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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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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 (ICPMS) 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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Authors and Affiliations

  1. Department of Medical Oncology, Shuguang Hospital & Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China

    Hua Sui  (隋 华), Hui-rong Zhu  (朱惠蓉), Zhong-ze Fan  (范忠泽) & Qi Li  (李 琦)

  2. Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612, USA

    Jie Wu  (吴 杰)

  3. Department of Biomedical Sciences, Cornell University, Ithaca, New York, 14853-6401, USA

    Alexander Yu Nikitin

  4. Department of Chemistry, University of South Florida, Tampa, Florida, 33620, USA

    Jian-feng Cai  (蔡健锋)

Authors
  1. Hua Sui  (隋 华)
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  2. Hui-rong Zhu  (朱惠蓉)
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  3. Jie Wu  (吴 杰)
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  4. Alexander Yu Nikitin
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  5. Jian-feng Cai  (蔡健锋)
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  6. Zhong-ze Fan  (范忠泽)
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  7. Qi Li  (李 琦)
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Corresponding author

Correspondence to Qi Li  (李 琦).

Additional information

Supported by the National Natural Science Foundation of China (No.81202812), Science and Technology Commission of Shanghai Municipality (No. 10ZR1427400), Program of Shanghai Municipal Education Commission (No. 09YZ132, 2011JW57), and Shanghai Municipal Health Bureau (No. 2011ZJ030, 20114Y013)

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Sui, H., Zhu, Hr., Wu, J. et al. 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. Chin. J. Integr. Med. 20, 610–617 (2014). https://doi.org/10.1007/s11655-013-1452-4

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  • DOI: https://doi.org/10.1007/s11655-013-1452-4

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