Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 2, pp 165–175 | Cite as

Rutin and orlistat produce antitumor effects via antioxidant and apoptotic actions

  • Amira Saleh
  • Hassan M. ElFayoumi
  • Mahmoud Youns
  • Waleed BarakatEmail author
Original Article


Cancer is a broad term used to describe a large number of diseases characterized by uncontrolled cell proliferation that leads to tumor production. Cancer is associated with mutations in genes controlling proliferation and apoptosis, oxidative stress, fatty acid synthase (FAS) expression, and other mechanisms. Currently, most antineoplastic drugs have severe adverse effects and new effective and safe drugs are needed. This study aims to investigate the possible anticancer activity of rutin and orlistat which are both safely used clinically in humans against two breast cancer models (in vivo EAC and in vitro MCF7) and the pancreatic cancer cell line (PANC-1). Our results have shown that both rutin and orlistat exerted an in vivo anticancer activity as evidenced by the decrease in tumor volume, CEA level, cholesterol content, FAS, and the exerted antioxidant action (reduced MDA level and increased GSH content) and through histopathological examination. In addition, both were cytotoxic to MCF-7 and Panc-1 cell lines by promoting apoptosis. In conclusion, the anticancer activity of rutin and orlistat makes them promising candidates for cancer treatment alone or in combination with other anticancer drugs specially that they are used clinically with an acceptable safety profile.


Rutin Orlistat Ehrlich ascites carcinoma Mice MCF-7 PANC-1 


Author contribution

AS performed the in vivo study and analyzed data. HE designed the study and revised the manuscript. MY performed the in vitro study. WB designed the study, analyzed data, and revised the manuscript. All authors read and approved the manuscript.

Compliance with ethical standards

All experimental procedures were approved by the Ethical Committee for Animal Handling at Zagazig University (ECAHZU).

Conflict of interest

The authors declare that they have no conflict of interests.


