title: Oroxylin A improves the sensitivity of HT-29 human colon cancer cells to 5-FU through modulation of the COX-2 signaling pathway.
abstract: 5-Fluorouracil (5-FU) is a principal drug for the treatment of colorectal cancer. Due to its low response and high toxicity, synergistic effects of 5-FU in combination with other drugs have been widely researched. This study investigated whether oroxylin A improved the sensitivity of HT-29 human colon cancer cells to 5-FU. A correlation between COX-2 inhibition by oroxylin A and a synergistic effect of 5-FU on the growth of HT-29 cells was observed, and a COX-2 pathway for this effect was recognized; oroxylin A evidently elevated the level of reactive oxygen species in HT-29 cells, which subsequently inhibited COX-2 expression and enhanced the susceptibility of HT-29 cells to 5-FU. Likely also related to COX-2 inhibition, oroxylin A decreased PGE(2) levels in HT-29 cells. The synergistic effect of 5-FU induced by oroxylin A was also found in the suppression of Bcl-2 and in the activation of P53, Bax, PARP, and procaspase-3 proteins in HT-29 cells. Ultimately, a combination of 5-FU with oroxylin A significantly reduced the growth of HT-29 tumors in nude mice compared with treatment with 5-FU or oroxylin A alone. In conclusion, a combination of 5-FU and oroxylin A has a significant synergistic effect in the inhibition of HT-29 cell proliferation in vitro and controls HT-29 tumor growth in vivo. This synergistic effect may be mainly related to COX-2 inhibition by oroxylin A in HT-29 cells.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ha
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Bin-Bin
authors.initials: BB
authors.lastname: Zhu
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.forename: Xue
authors.initials: X
authors.lastname: Ke
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Yang
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction
chemical_list: D000964:Antimetabolites, Antineoplastic; D052246:Cyclooxygenase 2 Inhibitors; D005419:Flavonoids; C080669:5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D005472:Fluorouracil