Dual Inhibition of NOX2 and Receptor Tyrosine Kinase by BJ-1301 Enhances Anticancer Therapy Efficacy via Suppression of Autocrine-Stimulatory Factors in Lung Cancer.

Jaya Gautam,Myo-Hyeon Park,Hyunyoung Jeong,Jin-Mo Ku,Ying Wang,Sushil Chandra Regmi,Byeong-Seon Jeong,Suhrid Banskota,Tae-Gyu Nam,Jung-Ae Kim

doi:10.1158/1535-7163.mct-16-0915

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 TGFα 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. Mol Cancer Ther; 16(10); 2144-56. ©2017 AACR.

Highlights

Lung cancer is the leading cause of cancer-associated deaths [1], and non–small cell lung cancer (NSCLC) constitutes over 80% of lung cancers
BJ-1301 inhibits growth of cisplatin-resistant lung cancer cells To determine whether NOX2 inhibition by BJ-1301 in cancer cells leads to altered lung cancer cell proliferation, we examined A549 and H1299 (p53 null) human NSCLC proliferation in the presence of BJ-1301. a-TOH, cisplatin, and sunitinib were included as controls
We report that BJ-1301 inhibits the regulatory network composed of receptor tyrosine kinase (RTK) and NADPH oxidase and effectively blocks overall RTK activation and angiogenesis, presenting a potent and efficacious therapeutic agent against lung cancer

Summary

Introduction

Lung cancer is the leading cause of cancer-associated deaths [1], and non–small cell lung cancer (NSCLC) constitutes over 80% of lung cancers. With advancements in the study of cancer biomarkers, NSCLC treatments have gone from platinum-based chemotherapy (associated with a low response rate) to targeted therapy using inhibitors of EGFR tyrosine kinase based on the identification of sensitizing mutations within EGFRs [2, 3]. The number of cases suitable for such EGFR-targeted therapy is small [4], and the overall 5-year survival rate is still low [5]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

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