Skip to main content

Wenxia Changfu Formula (温下肠腑方) induces apoptosis of lung adenocarcinoma in a transplanted tumor model of drug-resistance nude mice

Chinese Journal of Integrative Medicine volume 22, pages 752–758 (2016)Cite this article

Abstract

Objective

To explore the apoptosis mechanism of Wenxia Changfu Formula (温下肠腑方, WCF) in reversing drug resistance of lung cancer in vivo.

Methods

Thirty model mice were randomly assigned to three groups: control group, cisplatin (CDDP) group, and WCF group. A transplanted tumor model of lung adenocarcinoma was established in all groups. Mice in the WCF group received intragastric administration of WCF (0.2 mL/10 g body weight) everyday in addition to CDDP intraperitoneally (5 mg/kg body weight) twice a week. The mice in the CDDP group received CDDP intraperitoneally (5 mg/kg body weight) twice a week, while the control group received normal saline intraperitoneally (0.2 mL/10 g body weight) everyday. The weight of the nude mice and respective tumors, tumor volume and tumor-inhibiting rate were measured. Electron microscopy was used to observe the existence of apoptosis body. Apoptosis index (AI) was detected by TdT-mediated dUTP nick end labeling staining. The expression of Fas and FasL mRNA was investigated by reverse transcription polymerase chain reaction, while immunohistochemistry was applied to detect the protein expression of Fas and FasL, caspase-3 and caspase-activated DNase (CAD), respectively.

Results

Compared with CDDP group and control group, WCF could significantly reduce the tumor volume from the 19th day and alleviate the tumor weight (P <0.05), and the apoptosis body was found in tumor cells in the WCF group. WCF could also enhance the level of AI, up-regulate the expression of caspase apoptosis pathway related protein caspase-3 and CAD, as well as the expression of Fas, FasL mRNA and protein (P <0.05).

Conclusion

WCF could improve the sensitivity of tumor cells to CDDP and reverse the drug resistance by inducing the apoptosis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Schwarzenbach H. Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. Med Oncol 2002;19:87–104.

    CAS  Article  PubMed  Google Scholar 

  2. Chai S, To KK, Lin G. Circumvention of multi-drug resistance of cancer cells by Chinese herbal medicines. Chin Med 2010;5:26.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ji XM, Ouyang B, Wang CY, Zhang YQ, Jiang T. Wenxiafang, a traditional Chinese college of basic medical sciences, chemotherapeutic resistance in A549/DDP cells by down-regulating expression levels of P-gp, LRP and MRP. Chin Remed Clin (Chin) 2006;6:885–888.

    Google Scholar 

  4. Bria E, Cuppone F, Cecere FL, Milella M, Nistico C, Cognetti F, et al. Adjuvant chemotherapy for non-small cell lung cancer. J Thorac Oncol 2007;2:S7–S11.

    Article  PubMed  Google Scholar 

  5. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589–2597.

    CAS  Article  PubMed  Google Scholar 

  6. Zhang MC, Hu CP. The molecular mechanism of DDP drug resistance in lung cancer. Int J Respir (Chin) 2006;26:152–155.

    Google Scholar 

  7. Stewart DJ. Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 2007;63:12–31.

    Article  PubMed  Google Scholar 

  8. Wang WP, Ji XM, Ouyang B, Wang ZX, Yu HY, Wu ZC. The research of reversing multidrug resistance in lung cancer. World J Integr Tradit West Med (Chin) 2011;6:820–823.

    Google Scholar 

  9. Meng S, Zhou Z, Chen F, Kong X, Liu H, Jiang K, et al. Newcastle disease virus induces apoptosis in cisplatinresistant human lung adenocarcinoma A549 cells in vitro and in vivo. Cancer Lett 2012;317:56–64.

    CAS  Article  PubMed  Google Scholar 

  10. Liu XD, Sun H, Liu GT. Tumor chemosensitization strategies based on apoptosis manipulations. Chin Pharmacol Bull (Chin) 2009;25:1261–1264.

    CAS  Google Scholar 

  11. Ji XM, Ouyang B, Wang CY. Wenxia Formular restrain the multiplication of the A549 cells and the infection to the expression of PCNA, Rb and CyclinD1. Chin Arch Tradit Chin Med (Chin) 2010;28:721–723.

    Google Scholar 

  12. Ji XM, Ouyang B, Li WH, Wang CY. Effect of Wenxiachangfufang on PCNA, p16 and cyclinD1 in mice with Lewis lung carcinoma. Lishizhen Med Mater Med Res (Chin) 2011;22:96–98.

    Google Scholar 

  13. Ji XM, Ouyang B, Lui H, Liu GW, Wu ZC, Yu HY, et al. In vitro and in vivo inhibitory effect of the combination of WCF with cisplatin in non-small cell lung cancer. Chin J Integr Med 2011;17:908–916.

    Article  PubMed  Google Scholar 

  14. Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells. Cancer Sci 2008;99:738–746.

    CAS  Article  PubMed  Google Scholar 

  15. Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 2008;27:7274–7284.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Dickens LS, Powley IR, Hughes MA, MacFarlane M. The 'complexities' of life and death: death receptor signalling platforms. Exp Cell Res 2012;318:1269–1277.

    CAS  Article  PubMed  Google Scholar 

  17. Lee EW, Kim JH, Ahn YH, Seo J, Ko A, Jeong M, et al. Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis. Nat Commun 2012;3:978–989.

    Article  PubMed  Google Scholar 

  18. Abbosh PH, Montgomery JS, Starkey JA, Novotny M, Zuhowski EG, Egorin MJ, et al. Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. Cancer Res 2006;66:5582–5591.

    CAS  Article  PubMed  Google Scholar 

  19. Hussain M, Rao M, Humphries AE, Hong JA, Liu F, Yang M, et al. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res 2009;69:3570–3578.

    CAS  Article  PubMed  Google Scholar 

  20. Hu S, Yu L, Li Z, Shen Y, Wang J, Cai J, et al. Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo. Cancer Biol Ther 2010;10:788–795.

    CAS  Article  PubMed  Google Scholar 

  21. de Bruyn M, Bremer E, Helfrich W. Antibody-based fusion proteins to target death receptors in cancer. Cancer Lett 2013;332:175–183.

    CAS  Article  PubMed  Google Scholar 

  22. Ougolkov AV, Bilim VN, Billadeau DD. Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res 2008;14:6790–6796.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

  1. School of Basic Medical Science, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China

    Xu-ming Ji, Zhi-chun Wu, Guo-wei Liu, Hua-yun Yu & Bing Ouyang

  2. Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250012, China

    Heng Liu

  3. Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Zheng-tao Wang & Xiao-hui Wei

Authors
  1. Xu-ming Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-chun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guo-wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hua-yun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zheng-tao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-hui Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bing Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhi-chun Wu.

Additional information

Supported by the National Natural Science Foundation of China (No. 81072832, 81273634), and the Opening Project of Shanghai Key Laboratory of Complex Prescription (No. 11DZ2272300), National Science and Technology Major Projects for "Major New Drugs Innovation and Development (No. 2010Z0940)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ji, Xm., Wu, Zc., Liu, Gw. et al. Wenxia Changfu Formula (温下肠腑方) induces apoptosis of lung adenocarcinoma in a transplanted tumor model of drug-resistance nude mice. Chin. J. Integr. Med. 22, 752–758 (2016). https://doi.org/10.1007/s11655-015-2087-4

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11655-015-2087-4

Keywords

  • Wenxia Changfu Formula
  • animal model
  • drug resistance
  • apoptosis
  • in vivo