Background: Patients with inflammatory bowel disease, which includes ulcerative colitis and Crohn’s disease, are at a significantly increased risk of developing colorectal cancer, and aberrant interleukin (IL)-6/STAT3 signaling pathway exists in both inflammatory bowel disease and inflammation-related gastrointestinal cancers. We have previously found that oroxylin A inhibited the NF-κB signaling in human colon tumor HCT-116 cells. However, whether oroxylin A could inhibit the colitis-associated carcinogenesis remains to be determined.
Methods: HCT-116 cells were treated with various concentrations of oroxylin A. Expression of relative proteins of IL-6/STAT3 signaling pathway was assayed by Western blot and immunofluorescence analysis. Mouse model for colitis-associated colorectal cancer was induced by a combined treatment with 10 mg/kg azoxymethane (AOM) followed by 3 cycles of 2.5% dextran sodium sulfate in C57BL/6 mice. IL-6 and IL-1β gene expression were analyzed by quantitative real-time PCR. Expression of relative proteins was examined by immunohistochemistry and Western blot.
Results: Oroxylin A effectively inhibited IL-6/STAT3 pathway in human HCT-116 cells, and the effect of oroxylin A was reversible. Dietary administration of oroxylin A throughout the experimental period significantly reduced the tumor burden, inhibited cell proliferation, and induced apoptosis in colon carcinomas. The expression of inflammatory cytokines IL-6 and IL-1β decreased in tumors in oroxylin A–treated mice. The IL-6/STAT3 signaling pathway was attenuated in oroxylin A–treated mice.
Conclusions: Our results demonstrated that oroxylin A inhibits colitis-associated carcinogenesis through modulating IL-6/STAT3 pathway in AOM/dextran sodium sulfate mouse model and in HCT-116 cells.
Article first published online 2 July 2013
*State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China;
†Department of Pharmacy, Nanjing Pukou Hospital, Nanjing, China;
‡Department of Neurosurgery, Wuxi Second Hospital Affiliated Nanjing Medical University, Wuxi, China; and
§Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
Reprints: Rong Hu, PhD, State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China (e-mail: firstname.lastname@example.org); Zhiyu Li, PhD, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China (e-mail: email@example.com).
X. Yang and F. Zhang contributed equally to this work.
Supported by the Natural Science Foundation of China (Grants 81173087, 81202611, 91029744, and 30801410), the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (Grant ZJ11173), and the Fundamental Research Funds for the Central Universities from China Pharmaceutical University (Grant JKQ2011008).
The authors have no conflicts of interest to disclose.
Received February 05, 2013
Accepted March 24, 2013