Improvement of the Selectivity Index (SI) and Cytotoxicity Activity of Doxorubicin Drug by Panax ginseng Plant Extract

Document Type : Original Articles

Authors

University of Kufa, Faculty of Science, Department of Biology, Iraq

Abstract

In China, Japan, and Korea, Panax ginseng has been used in traditional medicine for thousands of years. Panax is a plant used as a general tonic or adaptogen for chronically ill patients. The current study evaluated the cytotoxicity of Panax ginseng extract (PGE). Different cell lines (HCT-116, LNCaP, and normal cell line VERO) were treated with different inhibitory agentsat different concentrations (1000, 500, 250, 125, 62.5, and 31.25 µg/ml) as follows: G1 (Methanol Panax ginseng extract, PGE), G2 (Doxorubicin, DOX), and G3 (Methanol Panax ginseng extract +DOX, PDD). Each inhibitory agent group was used to treat the cancerous cell lines HCT-116, LNCaP, and normal cell line (VERO) to obtain IC50% by MTT assay. The inhibitory ability of the 1000 μg/ml PGE was significantly increased in all the three-cell lines compared with other concentrations. The recorded data revealed that the inhibition ability of PGE and Doxorubicin towards the HCT-116 cell line significantly increased compared with the other cell lines. The interaction between different PGE concentrations and cell lines showed that the 1000 μg/ml PEG had the highest inhibitory effects on HCT-116 compared with other combinations. The interaction between different DOX concentrations and different types of cell lines showed that the 1000 μg/ml DOX had the highest inhibitory effects on LNCap compared with other combinations. The PGD inhibition ability reflected a significantly higher difference toward the HCT-116 cell line as compared with other cell lines. IC50% is the concentrations (µg/ml) to kill 50% of cell line. It was calculated by MTT assay for three cell lines: HCT-116, LNCaP, and VERO. The rate of effectiveness of the inhibitory factors (PGE, DOX, and PGD) showed highly significant differences toward the cell line HCT-116 compared to the other cell lines. This indicates the safety of the PGE compound and its low toxicity toward normal cells, quite the opposite of cancer cells as compared to the common drug DOX and combined PGD (PGE+DOX). PGD combined with DOX (PGE + DOX) showed antagonistic results toward the HCT116, LNCaP, and VERO cell lines, while UDE combined with DOX (UDE+DOX) showed synergistic activity.

Keywords

Main Subjects


Article Title [French]

Amélioration de l'Indice de Sélectivité (IS) et de l'Activité de Cytotoxicité du Médicament Doxorubicine par l'extrait de Plante Panax ginseng

Abstract [French]

En Chine, au Japon et en Corée, le Panax ginseng est utilisé en médecine traditionnelle depuis des milliers d'années. Panax est une plante utilisée comme tonique général ou adaptogène pour les patients atteints de maladies chroniques. La présente étude a évalué la cytotoxicité de l'extrait de Panax ginseng (EPG). Différentes lignées cellulaires (HCT-116, LNCaP et lignée cellulaire normale VERO) ont été traitées avec différents agents inhibiteurs à différentes concentrations (1000, 500, 250, 125, 62.5 et 31.25 µg/ml) comme suit: G1 (Extrait méthanol Panax ginseng, EPG), G2 (Doxorubicine, DOX) et G3 (Extrait méthanol Panax ginseng +DOX, PDD). Chaque groupe d'agents inhibiteurs a été utilisé pour traiter les lignées cellulaires cancéreuses HCT-116, LNCaP et la lignée cellulaire normale (VERO) pour obtenir une CI50% par dosage MTT. La capacité inhibitrice de l'EPG à 1000 g/ml a été significativement augmentée dans toutes les lignées à trois cellules par rapport aux autres concentrations. Les données enregistrées ont révélé que la capacité d'inhibition de l'EPG et de la doxorubicine envers la lignée cellulaire HCT-116 a considérablement augmenté par rapport aux autres lignées cellulaires. L'interaction entre différentes concentrations de l'EPG et des lignées cellulaires a montré que le PEG à 1000 ug/ml avait les effets inhibiteurs les plus élevés sur HCT-116 par rapport à d'autres combinaisons. L'interaction entre différentes concentrations de DOX et différents types de lignées cellulaires a montré que la DOX à 1000 g/ml avait les effets inhibiteurs les plus élevés sur LNCap par rapport à d'autres combinaisons. La capacité d'inhibition du PGD reflétait une différence significativement plus élevée envers la lignée cellulaire HCT-116 par rapport aux autres lignées cellulaires. IC50% est la concentration (µg/ml) pour tuer 50% de la lignée cellulaire. Il a été calculé par dosage MTT pour trois lignées cellulaires: HCT-116, LNCaP et VERO. Le taux d'efficacité des facteurs inhibiteurs (EPG, DOX et PGD) a montré des différences très significatives envers la lignée cellulaire HCT-116 par rapport aux autres lignées cellulaires. Cela indique la sécurité du composé EPG et sa faible toxicité envers les cellules normales, tout à fait le contraire des cellules cancéreuses par rapport au médicament commun DOX et au PGD combiné (EPG + DOX). Le PGD combiné à la DOX (EPG + DOX) a montré des résultats antagonistes envers les lignées cellulaires HCT116, LNCaP et VERO, tandis que l'UDE combiné à la DOX (UDE + DOX) a montré une activité synergique.

