title: Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF.
abstract: Curcumin induces cancer cell growth arrest and apoptosis in vitro, but its poor bioavailability in vivo limits its antitumor efficacy. We have previously evaluated the bioavailability of novel analogues of curcumin compared with curcumin, and we found that the analogue CDF exhibited greater systemic and pancreatic tissue bioavailability. In this study, we evaluated the effects of CDF or curcumin alone or in combination with gemcitabine on cell viability and apoptosis in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer (PC) cell lines. Mechanistic investigations revealed a significant reduction in cell viability in CDF-treated cells compared with curcumin-treated cells, which were also associated with the induction of apoptosis, and these results were consistent with the downregulation of Akt, cyclooxygenase-2, prostaglandin E(2), vascular endothelial growth factor, and NF-kappaB DNA binding activity. We have also documented attenuated expression of miR-200 and increased expression of miR-21 (a signature of tumor aggressiveness) in gemcitabine-resistant cells relative to gemcitabine-sensitive cells. Interestingly, CDF treatment upregulated miR-200 expression and downregulated the expression of miR-21, and the downregulation of miR-21 resulted in the induction of PTEN. These results prompt further interest in CDF as a drug modality to improve treatment outcome of patients diagnosed with PC as a result of its greater bioavailability in pancreatic tissue.
authors.affiliation: Division of Hematology/Oncology, Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
authors.forename: Kristin
authors.initials: K
authors.lastname: Dominiak
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Schaffert
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Philip A
authors.initials: PA
authors.lastname: Philip
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D018076:DNA, Complementary; D004273:DNA, Neoplasm; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; C497962:cycloart-23Z-ene-3 beta,25-diol-3 beta-trans-ferulate; D003841:Deoxycytidine; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D003474:Curcumin; D015232:Dinoprostone; D000093542:Gemcitabine
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