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Antitumor Pharmacology

Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines

Abstract

Aim:

To investigate whether paeonol (Pae) has synergistic effects with cisplatin (CDDP) on the growth-inhibition and apoptosis-induction of human hepatoma cell lines HepG2 and SMMC-7721.

Methods:

The cytotoxic effect of drugs was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The coefficient of drug interaction was used to analyze the nature of drug interactions. Morphological changes were observed by acridine orange fluorescence staining. Cell cycle and the apoptosis rate were detected by flow cytometry. Bcl-2 and Bax expression were assayed by immunohistochemical staining.

Results:

Pae or CDDP had antiproliferative effect on the 2 cell lines in a dose-dependent manner, with different sensitivities to drugs. More interestingly, a synergistic inhibitory effect on the viability of the 2 cell lines was observed after treatment with a combination of Pae (15.63, 31.25, and 62.5 mg/L) with various concentrations of CDDP. Further study showed typical morphological changes of apoptosis if the cells were exposed to the two agents for 24 h. The apoptotic rate of the cells with combination treatment was significantly higher than that of cells treated with Pae or CDDP alone. The expression of Bcl-2 decreased and that of Bax increased in the treated groups, especially in the combination group, with the ratio of Bcl-2/Bax decreasing correspondingly. Additionally, a combination of Pae with CDDP resulted in a stronger S phase arrest, compared with Pae or CDDP alone.

Conclusion:

Pae, in combination with CDDP, had a significantly synergistic growth-inhibitory and apoptosis-inducing effect on the 2 human hepatoma cell lines, which may be useful in hepatoma treatment.

References

  1. McGlynn KA, London WT . Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol, 2005; 19: 3–23.

    Article  Google Scholar 

  2. Teo EK, Fock KM . Hepatocellular carcinoma: an Asian perspective. Dig Dis, 2001; 19: 263–8.

    CAS  Article  Google Scholar 

  3. Johnson PJ . Hepatocellular carcinoma: is current therapy really altering outcome? Gut 2002; 51: 459–62.

    CAS  Article  Google Scholar 

  4. Shu X, McCulloch M, Xiao H, Broffman M, Gao J . Chinese herbal medicine and chemotherapy in the treatment of hepato-cellular carcinoma: a meta-analysis of randomized controlled trials. Integr Cancer Ther, 2005; 4: 219–29.

    Article  Google Scholar 

  5. Riley CM, Ren TC . Simple method for the determination of paeonol in human and rabbit plasma by high performance liquid chromatography using solid-phase extraction and ultraviolet detection. J Chromatogr, 1989; 489: 432–7.

    CAS  Article  Google Scholar 

  6. Sun YC, Shen YX, Sun GP . Advances in the studies of major pharmacological activity of paeonol. Chin Tradit Pat Med, 2004; 26: 579–82. Chinese.

    Google Scholar 

  7. Jiang SP, Chen YX . Advances and application in the studies of the Pycnostelma paniculatum (Bunge) K.S. and paeonol. China J Chin Mater Med, 1994; 19: 311–4. Chinese.

    CAS  Google Scholar 

  8. Sun G P, Wang H, Shen YX, Xu SY . Inhibitory effects of paeonol on the proliferation on four tumor cell lines. Anhui Med Pharm J, 2004; 8: 85–7. Chinese.

    Google Scholar 

  9. Sun GP, Shen YX, Zhang LL, Zhou AW, Wei W, Xu SY . Study on immunomodulation and antitumor activity of paeonol in HepA tumor mice. Chin Pharm Bull, 2003; 19: 160–2. Chinese.

    CAS  Google Scholar 

  10. Sun GP, Shen YX, Zhang LL, Wang H, Wei W, Xu SY . Antitumor effect of paeonol in vitro and in vivo. Acta Univ Med Anhui 2002; 37: 183–5. Chinese.

    Google Scholar 

  11. Ji CY, Tan SY, Liu CQ . Inhibitory effect of paeonol on the proliferation of human colorectal cancer cell line HT-29 and its synergistic effect with chemotherapy agents. Chin J Clin Gastroenterol, 2005; 17: 122–4. Chinese.

    Google Scholar 

  12. Cao SS, Zhen YS . Potentiation of antimetabolite antitumor activity in vivo by dipyridamole and amphotericin B. Cancer Chemother Pharmacol, 1989; 24: 181–6.

