Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Protective Effect of Astragalus polysaccharides on Liver Injury Induced by Several Different Chemotherapeutics in Mice

  • Liu, Wen (Department of Pathology and Pathophysiology, Research Center of Food and Drug Evaluation, School of Medicine, Wuhan University) ;
  • Gao, Fang-Fang (Department of Pathology and Pathophysiology, Research Center of Food and Drug Evaluation, School of Medicine, Wuhan University) ;
  • Li, Qun (Renmin Hospital of Wuhan University, the First College of Clinical Medicine of Wuhan University) ;
  • Lv, Jia-Wei (Zhongnan Hospital of Wuhan University, the Second College of Clinical Medicine of Wuhan University) ;
  • Wang, Ying (Department of Pathology and Pathophysiology, Research Center of Food and Drug Evaluation, School of Medicine, Wuhan University) ;
  • Hu, Peng-Chao (Department of Pathology and Pathophysiology, Research Center of Food and Drug Evaluation, School of Medicine, Wuhan University) ;
  • Xiang, Qing-Ming (Zhongnan Hospital of Wuhan University, the Second College of Clinical Medicine of Wuhan University) ;
  • Wei, Lei (Department of Pathology and Pathophysiology, Research Center of Food and Drug Evaluation, School of Medicine, Wuhan University)
  • Published : 2015.01.06
Download PDF
⟨ Previous Next ⟩

Abstract

Side effects are an unavoidable consequence of chemotherapy drugs, during which liver injury often takes place. The current study was designed to investigate the protective effect of Astragalus polysaccharides (APS) against the hepatotoxicity induced by frequently-used chemical therapy agents, cyclophosphamide (CTX), docetaxel (DTX) and epirubicin (EPI)) in mice. Mice were divided into five groups, controls, low or high dose groups ($DTX_L$, $CTX_L$, $EPI_L$ or $DTX_H$, $CTX_H$, $EPI_H$), and low or high dose chemotherapeutics+APS groups ($DTX_L$+APS, $CTX_L$+APS, $EPI_L$+APS or $DTX_H$+APS, $CTX_H$+APS, $EPI_H$+APS). Controls were treated with equivalent normal saline for 28 days every other day; low or high dose group were intraperitoneal (i.p) injected with low or high doses of CTX, DTX and EPI for 28 days every other day; low or high dose chemotherapeutics+APS group were separately intraperitoneal (i.p) injected with chemotherapeutics for 28 days every other day and i.p with APS (100 mg/kg) for 7 days continually from the 22th to the 28th days. The body weight, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histopathological features, and ultrastructure morphological change of liver tissues, protein expression level of caspase-3 were estimated at different time points. With high dose treatment of DTX, CTX and EPI, weight gain was inhibited and serum levels of ALT and AST were significantly increased. Sections of liver tissue showed massive hepatotoxicity in $CTX_H$ group compared to the control group, including hepatic lobule disorder, granular and vacuolar degeneration and necrosis in hepatic cells. These changes were confirmed at ultrastructural level, including obvious pyknosis, heterochromatin aggregation, nuclear membrane resolution, and chondrosome crystal decrease. Western blotting revealed that the protein levels of caspase-3 increased in $CTX_H$ group. The low dose groups exhibited trivial hepatotoxicity. More interestingly, after 100 mg/kg APS, liver injury was redecued not only regarding serum transaminase activities (low or high dose chemotherapeutics+APS group), but also from pathological and ultrastructural changes and the protein levels of caspase-3 ($CTX_H$+APS group). In conclusion, DTX, CTX and EPI induce liver damage in a dose dependent manner, whereas APS exerted protective effects.

