Capsaicin Displays AntiProliferative Activity against Human Small Cell Lung Cancer in Cell Culture and Nude Mice Models via the E 2 F Pathway

Background: Small cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays antiproliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo. Methodology/Principal Findings: BrdU assays and PCNA ELISAs showed that capsaicin displays robust anti-proliferative activity in four human SCLC cell lines. Furthermore, capsaicin potently suppressed the growth of H69 human SCLC tumors in vivo as ascertained by CAM assays and nude mice models. The second part of our study attempted to provide insight into molecular mechanisms underlying the anti-proliferative activity of capsaicin. We found that the anti-proliferative activity of capsaicin is correlated with a decrease in the expression of E2F-responsive proliferative genes like cyclin E, thymidylate synthase, cdc25A and cdc6, both at mRNA and protein levels. The transcription factor E2F4 mediated the anti-proliferative activity of capsaicin. Ablation of E2F4 levels by siRNA methodology suppressed capsaicin-induced G1 arrest. ChIP assays demonstrated that capsaicin caused the recruitment of E2F4 and p130 on E2F-responsive proliferative promoters, thereby inhibiting cell proliferation. Conclusions/Significance: Our findings suggest that the anti-proliferative effects of capsaicin could be useful in the therapy of human SCLCs. Citation: Brown KC, Witte TR, Hardman WE, Luo H, Chen YC, et al. (2010) Capsaicin Displays Anti-Proliferative Activity against Human Small Cell Lung Cancer in Cell Culture and Nude Mice Models via the E2F Pathway. PLoS ONE 5(4): e10243. doi:10.1371/journal.pone. 0010243 Editor: Dong-Yan Jin, University of Hong Kong, Hong Kong Received January 8, 2010; Accepted March 24, 2010; Published April 20, 2010 Copyright: 2010 Brown et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a Center of Biochemical Research Excellence Pilot Research Grant from the National Institutes of Health (grant number 5P20RR020180); the Pharmaceutical Manufacturers Association Foundation Research Starter Grant; the Marshall University ADVANCE fellowship; a Grant-in-Aid undergraduate research grant from National Aeronautics and Space Administration; and a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (grant number 82115). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: dasgupta@marshall.edu . These authors contributed equally to this work.