Journal
TOXICOLOGY LETTERS
Volume 295, Issue -, Pages 88-98Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2018.05.033
Keywords
PDGFR beta; CP-673451; Nrf2; Cisplatin; NSCLC
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Funding
- project of the new star of Zhujiang science and technology [201710010001]
- National Natural Science Foundation of China [81672836, 81472205]
- Key laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing [2017 Open Project-2]
- Guangdong Key Laboratory of Pharmaceutical Bioactive Substances
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Platelet-derived growth factor receptors (PDGFRs) are abundantly expressed by stromal cells in the non-small cell lung cancer (NSCLC) microenvironment, and in a subset of cancer cells, usually with their overexpression and/or activating mutation. However, the effect of PDGFR inhibition on lung cancer cells themselves has been largely neglected. In this study, we investigated the anticancer activity of CP-673451, a potent and selective inhibitor of PDGFR beta, on NSCLC cell lines (A549 and H358) and the potential mechanism. The results showed that inhibition of PDGFR beta by CP-673451 induced a significant increase in cell apoptosis, accompanied by ROS accumulation. However, CP-673451 exerted less cytotoxicity in normal lung epithelial cell line BEAS-2B cells determined by MTT and apoptosis assay. Elimination of ROS by NAC reversed the CP-673451-induced apoptosis in NSCLC cells. Furthermore, CP-673451 down-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) probably through inhibition of PI3K/Akt pathway. Rescue of Nrf2 activity counteracted the effects of CP-673451 on cell apoptosis and ROS accumulation. Silencing PDGFR beta expression by PDGFR beta siRNA exerted similar effects with CP-673451 in A549 cells, and when PDGFR beta was knockdowned by PDGFR beta siRNA, CP-673451 produced no additional effects on cell viability, ROS and GSH production, Nrf2 expression as well as PI3K/Akt pathway activity. Specifically, Nrf2 plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and we found that combination of CP-673451 and cisplatin produced a synergistic anticancer effect and substantial ROS production in vitro. Therefore, these results clearly demonstrate the effectiveness of inhibition of PDGFR beta against NSCLC cells and strongly suggest that CP-673451 may be a promising adjuvant chemotherapeutic drug.
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