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| Effects of Jianpi Jiedu Recipe (健脾解毒方) on Reversion of P-Glycoprotein-Mediated Multidrug Resistance through COX-2 Pathway in Colorectal Cancer |
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| KeyWord:colorectal cancer, multidrug resistance, P-glycoprotein, multidrug resistance gene, cyclooxygenase-2, Jianpi Jiedu Recipe, Chinese medicine |
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| Abstract: |
| Objective: To evaluate the underlying mechanism of Jianpi Jiedu Recipe (健脾解毒方, JJR) in the reversion of multidrug resistance concerning colorectal cancer in vitro and in vivo. Methods: Mice were treated orally with JJR at a daily 4.25 g/(kg?day) or injected with vinblastine (VCR) 2.5 mg/(kg?day) for 3 weeks after having been inoculated with HCT8/V cells; tumor tissues were assayed by hematoxylin and eosin staining. Firstly, the effects of JJR on the expression of cyclooxygenase-2 (COX-2) were tested by real-time polymerase chain reaction (PCR) technique and COX-2 gene silenced by siRNA. Secondly, the variation of intracellular concentration of oxaliplatin (L-OHP) was evaluated by the inductively coupled plasma mass spectroscopy (ICP-MS) in HCT8/V and its COX-2 siRNA cells; the concentration of JJR combined with chemotherapeutic drugs and the reverse effect of multidrug resistance (MDR) in HCT8/V cells was evaluated by the MTT assay. Thirdly, real-time quantitative PCR and Western blot analysis were used to detect the multidrug resistance gene 1 (MDR1) mRNA and P-gp expression. Results: JJR had an inhibitory effect on the growth of tumors in vivo, and it, in combination with chemotherapeutic drugs, could reverse the drug-resistance of HCT8/V cells and increase the sensitivity of HCT8/V cells to VCR, DDP, 5-Fu, and THP. ICP-MS results showed that JJR could increase the concentration of drugs in HCT8/V cells (P<0.01). Furthermore, it was shown that JJR could reverse drug resistance of colorectal cancer cells by decreasing MDR1 expression and P-gp level via downregulation of COX-2, which has been represented as one of the major mechanisms that contributes to the MDR phenotype (P<0.01). Conclusion: JJR reversed multidrug resistance and enhanced the sensitivity to chemotherapy, which could be attributed to the down-regulation of COX-2 in MDR1/P-gp–mediated MDR colorectal cancer after chemotherapy. |
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