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: Jun Ha, Li Zhao, Qing Zhao, Jing Yao, Bin-Bin Zhu, Na Lu, Xue Ke, Hui-Ying Yang, Zhiyu Li, Qi-Dong You, Qing-Long Guo
• Journal: Biochemistry and cell biology = Biochimie et biologie cellulaire (Biochem Cell Biol) Vol. 90 Issue 4 Pg. 521-31 (Aug 2012) ISSN: 1208-6002 [Electronic] Canada
• PMID: 22607196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Cyclooxygenase 2 Inhibitors
• Flavonoids
• 5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one
• Cyclooxygenase 2
• PTGS2 protein, human
• Fluorouracil

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis
• Colonic Neoplasms (drug therapy, metabolism)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Drug Synergism
• Female
• Flavonoids (pharmacology)
• Fluorouracil (pharmacology)
• HT29 Cells (drug effects)
• Humans
• Mice
• Mice, Nude
• Signal Transduction