Antitumor activity of BJ-1207, a 6-amino-2,4,5-trimethylpyridin-3-ol derivative, in human lung cancer

Chem Biol Interact. 2018 Oct 1;294:1-8. doi: 10.1016/j.cbi.2018.08.007. Epub 2018 Aug 17.

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 (R2 = 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.

Keywords: Aminopyridin-3-ols; NADPH oxidase; Non-small cell lung cancer; Stem cell factor; Transforming growth factor-α.

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chickens
  • Chorioallantoic Membrane / metabolism
  • Chorioallantoic Membrane / pathology
  • Humans
  • Indoles / pharmacology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Pyrroles / pharmacology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Sunitinib
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Indoles
  • Pyridines
  • Pyrroles
  • Reactive Oxygen Species
  • NADPH Oxidases
  • Sunitinib