DWP-0016

The paper aimed to study the effect and the underlying mol. mechanisms of a novel histone deacetylases (HDAC) inhibitor named DWP0016 in lung carcinoma A549 cells and xenografts.In the in vitro test, A549 cells were treated with DWP0016 0.625-10 μmol·L^-1 for 48 h, then the cell viability was detected by MTT assay, the mRNA level of phosphatase and tensin homolog deleted on chromosome 10(PTEN) was detected by real-time PCR, and the expressions of total H3, acetylated-H3(Ac-H3), p21, PTEN, total-Akt and phosphorylated-Akt(p-Akt) were detected by Western blotting.In the in vivo test, Lewis lung cancer animal models were constructed by injecting the axilla with 0.2 mL Lewis tumor cell suspension.7 Days later, the animals received DWP0016 12.5, 25 and 50 mg·kg^-1 and pos. drug vorinostat(SAHA) 50 mg·kg^-1 by i.p., once daily, for 8 days.After treatment, the animals were sacrificed to get the tumors.The tumor specimens were weighed and the tumor growth inhibition rate was calculatedThe expressions of Ac-H3 and PTEN in the specimens were detected by immunohistochem. assay.In the in vitro test, MTT results showed that IC₅₀ of DWP0016 was 2.51 μmol·L^-1 and IC₅₀ of SAHA was 6.03 μmol·L^-1.Compared with normal control, DWP0016 significantly up-regulated the protein expressions of Ac-H3 and p21 at the concentration of 2.5 μmol·L^-1(P< 0.05).DWP0016 promoted the mRNA level and protein expression of PTEN while decreasing the expression of p-Akt in a concentration-dependent manner(P<0.05).In the in vivo test, compared with model group, the mean mass of tumor specimens from mice receiving DWP0016 12.5 mg·kg^-1 significantly decreased (P<0.05) with a tumor growth inhibition rate of 42.0%.The tumor growth inhibition rate in DWP0016 50 mg·kg^-1 group was higher than in that in SAHA 50 mg·kg^-1 group(P<0.05).Compared with the model group, the expressions of Ac-H3 and PTEN in tumor specimens were up-regulated by DWP0016.DWP0016 effectively inhibits the proliferation of A549 cells and the tumor growth in xenografts.The mol. mechanisms are associated with the induction of Ac-H3, the activation of p21 and PTEN, and the down-regulation of p-Akt.DWP0016 is a potent compound to be developed as an anti-tumor agent for clinic application in the future.