  1. Abu-Zeid M, Hori H, Nagasawa H, UTO Y, INAYAMA S (2000) Studies of methyl 2-Nitroimidazole-1-acetohydroxamate (KIN-804). 1: effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma. Biol Pharm Bull 23(2):190–194Google Scholar
  2. Adwas AA, Elkhoely AA, Kabel AM, Abdel-Rahman MN, Eissa AA (2016) Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice. J Infect Chemother 22(1):36–43Google Scholar
  3. Ahmed LA, EL-Maraghy SA (2013) Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: possible mechanism of cardioprotection. Biochem Pharmacol 86(9):1301–1310Google Scholar
  4. Ahmed MF, Youns M (2013) Synthesis and biological evaluation of a novel series of 6,8-dibromo-4(3H) quinazolinone derivatives as anticancer agents. Arch Pharm 346(8):610–617Google Scholar
  5. Ahmed HH, Hegazi MM, Abd-Allac HI, Eskander EF, Ellithey MS (2011) Antitumour and antioxidant activity of some Red Sea seaweeds in Ehrlich ascites carcinoma in vivo. Z Naturforsch C 66(7–8):367–376Google Scholar
  6. Alonso-Castro AJ, Domínguez F, García-Carrancá A (2013) Rutin exerts antitumor effects on nude mice bearing SW480 tumor. Arch Med Res 44(5):346–351Google Scholar
  7. Assaad HI, Zhou L, Carroll RJ, Wu G (2014) Rapid publication-ready MS-Word tables for one-way ANOVA. SpringerPlus 3:474Google Scholar
  8. Attia MA, Weiss DW (1966) Immunology of spontaneous mammary carcinomas in mice V. Acquired tumor resistance and enhancement in strain A mice infected with mammary tumor virus. Cancer Res 26(8 Part 1):1787–1800Google Scholar
  9. Auersperg M, PogaÄ nik A, Kloboves-Prevodnik V, Serša G, Čemažar M (2006) Schedule-dependency of doxorubicin and vinblastine in EAT tumours in mice. Radiol Oncol 40(4)Google Scholar
  10. Bai XY, Liu YG, Song W, Li YY, Hou DS, Luo HM, Liu P (2018) Anticancer activity of tetrandrine by inducing pro-death apoptosis and autophagy in human gastric cancer cells. J Pharm Pharmacol 70:1048–1058Google Scholar
  11. Bougoulia M, Triantos A, Koliakos G (2006) Effect of weight loss with or without orlistat treatment on adipocytokines, inflammation, and oxidative markers in obese women. Hormones (Athens) 5(4):259–269Google Scholar
  12. Brown AJ (2007) Cholesterol, statins and cancer. Clin Exp Pharmacol Physiol 34(3):135–141Google Scholar
  13. Buchwald H (1992) Cholesterol inhibition, cancer, and chemotherapy. Lancet 339(8802):1154–1156Google Scholar
  14. Capranico G, Zunino F (1992) DNA topoisomerase-trapping antitumour drugs. Eur J Cancer 28(12):2055–2060Google Scholar
  15. Cardwell CR, Hicks BM, Hughes C, Murray LJ (2014) Statin use after colorectal cancer diagnosis and survival: a population-based cohort study. J Clin Oncol 32(28):3177–3183Google Scholar
  16. Carvalho MA, Zecchin KG, Seguin F, Bastos DC, Agostini M, ALcC R et al (2008) Fatty acid synthase inhibition with orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. Int J Cancer 123(11):2557–2565Google Scholar
  17. Chen AY, Chen YC (2013) A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem 138(4):2099–2107Google Scholar
  18. Chen H, Miao Q, Geng M, Liu J, Hu Y, Tian L, Pan J, Yang Y (2013) Anti-tumor effect of rutin on human neuroblastoma cell lines through inducing G2/M cell cycle arrest and promoting apoptosis. Sci World J 2013:1–8Google Scholar
  19. Cheriyath V, Kuhns MA, Kalaycio ME, Borden EC (2011) Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma. Br J Cancer 104(6):957–967Google Scholar
  20. Cherry SM, Hunt PA, Hassold TJ (2004) Cisplatin disrupts mammalian spermatogenesis, but does not affect recombination or chromosome segregation. Mutat Res Genet Toxicol Environ Mutagen 564(2):115–128Google Scholar
  21. Chuang H-Y, Chang Y-F, Hwang J-J (2011) Antitumor effect of orlistat, a fatty acid synthase inhibitor, is via activation of caspase-3 on human colorectal carcinoma-bearing animal. Biomed Pharmacother 65(4):286–292Google Scholar
  22. da Mota MF, de Carvalho FS, de Avila RI, de Avila PHM, Cortez AP, Menegatti R et al (2018) LQFM030 reduced Ehrlich ascites tumor cell proliferation and VEGF levels. Life Sci 201(1–8)Google Scholar
  23. Da Silva R, De Oliveira T, Nagem T, Pinto A, Albino L, De Almeida M et al (2001) Hypocholesterolemic effect of naringin and rutin flavonoids. Arch Latinoam Nutr 51(3):258–264Google Scholar
