Dual Inhibition of NOX2 and Receptor Tyrosine Kinase by BJ-1301 Enhances Anticancer Therapy Efficacy via Suppression of Autocrine-Stimulatory Factors in Lung Cancer
- Authors
- Gautam, Jaya; Ku, Jin-Mo; Regmi, Sushil Chandra; Jeong, Hyunyoung; Wang, Ying; Banskota, Suhrid; Park, Myo-Hyeon; Nam, Tae-Gyu; Jeong, Byeong-Seon; Kim, Jung-Ae
- Issue Date
- Oct-2017
- Publisher
- AMER ASSOC CANCER RESEARCH
- Keywords
- ENDOTHELIAL GROWTH-FACTOR; NADPH OXIDASES; ALPHA-TOCOPHEROL; HYDROGEN-PEROXIDE; EPITHELIAL-CELLS; VITAMIN-E; ANGIOGENESIS; KIT; METAANALYSIS; TOCOTRIENOL
- Citation
- MOLECULAR CANCER THERAPEUTICS, v.16, no.10, pp.2144 - 2156
- Indexed
- SCIE
SCOPUS
- Journal Title
- MOLECULAR CANCER THERAPEUTICS
- Volume
- 16
- Number
- 10
- Start Page
- 2144
- End Page
- 2156
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/8939
- DOI
- 10.1158/1535-7163.MCT-16-0915
- ISSN
- 1535-7163
- Abstract
- NADPH oxidase-derived reactive oxygen species (ROS) potentiate receptor tyrosine kinase (RTK) signaling, resulting in enhanced angiogenesis and tumor growth. In this study, we report that BJ-1301, a hybrid of pyridinol and alpha-tocopherol, exerts anticancer effects by dual inhibition of NADPH oxidase and RTK activities in endothelial and lung cancer cells. BJ-1301 suppresses ROS production by blocking translocation of NADPH oxidase cytosolic subunits to the cell membrane, thereby inhibiting activation. The potency of RTK inhibition by BJ-1301 was lower than that of sunitinib (a multi-RTK inhibitor), but the inhibition of downstream signaling pathways (e.g., ROS generation) and subsequent biological changes (e.g., NOX2 induction) by BJ-1301 was superior. Consistently, BJ-1301 inhibited cisplatin-resistant lung cancer cell proliferation more than sunitinib did. In xenograft chick or mouse tumor models, BJ-1301 inhibited lung tumor growth, to an extent greater than that of sunitinib or cisplatin. Treatments with BJ-1301 induced regression of tumor growth, potentially due to downregulation of autocrine-stimulatory ligands for RTKs, such as TGFa and stem cell factor, in tumor tissues. Taken together, the current study demonstrates that BJ-1301 is a promising anticancer drug for the treatment of lung cancer.
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