title: 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.
abstract: 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.
authors.affiliation: Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia.
authors.forename: Puteri
authors.initials: P
authors.lastname: Baharuddin
authors.affiliation: Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia.
authors.forename: Nazilah
authors.initials: N
authors.lastname: Satar
authors.affiliation: Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia.
authors.forename: Kamal Shaik
authors.initials: KS
authors.lastname: Fakiruddin
authors.affiliation: Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia.
authors.forename: Norashikin
authors.initials: N
authors.lastname: Zakaria
authors.affiliation: Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia.
authors.forename: Moon Nian
authors.initials: MN
authors.lastname: Lim
authors.affiliation: Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia.
authors.forename: Narazah Mohd
authors.initials: NM
authors.lastname: Yusoff
authors.affiliation: Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia.
authors.forename: Zubaidah
authors.initials: Z
authors.lastname: Zakaria
authors.affiliation: Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia.
authors.forename: Badrul Hisham
authors.initials: BH
authors.lastname: Yahaya
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019938:Cyclin D1; D003474:Curcumin; D002945:Cisplatin