect on the cell cycle; however, the inhibitors partially abrogated 2,3-DCPE-induced S phase arrest. Flow cytometry assays revealed that caffeine (2 mM) reduced the proportion of S phase cells from 83 to 39.6% and that wortmannin (500 nM) reduced the proportion of S phase cells from 83 to 48.2%. Furthermore, wortmannin and caffeine inhibited the 2,3-DCPE-mediated phosphorylation of Chk1 and the degradation of Cdc25A. However, these ATM/ATR inhibitors had limited effect on 2,3-DCPE-induced apoptosis. Taken together, the data of the current study indicated that 2,3-DCPE caused DNA damage in colon cancer cells and that 2,3-DCPE-induced S phase arrest was associated with the activation of the ATM/ATR-Chk1-Cdc25A pathway.

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S2758 Wortmannin (KY 12420) Wortmannin (KY 12420, SL-2052, BRN 0067676, NSC 627609) is the first described PI3K inhibitor with IC50 of 3 nM in a cell-free assay, with little selectivity within the PI3K family. Wortmannin blocks autophagosome formation and potently inhibits DNA-PK/ATM with IC50 of 16 nM and 150 nM in cell-free assays. Wortmannin also inhibits PLK1 activity.

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