Keywords

References

  1. Anonymous (2003). Astragalus membranaceus. Monograph. Altern Med Rev, 8, 72-7.
  2. Al-Sayed E, Martiskainen O, Seif el-Din SH, et al (2014). Hepatoprotective and antioxidant effect of Bauhinia hookeri extract against carbon tetrachloride-induced hepatotoxicity in mice and characterization of its bioactive compounds by HPLC-PDA-ESI-MS/MS. Biomed Res Int, 2014, 245171.
  3. Alexandre J, Bleuzen P, Bonneterre J, et al (2000). Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol, 18, 562-73.
  4. Basu A, Bhattacharjee A, Roy SS, et al (2014). Vanadium as a chemoprotectant: effect of vanadium (III)-L-cysteine complex against cyclophosphamide-induced hepatotoxicity and genotoxicity in Swiss albino mice. J Biol Inorg Chem, 19, 981-96. https://doi.org/10.1007/s00775-014-1141-6
  5. Bissery MC, Nohynek G, Sanderink GJ, et al (1995). Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: Preclinical experience. Anticancer Drugs, 6, 63-8. https://doi.org/10.1097/00001813-199512006-00011
  6. Chen X, Ye G, Zhang C, et al (2013). Superior outcome after neoadjuvant chemotherapy with docetaxel, anthracycline, and cyclophosphamide versus docetaxel plus cyclophosphamide: results from the NATT trial in triple negative or HER2 positive breast cancer. Breast Cancer Res Treat, 142, 549-58. https://doi.org/10.1007/s10549-013-2761-1
  7. de Jonge ME, Huitema AD, Beijnen JH, et al (2006). High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy. Br J Cancer, 94, 1226-30. https://doi.org/10.1038/sj.bjc.6603097
  8. Ding Y, Zhao L, Mei H, et al (2008). Exploration of Emodin to treat alpha-naphthylisothiocyanate-induced cholestatic hepatitis via anti-inflammatory pathway. Eur J Pharmacol, 590, 377-86. https://doi.org/10.1016/j.ejphar.2008.06.044
  9. Dobbs NA, Twelves CJ, Gregory W, et al (2003). Epirubicin in patients with liver dysfunction: development and evaluation of a novel dose modification scheme. Eur J Cancer, 39, 580-6. https://doi.org/10.1016/S0959-8049(02)00669-X
  10. Fan L, Strasser-Weippl K, Li JJ, et al (2014). Breast cancer in China. Lancet Oncol, 15, e279-89. https://doi.org/10.1016/S1470-2045(13)70567-9
  11. Fang Y, Wang L, Xia GH, et al (2014). Clinical investigation of efficacy of albumin bound paclitaxel plus platinum compounds as first-line chemotherapy for stage III/IV squamous non-small cell lung cancer. Asian Pac J Cancer Prev, 15, 7453-7. https://doi.org/10.7314/APJCP.2014.15.17.7453
  12. Field KM, Dow C, Michael M (2008). Part I: Liver function in oncology: biochemistry and beyond. Lancet Oncol, 9, 1092-101. https://doi.org/10.1016/S1470-2045(08)70279-1
  13. Fisher B, Brown AM, Dimitrov NV, et al (1990). Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifennonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol, 8, 1483-96.
  14. Horton AA, Fairhurst S (1987). Lipid peroxidation and mechanisms of toxicity. Crit Rev Toxicol, 18, 27-79. https://doi.org/10.3109/10408448709089856
  15. Jia R, Cao L, Xu P, et al (2012). In vitro and in vivo hepatoprotective and antioxidant effects of Astragalus polysaccharides against carbon tetrachloride-induced hepatocyte damage in common carp (Cyprinus carpio). Fish Physiol Biochem, 38, 871-81. https://doi.org/10.1007/s10695-011-9575-z
  16. Joerger M (2014). Metabolism of the taxanes including nabpaclitaxel. Expert Opin Drug Metab Toxicol, 1-12 [Epub ahead of print].
  17. Kebieche M, Lakroun Z, Lahouel M, et al (2009). Evaluation of epirubicin-induced acute oxidative stress toxicity in rat liver cells and mitochondria, and the prevention of toxicity through quercetin administration. Exp Toxicol Pathol, 61, 161-7. https://doi.org/10.1016/j.etp.2008.06.002
  18. King PD, Perry MC (2001). Hepatotoxicity of chemotherapy. Oncologist, 6, 162-76. https://doi.org/10.1634/theoncologist.6-2-162
  19. Liu X, Yang Y, Zhang X, et al (2010). Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor-beta/Smad in HepG2 cell. J Gastroenterol Hepatol, 25, 420-6. https://doi.org/10.1111/j.1440-1746.2009.05981.x
  20. Lu AF, Qi MJ, Li ZL, et al (2010). Callus cultivation and determination of flavonoids from Tetrastigma hemsleyanum. Zhong Yao Cai, 33, 1042-5.
  21. Lubgan D, Marczak A, Walczak M, et al (2006). Pharmacological mechanisms of Doxorubicin activity (DOX)-current state of knowledge. Przegl Lek, 63, 782-8.
  22. Ma B, Yeo W, Hui P, et al (2002a). Acute toxicity of adjuvant doxorubicin and cyclophosphamide for early breast cancer-a retrospective review of Chinese patients and comparison with an historic Western series. Radiother Oncol, 62, 185-9. https://doi.org/10.1016/S0167-8140(02)00003-8
  23. Ma XQ, Shi Q, Duan JA, et al (2002b). Chemical analysis of Radix Astragali (Huangqi) in China: a comparison with its adulterants and seasonal variations. J Agric Food Chem, 50, 4861-6. https://doi.org/10.1021/jf0202279
  24. Matovina-Brko G, Ruzic M, Fabri M, et al (2014). Treatment of acute hepatitis C in breast cancer patient: a case report. J Chemother, 26, 180-3. https://doi.org/10.1179/1973947813Y.0000000129
  25. McDonald GB, Slattery JT, Bouvier ME, et al (2003). Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood, 101, 2043-8. https://doi.org/10.1182/blood-2002-06-1860
  26. McQuade JL, Meng Z, Chen Z, et al (2012). Utilization of and Attitudes towards Traditional Chinese Medicine Therapies in a Chinese Cancer Hospital: A Survey of Patients and Physicians. Evid Based Complement Alternat Med, 2012, 504507.
  27. Murialdo R, Gallo M, Boy D, et al (2014). Sequential dose-dense 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel in patients with early breast cancer with four or more positive lymph nodes. Tumori, 100, 128-35.
  28. Na D, Liu FN, Miao ZF, et al (2009). Astragalus extract inhibits destruction of gastric cancer cells to mesothelial cells by anti-apoptosis. World J Gastroenterol, 15, 570-7. https://doi.org/10.3748/wjg.15.570
  29. Naume B, Synnestvedt M, Falk RS, et al (2014). Clinical outcome with correlation to disseminated tumor cell (DTC) status after DTC-guided secondary adjuvant treatment with docetaxel in early breast cancer. J Clin Oncol, 32, 3848-57. https://doi.org/10.1200/JCO.2014.56.9327
  30. Ozben T (2007). Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci, 96, 2181-96. https://doi.org/10.1002/jps.20874
  31. Peng X, Chen B, Lim CC, et al (2005). The cardiotoxicology of anthracycline chemotherapeutics: translating molecular mechanism into preventative medicine. Mol Interv, 5, 163-71. https://doi.org/10.1124/mi.5.3.6
  32. Shin HJ, Lee HS, Kim YI, et al (2014). Hepatotoxicity of antituberculosis chemotherapy in patients with liver cirrhosis. Int J Tuberc Lung Dis, 18, 347-51. https://doi.org/10.5588/ijtld.13.0545
  33. Shokrzadeh M, Naghshvar F, Ahmadi A, et al (2014). The potential ameliorative effects of melatonin against cyclophosphamide-induced DNA damage in murine bone marrow cells. Eur Rev Med Pharmacol Sci, 18, 605-11.
  34. Thatishetty AV, Agresti N, O'Brien CB (2013). Chemotherapyinduced hepatotoxicity. Clin Liver Dis, 17, 671-86. https://doi.org/10.1016/j.cld.2013.07.010
  35. Tian QE, Li HD, Yan M, et al (2012). Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice. World J Gastroenterol, 18, 7079-86. https://doi.org/10.3748/wjg.v18.i47.7079
  36. Varbiro G, Veres B, Gallyas F, et al (2001). Direct effect of Taxol on free radical formation and mitochondrial permeability transition. Free Radic Biol Med, 31, 548-58. https://doi.org/10.1016/S0891-5849(01)00616-5
  37. Wang XH, Jia HL, Deng L, et al (2014). Astragalus polysaccharides mediated preventive effects on bronchopulmonary dysplasia in rats. Pediatr Res, 76, 347-54. https://doi.org/10.1038/pr.2014.107
  38. Yang B, Xiao B, Sun T (2013). Antitumor and immunomodulatory activity of Astragalus membranaceus polysaccharides in H22 tumor-bearing mice. Int J Biol Macromol, 62, 287-90. https://doi.org/10.1016/j.ijbiomac.2013.09.016
  39. Yeo W, Mok TS, Tse KK, et al (2002). Phase II study of docetaxel and epirubicin in Chinese patients with metastatic breast cancer. Anticancer Drugs, 13, 655-62. https://doi.org/10.1097/00001813-200207000-00013
  40. Zhao LH, Ma ZX, Zhu J, et al (2011). Characterization of polysaccharide from Astragalus radix as the macrophage stimulator. Cell Immunol, 271, 329-34. https://doi.org/10.1016/j.cellimm.2011.07.011

