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.
Similar content being viewed by others
Article PDF
References
McGlynn KA, London WT . Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol, 2005; 19: 3–23.
Teo EK, Fock KM . Hepatocellular carcinoma: an Asian perspective. Dig Dis, 2001; 19: 263–8.
Johnson PJ . Hepatocellular carcinoma: is current therapy really altering outcome? Gut 2002; 51: 459–62.
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.
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.
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.
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.
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.
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.
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.
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.
Cao SS, Zhen YS . Potentiation of antimetabolite antitumor activity in vivo by dipyridamole and amphotericin B. Cancer Chemother Pharmacol, 1989; 24: 181–6.
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.
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.
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.
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.
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.
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.
Gottesman MM . Mechanisms of cancer drug resistance. Annu Rev Med, 2002; 53: 615–27.
Kaufmann SH, Vaux DL . Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene, 2003; 22: 7414–30.
Schweitzer VG . Cisplatin-induced cytotoxicity: the effect of pigmentation and inhibitory agents. Laryngoscope, 1993; 103: 1–52.
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.
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.
Adams JM, Cory S . The Bcl-2 protein family: arbiters of cell survival. Science, 1998; 281: 1322–6.
Reed JC . Bcl-2 and the regulation of programmed cell death. J Cell Biol, 1994; 124: 1–6.
Reed JC . Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol, 1997; 34: 9–19.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
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).
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2007.00564.x
Keywords
This article is cited by
-
Paeonol inhibits proliferation and induces cell apoptosis of human T24 and 5637 bladder cancer cells in vitro and in vivo
Clinical and Translational Oncology (2021)
-
Bruton’s tyrosine kinase and RAC1 promote cell survival in MLL-rearranged acute myeloid leukemia
Leukemia (2018)
-
Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation
Scientific Reports (2017)
-
Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3
Journal of Physiology and Biochemistry (2017)
-
Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors
Scientific Reports (2016)