Antitumor activity of BJ-1207, a 6-amino-2, 4, 5-trimethylpyridin-3-ol derivative, in human lung cancer. (1st October 2018)

• Record Type: Journal Article
• Authors: Gautam, Jaya; Banskota, Suhrid; Chaudhary, Prakash; Dahal, Sadan; Kim, Dong-Guk; Kang, Han-eol; Lee, Iyn-Hyang; Nam, Tae-gyu; Jeong, Byeong-Seon; Kim, Jung-Ae
• Is Part Of: Chemico-biological interactions. Volume 294(2018)
• Page Start: 1
• Page End: 8
• Publication Date: 2018-10-01
• Subjects: Aminopyridin-3-ols -- Non-small cell lung cancer -- NADPH oxidase -- Stem cell factor -- Transforming growth factor-α; Akt protein kinase B -- CAM chick chorioallantoic membrane -- c-KIT cellular homolog of the feline sarcoma viral oncogene v-kit -- DPPH 1, 1-diphenyl-2-picrylhydrazyl -- DUOX1 dual oxidase 1 -- EGFR epidermal growth factor receptor -- HER2 human epidermal growth factor receptor 2 -- KDR kinase insert domain receptor -- MAPKs mitogen-activated protein kinases -- NOX NADPH oxidase -- ROS reactive oxygen species -- NSCLC non-small cell lung cancer -- PI3K phosphoinositide 3-kinase -- RTK receptor tyrosine kinase -- SCF stem cell factor -- TPA 12-O-tetradecanoylphorbol-13-acetate -- TGF-α transforming growth factor-α -- VEGFR2 vascular endothelial growth factor; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2018.08.007
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Enhanced expression of NADPH oxidase (NOX) and the subsequent production of reactive oxygen species (ROS) are associated with lung cancer. In the present study, fifty 6-amino-2, 4, 5-trimethylpyridin-3-ol derivatives were screened for anticancer activity by targeting NOX2-derived ROS. The compounds suppressed ROS production and decreased cancer cell viability (R 2 = 0.79). Among the derivatives, the compound coded BJ-1207, which contained a 4-(hydroxydiphenylmethyl)piperidine moiety, exhibited the most effective anticancer activity against A549 lung cancer cell line and eight other cancer cell lines, including H1299, MCF-7, MDA-MB-231, HT-29, SW620, Mia PaCa-2, PANC-1, and U937. BJ-1207 also showed significantly lower inhibitory effects on kinase insert domain receptor (KDR) and c-KIT tyrosine kinase but higher inhibitory activity on NOX than those of sunitinib, a multi-receptor tyrosine kinase (RTK) inhibitor. In addition, BJ-1207-induced inhibition of RTK-downstream signaling pathways, such as ROS production, and expression of target genes, such as stem cell factor and transforming growth factor-α, were similar to those induced by sunitinib. In the xenograft chick tumor model, BJ-1207 inhibited lung tumor growth to a similar or much greater extent than that of sunitinib or cisplatin, respectively. Overall, the present study showed that BJ-1207, a vitamin B6 -derived 2, 4, 5-trimethylpyridin-3-ol compound with azacyclonol moiety at C (6)-position of the pyridine ring, inhibited NOX activity and that it is a promising lead compound for developing anticancer drugs against lung cancer. Highlights: In aminopyridinol-treated A549 cells, cell viability decrease correlates ROS suppression. BJ-1207 is the strongest NADPH oxidase (NOX) inhibitor among the derivatives. BJ-1207 is a much weaker multi-receptor tyrosine kinase inhibitor than sunitinib. Anti-tumor activity of BJ-1207 was similar to sunitinib, but much better than cisplatin. BJ-1207 is a promising lead compound to develop therapeutics against lung cancer.