Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines

• Published in: Oncology reports Vol. 35; no. 1; pp. 13 - 25
• Main Authors: BAHARUDDIN, PUTERI, SATAR, NAZILAH, FAKIRUDDIN, KAMAL SHAIK, ZAKARIA, NORASHIKIN, LIM, MOON NIAN, YUSOFF, NARAZAH MOHD, ZAKARIA, ZUBAIDAH, YAHAYA, BADRUL HISHAM
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01-01-2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Brain cancer; Breast cancer; cancer stem-like cells; Cancer therapies; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Care and treatment; Cell Cycle - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Cisplatin; Cisplatin - pharmacology; curcumin; Curcumin - pharmacology; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Drug dosages; Drug interactions; Drug Synergism; Enzymes; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Humans; Kinases; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Metastasis; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; non-small cell lung cancer; Observations; Patient outcomes; Proteins; Signal Transduction - drug effects; Standard deviation; Stem cells; Studies; Tumor proteins; Tumors; Turmeric
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2015.4371

Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10-40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC.