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

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-?B 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.

SUBMITTER: Cai F

PROVIDER: S-EPMC5777791 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Cai Fangfang F Chen Minghui M Zha Daolong D Zhang Peng P Zhang Xiangyu X Cao Nini N Wang Jishuang J He Yan Y Fan Xinxin X Zhang Wenjing W Fu Zhongping Z Lai Yueyang Y Hua Zi-Chun ZC Zhuang Hongqin H

Oncotarget 20171214 70

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 <i>in vitro</i> ...[more]

PMID: 29383179

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Project description:BackgroundGambogic acid (GA) has been reported to have potent anticancer activity and is authorised to be tested in phase II clinical trials for treatment of non-small-cell lung cancer (NSCLC). The present study aims to investigate whether GA would be synergistic with cisplatin (CDDP) against the NSCLC.Methods1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI) isobologram, western blot, quantitative PCR, flow cytometry, electrophoretic mobility shift assay, xenograft tumour models and terminal deoxynucleotide transferase-mediated dUTP nick-end labelling analysis were used in this study.ResultsThe cell viability results showed that sequential CDDP-GA treatment resulted in a strong synergistic action in A549, NCI-H460, and NCI-H1299 cell lines, whereas the reverse sequence and simultaneous treatments led to a slight synergistic or additive action. Increased sub-G1 phase cells and enhanced PARP cleavage demonstrated that the sequence of CDDP-GA treatment markedly increased apoptosis in comparison with other treatments. Furthermore, the sequential combination could enhance the activation of caspase-3, -8, and 9, increase the expression of Fas and Bax, and decrease the expression of Bcl-2, survivin and X-inhibitor of apoptosis protein (X-IAP) in A549 and NCI-H460 cell lines. In addition, increased apoptosis was correlated with enhanced reactive oxygen species generation. Importantly, it was found that, followed by CDDP treatment, GA could inhibit NF-κB and mitogen-activated protein kinase (MAPK)/heme oxygenase-1 (HO-1) signalling pathways, which have been validated to reduce ROS release and confer CDDP resistance. The roles of NF-κB and MAPK pathways were further confirmed by using specific inhibitors, which significantly increased ROS release and apoptosis induced by the sequential combination of CDDP and GA. Moreover, our results indicated that the combination of CDDP and GA exerted increased antitumour effects on A549 xenograft models through inhibiting NF-κB, HO-1, and subsequently inducing apoptosis.ConclusionGambogic acid sensitises lung cancer cells to CDDP in vitro and in vivo in NSCLC through inactivation of NF-κB and MAPK/HO-1 signalling pathways, providing a rationale for the combined use of CDDP and GA in lung cancer chemotherapy.

Dataset Information

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

Publications

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

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