title: Gender differences in gemcitabine (Gemzar) efficacy in cancer cells: effect of indole-3-carbinol.
abstract: Pancreatic cancer has a poor prognosis, mainly due to lack of effective therapies. This study demonstrated the ability of dietary agent, indole-3-carbinol (I3C), to lower the LD(50) of gemcitabine (Gemzar) in decreasing growth of both male (MiaPaca2) and female (SU86.86) pancreatic cancer cells. Female pancreatic cancer cells were more resistant to gemcitabine alone. Additionally, RT-PCR analysis of MiaPaca2 cells treated with 1, 10 or 100 μM of I3C showed that I3C reactivated the tumor suppressor gene p16INK4a in pancreatic cancer cells. Methylated-specific PCR analysis indicated that I3C demethylated the promoter region of p16 INK4a, which was methylated in the untreated cancer cells. p16INK4a inactivation through promoter hypermethylation is considered an early event in pancreatic carcinogenesis. A positive control using 5-azacytidine also reactivated p16INK4a. This study demonstrated the potential of I3C, a possible non-toxic hypomethylating agent, combined with the anticancer agent, gemcitabine, to be a powerful strategy for treating pancreatic cancer.
authors.affiliation: FDA/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. Beverly.lyn-cook@fda.hhs.gov
authors.forename: Beverly D
authors.initials: BD
authors.lastname: Lyn-Cook
authors.forename: Sulma I
authors.initials: SI
authors.lastname: Mohammed
authors.forename: Cornelius
authors.initials: C
authors.lastname: Davis
authors.forename: Beverly
authors.initials: B
authors.lastname: Word
authors.forename: Aaron
authors.initials: A
authors.lastname: Haefele
authors.forename: Honggang
authors.initials: H
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Hammons
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019942:Genes, p16 / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D000093542:Gemcitabine
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D003841:Deoxycytidine; C016517:indole-3-carbinol; D015254:DNA Modification Methylases; D000093542:Gemcitabine