Keywords [French]

  • Panax ginseng
  • HCT-116
  • LNCap
  • Vero
  • Doxorubicine
  • indice d'interaction
  • indice de sélectivité
  1. Jung MY, Jeon BS, Bock JY. Free, esterified, and insoluble-bound phenolic acids in white and red Korean ginsengs (Panax ginseng C.A. Meyer). Food Chem. 2002;79(1):105-11.
  2. Baeg IH, So SH. The world ginseng market and the ginseng (Korea). J Ginseng Res. 2013;37(1):1-7.
  3. Scholar G. Ministry_of_AgricultureFaRA, Ginseng Statistical Data (No. 11-1543000-000004-10) Ministry of Agriculture FaRA 2013:2-7.
  4. Kwok HH, Ng WY, Yang MS, Mak NK, Wong RN, Yue PY. The ginsenoside protopanaxatriol protects endothelial cells from hydrogen peroxide-induced cell injury and cell death by modulating intracellular redox status. Free Radic Biol Med. 2010;48(3):437-45.
  5. Naval MV, Gomez-Serranillos MP, Carretero ME, Villar AM. Neuroprotective effect of a ginseng (Panax ginseng) root extract on astrocytes primary culture. J Ethnopharmacol. 2007;112(2):262-70.
  6. Song X, Chen J, Sakwiwatkul K, Li R, Hu S. Enhancement of immune responses to influenza vaccine (H3N2) by ginsenoside Re. Int Immunopharmacol. 2010;10(3):351-6.
  7. Wang CZ, Mehendale SR, Yuan CS. Commonly used antioxidant botanicals: active constituents and their potential role in cardiovascular illness. Am J Chin Med. 2007;35(4):543-58.
  8. Y.G. Gao, P. Zang, J.X. Hao, P. Li, X. Li, P.J. Zhang, et al. he evaluation of contents of nine ginsenoside monomers in four commercial ginseng by reverse phasehigh performance liquid chromatography (RP-HPLC) J Med Plants Res. 2012;6:3030-6.
  9. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305(22):2295-303.
  10. Sweilem HbA. Implications of the use of collateral and their potential impact on national security. Naif Arab University (NAUSS). 2011;503.
  11. Almowafy R, Taha YA. Monthly Archives2013.
  12. Homady MH, Kadhim HA, Al-Kelaby KKA, Aziz DZ, Kadhim NJ. Cytotoxic activity of compounded anthracycline against rhabdomyosarcoma cancer cell )line. Plant Archives. 2018;18(1):941-6.
  13. Remesh A. Toxicities of anticancer drugs and its management. Int J Basic Clin Pharmacol. 2017;1(1):2-12.
  14. Konstat-Korzenny E, Ascencio-Aragon JA, Niezen-Lugo S, Vazquez-Lopez R. Artemisinin and Its Synthetic Derivatives as a Possible Therapy for Cancer. Med Sci (Basel). 2018;6(1.(
  15. Sak K. Chemotherapy and dietary phytochemical agents. Chemother Res Pract. 2012;2012:282570.
  16. Ali M, Abbasi BH, Ahmad N, Khan H, Ali GS. Strategies to enhance biologically active-secondary metabolites in cell cultures of Artemisia - current trends. Crit Rev Biotechnol. 2017;37(7):833-51.
  17. Hashym QM, Al-Zahra JMA, Kadhim NJ. Reducing the Heart Biochemical and Histological Effect of Doxorubicin by Artemisinin Compound. Plant Archives. 2019;19(1):268-71.
  18. Bakrania K, Edwardson CL, Bodicoat DH, Esliger DW, Gill JM, Kazi A, et al. Associations of mutually exclusive categories of physical activity and sedentary time with markers of cardiometabolic health in English adults: a cross-sectional analysis of the Health Survey for England. BMC Public Health. 2016;16:25.
  19. Kadhim NJ, Al-Rekaby LS, Redha AA, J. C. Chemical composition and antioxidant capacity of eggplant parts during vegetative and flowering stage. J Phys Conf Ser 2019;1294(1 ):092013.
  20. Barrera G. Oxidative stress and lipid peroxidation products in cancer progression and therapy. ISRN Oncol. 2012;2012:137289.
  21. Wang Z, Mi, H., Hamza W, Florian R. Multi-perspective context matching for machine comprehension. arXiv preprint arXiv. 2016:1612.04211.
  22. Tong P, Coombes KR, Johnson FM, Byers LA, Diao L, Liu DD, et al. drexplorer: A tool to explore dose-response relationships and drug-drug interactions. Bioinformatics. 2015;31(10):1692-4.
