Curcumol potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer

// Fangfang Cai 1, * , Minghui Chen 1, 2, * , Daolong Zha 1 , Peng Zhang 2 , Xiangyu Zhang 1 , Nini Cao 1 , Jishuang Wang 2 , Yan He 2 , Xinxin Fan 2 , Wenjing Zhang 2 , Zhongping Fu 2 , Yueyang Lai 1, 3 , Zi-Chun Hua 1, 2 and Hongqin Zhuang 1 1 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China 2 State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China 3 Nanjing Industrial Innovation Center for Pharmaceutical Biotechnology, Nanjing, China * These authors have contributed equally to this work Correspondence to: Hongqin Zhuang, email: hqzhuang@nju.edu.cn Zi-Chun Hua, email: hzc1117@nju.edu.cn Keywords: celecoxib; curcumol; synergism; apoptosis; tumor metastasis Received: August 16, 2017      Accepted: December 05, 2017      Published: December 14, 2017 ABSTRACT Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. Celecoxib and curcumol are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. In the present study, we evaluated the effects of celecoxib and curcumol alone and in combination on cell proliferation, invasion, migration, cell cycle and apoptosis induction in non-small cell lung cancer (NSCLC) cells using in vitro and in vivo experiments. Our data showed that the sensitivity of a combined therapy using low concentration of celecoxib and curcumol was higher than that of celecoxib or curcumol alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle G1 arrest, and inhibition of survival MAPK and PI3K/AKT signaling pathway contributed to the synergistic effects of this combination therapy for induction of apoptosis. Additionally, either celecoxib alone or in combination with curcumol inhibited NSCLC cell migration and invasion by suppressing FAK and matrix metalloproteinase-9 activities. Furthermore, the combined treatment reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. Our results confirm and provide mechanistic insights into the prominent anti-proliferative activities of celecoxib and/or curcumol on NSCLC cells, which provide a rationale for further detailed preclinical and potentially clinical studies of this combination for the therapy of lung cancer.