title: Reversal of resistance towards cisplatin by curcumin in cervical cancer cells.
abstract: Epigenetic regulators like histone deacetylases (1 and 2), and viral onco-proteins (E6/E7) are known to be overexpressed in cervical cancer cells. The present study was designed to investigate the effect of curcumin on HDACs (1 and 2) and HPV E6/E7 in the cervical cancer cell line SiHa and a drug resistant clone SiHaR (derived from SiHa). It was further intended to investigate whether curcumin could sensitize the cells towards cisplatin induced cell killing by modulation of multi drug resistant proteins like MRP1 and Pgp1. Curcumin inhibited HDACs, HPV expression and differentially increased acetylation and up-regulation of p53 in SiHa and SiHaR, leading to cell cycle arrest at G1-S phase. Up-regulation of pRb, p21, p27 and corresponding inhibition of cyclin D1 and CDK4 were observed. Cisplatin resistance in SiHaR due to over-expression of MRP1 and Pgp1 was overcome by curcumin. Curcumin also sensitized both the cervical cancer cells towards cisplatin induced cell killing. Inhibition of HDACs and HPVs led to cell cycle arrest at G1/S phase by alteration of cell cycle regulatory proteins. Suppression of MRP1 and Pgp1 by curcumin resulted in sensitization of cervical cancer cells, lowering the chemotherapeutic dose of the drug cisplatin.
authors.affiliation: Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, Kolkata, India E-mail : mitacnci@yahoo.co.in.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Roy
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mukherjee
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000032:analysis; D056284:Histone Deacetylase 1 / Q000096:biosynthesis; D056464:Histone Deacetylase 2 / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000821:virology
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002945:Cisplatin; D003474:Curcumin; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors; D005978:Glutathione; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D018960:Hyaluronan Receptors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; C068651:E6 protein, Human papillomavirus type 16; C059731:oncogene protein E7, Human papillomavirus type 16; C495900:CDK4 protein, human; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; C421109:multidrug resistance-associated protein 1