    CAS  Article  Google Scholar 

  13. Horie N, Hirabayashi N, Takahashi Y, Miyauchi Y, Taguchi H, Takeishi K . Synergistic effect of green tea catechins on cell growth and apoptosis induction in gastric carcinoma cells. Biol Pharm Bull, 2005; 28: 574–9.

    CAS  Article  Google Scholar 

  14. Qi YL, Liao F, Zhao CQ, Lin YD, Zuo MX . Cytotoxicity, apoptosis induction, and mitotic arrest by a novel podophyllotoxin glucoside, 4DPG, in tumor cells. Acta Pharmacol Sin, 2005; 26: 1000–8.

    CAS  Article  Google Scholar 

  15. Tyagi AK, Agarwal C, Chan DC, Agarwal R . Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep, 2004; 11: 493–9.

    CAS  PubMed  Google Scholar 

  16. Yim D, Singh RP, Agarwal C, Lee S, Chi H, Agarwal R . A novel anticancer agent, decursin, induces G1 arrest and apoptosis in human prostate carcinoma cells. Cancer Res, 2005; 65: 1035–44.

    CAS  Article  Google Scholar 

  17. Sun GP, Wang H, Shen YX, Zhai ZM, Wei W, Xu SY . Study on effects of paeonol in inhibiting growth of K562 and inducing its apoptosis. Chin Pharm Bull, 2004; 20: 550–2. Chinese.

    CAS  Google Scholar 

  18. Liu CQ, Tan SY, Ji CY, Luo HS, Yu JP . The effects of paeonol on inhibiting the proliferation of human colorectal cancer cell line HT-29 and its molecule mechanism. Chin Pharm Bull, 2005; 21: 1251–4. Chinese.

    CAS  Article  Google Scholar 

  19. Gottesman MM . Mechanisms of cancer drug resistance. Annu Rev Med, 2002; 53: 615–27.

    CAS  Article  Google Scholar 

  20. Kaufmann SH, Vaux DL . Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene, 2003; 22: 7414–30.

    CAS  Article  Google Scholar 

  21. Schweitzer VG . Cisplatin-induced cytotoxicity: the effect of pigmentation and inhibitory agents. Laryngoscope, 1993; 103: 1–52.

    CAS  PubMed  Google Scholar 

  22. Nguyen HN, Sevin BU, Averette HE, Perras J, Ramos R, Donato D, et al. Cell cycle perturbations of platinum derivatives on two ovarian cancer cell lines. Cancer Invest, 1993; 11: 264–75.

    CAS  Article  Google Scholar 

  23. Potter AJ, Rabinovitch PS . The cell cycle phases of DNA damage and repair initiated by topoisomerase II-targeting chemotherapeutic drugs. Mutat Res, 2005; 572: 27–44.

    CAS  Article  Google Scholar 

  24. Adams JM, Cory S . The Bcl-2 protein family: arbiters of cell survival. Science, 1998; 281: 1322–6.

    CAS  Article  Google Scholar 

  25. Reed JC . Bcl-2 and the regulation of programmed cell death. J Cell Biol, 1994; 124: 1–6.

    CAS  Article  Google Scholar 

  26. Reed JC . Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol, 1997; 34: 9–19.

    CAS  PubMed  Google Scholar 

  27. Zhang CL, Wu LJ, Tashiro S, Onodera S, Ikejima T . Oridonin induces apoptosis of HeLa cells via altering expression of Bcl-2/ Bax and activating caspase-3/ICAD pathway. Acta Pharmacol Sin, 2004; 25: 691–8.

    CAS  PubMed  Google Scholar 

  28. Zhong L, Li CM, Hao XJ, Lou LG . Induction of leukemia cell apoptosis by cheliensisin A involves down-regulation of Bcl-2 expression. Acta Pharmacol Sin, 2005; 26: 623–8.

    CAS  Article  Google Scholar 

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Correspondence to Guo-ping Sun.

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Project supported by the Natural Science Foundation of Anhui Province (No 00044414, and 050430901), the Key Project of the Natural Science Foundation of the Department of Education, Anhui Province (No 2003Kj037zd), and the Natural Science Foundation of the Department of Health, Anhui Province (No 2002A025).

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Xu, Sp., Sun, Gp., Shen, Yx. et al. Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines . Acta Pharmacol Sin 28, 869–878 (2007). https://doi.org/10.1111/j.1745-7254.2007.00564.x

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  • DOI: https://doi.org/10.1111/j.1745-7254.2007.00564.x

Keywords

  • paeonol
  • cisplatin
  • drug interaction
  • human hepatoma cell line
  • apoptosis
  • cell cycle

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