  23. Chen S, Wang Z, Huang Y, O'Barr SA, Wong RA, Yeung S, et al. Ginseng and anticancer drug combination to improve cancer chemotherapy: a critical review. Evid Based Complement Alternat Med. 2014;2014:168940.
  24. Klempner SJ, Bubley G. Complementary and alternative medicines in prostate cancer: from bench to bedside? Oncologist. 2012;17(6):830-7.
  25. McDermott CL, Blough DK, Fedorenko CR, Arora NK, Zeliadt SB, Fairweather ME, et al. Complementary and alternative medicine use among newly diagnosed prostate cancer patients. Support Care Cancer. 2012;20(1):65-73.
  26. Sartiano GP, Lynch WE, Bullington WD. Mechanism of action of the anthracycline anti-tumor antibiotics, doxorubicin, daunomycin and rubidazone: preferential inhibition of DNA polymerase alpha. J Antibiot (Tokyo). 1979;32(10):1038-45.
  27. Effenberger-Neidnicht K, Schobert R. Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin. Cancer Chemother Pharmacol. 2011;67(4):867-74.
  28. Park HH, Choi SW, Lee GJ, Kim YD, Noh HJ, Oh SJ, et al. A formulated red ginseng extract inhibits autophagic flux and sensitizes to doxorubicin-induced cell death. J Ginseng Res. 2019;43(1):86-94.
  29. Kim SM, Lee SY, Cho JS, Son SM, Choi SS, Yun YP, et al. Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-kappaB. Eur J Pharmacol. 2010;631(1-3):1-9.
  30. Kim SM, Lee SY, Yuk DY, Moon DC, Choi SS, Kim Y, et al. Inhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel. Arch Pharm Res. 2009;32(5):755-65.
  31. Gu C, Qiao J, Zhu M, Du J, Shang W, Yin W, et al. Preliminary evaluation of the interactions of Panax ginseng and Salvia miltiorrhiza Bunge with 5-fluorouracil on pharmacokinetics in rats and pharmacodynamics in human cells. Am J Chin Med. 2013;41(2):443-58.
  32. B. X. Wang, J. C. Cui, A. J. Liu. The action of ginsenosides extracted from the stems and leaves of Panax ginseng in promoting animal growth. Acta Pharmaceutica Sinica. 1982;17(12):899-904.
  1. Du XF, Jiang CZ, Wu CF, Won EK, Choung SY. Synergistic immunostimulating activity of pidotimod and red ginseng acidic polysaccharide against cyclophosphamide-induced immunosuppression. Arch Pharm Res. 2008;31(9):1153-9.
  2. Liu TG, Huang Y, Cui DD, Huang XB, Mao SH, Ji LL, et al. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. BMC Cancer. 2009;9:250.
  3. Zhang Q, Kang X, Zhao W. Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem Biophys Res Commun. 2006;342(3):824-8.
  4. Ge M, Fang YY, Liu GP, Guan SD. Effect of Shengmai injection on diaphragmatic contractility in doxorubicin-treated rats. Chin J Integr Med. 2014;20(1):43-8.
  5. Chen Z, Wang P, Huang WX, Liu LM. [Experimental study on effects of shengmai injection: enhancing 5-FU anti-tumor efficacy and reducing its toxicity]. Zhong Xi Yi Jie He Xue Bao. 2005;3(6):49-79.
  6. Che CT, Wang ZJ, Chow MS, Lam CW. Herb-herb combination for therapeutic enhancement and advancement: theory, practice and future perspectives. Molecules. 2013;18(5):5125-41.
  7. Z. J. Wang, C. Xie, Y. Huang, C. W. K. Lam, M. S. S. Chow. Overcoming chemotherapy resistance with herbal medicines: past, present and future perspectives. Phytochem Rev. 2014;13(1):323-37.
  8. Hu Z, Yang X, Ho PC, Chan SY, Heng PW, Chan E, et al. Herb-drug interactions: a literature review. Drugs. 2005;65(9):1239-82.
  9. Sun H, Liu XD, Liu Q, Wang FP, Bao XQ, Zhang D. Reversal of P-glycoprotein-mediated multidrug resistance by the novel tetrandrine derivative W6. J Asian Nat Prod Res. 2015;17(6):638-48.
  10. Abdallah HM, Al-Abd AM, El-Dine RS, El-Halawany AM. P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review. J Adv Res. 2015;6(1):45-62.
  11. Lai GM, Chen YN, Mickley LA, Fojo AT, Bates SE. P-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines. Int J Cancer. 1991;49(5):696-703.
  12. S. Helms. Cancer prevention and therapeutics: Panax ginseng. Alternative Medicine Review. 2004;9(3):259-74.