  24. del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ (2000) Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10(1):95–112Google Scholar
  25. Dicker D, Herskovitz P, Katz M, Atar E, Bachar GN (2010) Computed tomography study of the effect of orlistat on visceral adipose tissue volume in obese subjects. Isr Med Assoc J 12(4):199–202Google Scholar
  26. Dowling S, Cox J, Cenedella RJ (2009) Inhibition of fatty acid synthase by Orlistat accelerates gastric tumor cell apoptosis in culture and increases survival rates in gastric tumor bearing mice in vivo. Lipids 44(6):489–498Google Scholar
  27. El-Ashmawy NE, Khedr NF, El-Bahrawy HA, Mansour HEA (2017) Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms. Eur J Nutr:1–9Google Scholar
  28. El-Ashmawy NE, Khedr NF, El-Bahrawy HA, Mansour HEA (2018) Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms. Eur J Nutr 57(3):981–989Google Scholar
  29. Elbialy NS, Mady MM (2015) Ehrlich tumor inhibition using doxorubicin containing liposomes. Saudi Pharm J 23(2):182–187Google Scholar
  30. El-Dayem SMA, Fouda FM, Ali EH, El Motelp BAA (2013) The antitumor effects of tetrodotoxin and/or doxorubicin on Ehrlich ascites carcinoma-bearing female mice. Toxicol Ind Health 29(5):404–417Google Scholar
  31. Enayat S, Ceyhan MS, Basaran AA, Gursel M, Banerjee S (2013) Anticarcinogenic effects of the ethanolic extract of Salix aegyptiaca in colon cancer cells: involvement of Akt/PKB and MAPK pathways. Nutr Cancer 65(7):1045–1058Google Scholar
  32. Fahim F, Esmat A, Mady E, Amin M (1997) Serum LDH and ALP isozyme activities in mice bearing solid Ehrlich carcinoma and/or treated with the maximum tolerated dose (MTD) of aloin. Dis Markers 13(3):183–193Google Scholar
  33. Ganeshpurkar A, Saluja AK (2017) The pharmacological potential of rutin. Saudi Pharm J 25(2):149–164Google Scholar
  34. Gautam R, Singh M, Gautam S, Rawat JK, Saraf SA, Kaithwas G (2016) Rutin attenuates intestinal toxicity induced by methotrexate linked with anti-oxidative and anti-inflammatory effects. BMC Complement Altern Med 16(1):1Google Scholar
  35. Gold P, Freedman SO (1965) Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J Exp Med 121(3):439–462Google Scholar
  36. Gönenç A, Özkan Y, Torun M, Şimşek B (2001) Plasma malondialdehyde (MDA) levels in breast and lung cancer patients. J Clin Pharm Ther 26(2):141–144Google Scholar
  37. Gumulec J, Fojtu M, Raudenska M, Sztalmachova M, Skotakova A, Vlachova J, Skalickova S, Nejdl L, Kopel P, Knopfova L, Adam V, Kizek R, Stiborova M, Babula P, Masarik M (2014) Modulation of induced cytotoxicity of doxorubicin by using apoferritin and liposomal cages. Int J Mol Sci 15(12):22960–22977Google Scholar
  38. Hasanpourghadi M, Abdul Majid N, Rais Mustafa M (2018) The role of miRNAs 34a, 146a, 320a and 542 in the synergistic anticancer effects of methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) with doxorubicin in breast cancer cells. PeerJ 6:e5577Google Scholar
  39. Hileman EO, Liu J, Albitar M, Keating MJ, Huang P (2004) Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother Pharmacol 53(3):209–219Google Scholar
  40. Hunyadi A, Martins A, Hsieh T-J, Seres A, Zupkó I (2012) Chlorogenic acid and rutin play a major role in the in vivo anti-diabetic activity of Morus alba leaf extract on type II diabetic rats. PLoS One 7(11):e50619Google Scholar
  41. Islam F, Khatun H, Khatun M, Ali SM, Khanam JA (2014) Growth inhibition and apoptosis of Ehrlich ascites carcinoma cells by the methanol extract of Eucalyptus camaldulensis. Pharm Biol 52(3):281–290Google Scholar
  42. Jacobs EJ, Newton CC, Thun MJ, Gapstur SM (2011) Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort. Cancer Res 71(5):1763–1771Google Scholar
  43. Jelinek D, Castillo JJ, Richardson LM, Luo L, Heidenreich RA, Garver WS (2012) The Niemann-Pick C1 gene is downregulated in livers of C57BL/6J mice by dietary fatty acids, but not dietary cholesterol, through feedback inhibition of the SREBP pathway. J Nutr 142(11):1935–1942Google Scholar
  44. Kabel AM, Omar MS, Balaha MF, Borg HM (2015) Effect of metformin and adriamycin on transplantable tumor model. Tissue Cell 47(5):498–505Google Scholar