Cited by

  1. The Anti-Oxidant and Antitumor Properties of Plant Polysaccharides vol.44, pp.03, 2016, https://doi.org/10.1142/S0192415X16500269
  2. Astragalus polysaccharides inhibits cell growth and pro-inflammatory response in IL-1β-stimulated fibroblast-like synoviocytes by enhancement of autophagy via PI3K/AKT/mTOR inhibition vol.22, pp.9, 2017, https://doi.org/10.1007/s10495-017-1387-x
  3. Chemosensitizing Effect of Astragalus Polysaccharides on Nasopharyngeal Carcinoma Cells by Inducing Apoptosis and Modulating Expression of Bax/Bcl-2 Ratio and Caspases vol.23, pp.1643-3750, 2017, https://doi.org/10.12659/MSM.903170
  4. vol.19, pp.10, 2016, https://doi.org/10.1089/jmf.2016.0048
  5. Aidi Injection, a Traditional Chinese Medicine Injection, Could Be Used as an Adjuvant Drug to Improve Quality of Life of Cancer Patients Receiving Chemotherapy: A Propensity Score Matching Analysis pp.1552-695X, 2018, https://doi.org/10.1177/1534735418810799
  6. Combined treatment with apatinib and docetaxel in A549 xenograft mice and its cellular pharmacokinetic basis vol.39, pp.10, 2018, https://doi.org/10.1038/aps.2018.16