  45. Kang D, Hamasaki N (2003) Mitochondrial oxidative stress and mitochondrial DNA. Clin Chem Lab Med 41(10):1281–1288Google Scholar
  46. Kim HY (2015) Statistical notes for clinical researchers: post-hoc multiple comparisons. Restor Dent Endod 40(2):172–176Google Scholar
  47. Knowles LM, Axelrod F, Browne CD, Smith JW (2004) A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2. J Biol Chem 279(29):30540–30545Google Scholar
  48. Kong CS, Kim KH, Choi JS, Kim JE, Park C, Jeong JW (2014) Salicin, an extract from white willow bark, inhibits angiogenesis by blocking the ROS-ERK pathways. Phytother Res 28(8):1246–1251Google Scholar
  49. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW (2004) Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res 64(6):2070–2075Google Scholar
  50. Kuhajda FP (2000) Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16(3):202–208Google Scholar
  51. Kuhajda FP (2006) Fatty acid synthase and cancer: new application of an old pathway. Cancer Res 66(12):5977–5980Google Scholar
  52. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR (1994) Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci 91(14):6379–6383Google Scholar
  53. Kumaraguruparan R, Subapriya R, Kabalimoorthy J, Nagini S (2002) Antioxidant profile in the circulation of patients with fibroadenoma and adenocarcinoma of the breast. Clin Biochem 35(4):275–279Google Scholar
  54. Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, Kanamori H, Khai NC, Maruyama R, Ogino A, Minatoguchi S, Fujiwara T, Fujiwara H (2006) Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation 113(4):535–543Google Scholar
  55. Lin J-P, Yang J-S, Lu C-C, Chiang J-H, Wu C-L, Lin J-J, Lin HL, Yang MD, Liu KC, Chiu TH, Chung JG (2009) Rutin inhibits the proliferation of murine leukemia WEHI-3 cells in vivo and promotes immune response in vivo. Leuk Res 33(6):823–828Google Scholar
  56. Lin J-P, Yang J-S, Lin J-J, Lai K-C, Lu H-F, Ma C-Y, Sai-Chuen Wu R, Wu KC, Chueh FS, Gibson Wood W, Chung JG (2012) Rutin inhibits human leukemia tumor growth in a murine xenograft model in vivo. Environ Toxicol 27(8):480–484Google Scholar
  57. Lown JW, Sim S-K, Majumdar KC, Chang R-Y (1977) Strand scission of DNA by bound adriamycin and daunorubicin in the presence of reducing agents. Biochem Biophys Res Commun 76(3):705–710Google Scholar
  58. Martinez-Villaluenga C, Rupasinghe SG, Schuler MA, Gonzalez de Mejia E (2010) Peptides from purified soybean β-conglycinin inhibit fatty acid synthase by interaction with the thioesterase catalytic domain. FEBS J 277(6):1481–1493Google Scholar
  59. Matés JM, Segura JA, Alonso FJ, Márquez J (2008) Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis. Arch Toxicol 82(5):273–299Google Scholar
  60. Mellou F, Loutrari H, Stamatis H, Roussos C, Kolisis FN (2006) Enzymatic esterification of flavonoids with unsaturated fatty acids: effect of the novel esters on vascular endothelial growth factor release from K562 cells. Process Biochem 41(9):2029–2034Google Scholar
  61. Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7(10):763–777Google Scholar
  62. Menendez JA, Vellon L, Lupu R (2005) Orlistat: from antiobesity drug to anticancer agent in Her-2/neu (erbB-2)-overexpressing gastrointestinal tumors? Exp Biol Med 230(3):151–154Google Scholar
  63. Migita T, Ruiz S, Fornari A, Fiorentino M, Priolo C, Zadra G, Inazuka F, Grisanzio C, Palescandolo E, Shin E, Fiore C, Xie W, Kung AL, Febbo PG, Subramanian A, Mucci L, Ma J, Signoretti S, Stampfer M, Hahn WC, Finn S, Loda M (2009) Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst 101(7):519–532Google Scholar
  64. Moll J, Barzaghi P, Lin S, Bezakova G, Lochmüller H, Engvall E, Lochmüller H, Engvall E, Müller U, Ruegg MA (2001) An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature 413(6853):302–307Google Scholar
  65. Montaigne D, Hurt C, Neviere R (2012) Mitochondria death/survival signaling pathways in cardiotoxicity induced by anthracyclines and anticancer-targeted therapies. Biochem Res Int 2012:951539Google Scholar
  66. Mordente A, Meucci E, Martorana GE, Giardina B, Minotti G (2001) Human heart cytosolic reductases and anthracycline cardiotoxicity. IUBMB Life 52(1):83–88Google Scholar
  67. Munir MT, Ponce C, Powell CA, Tarafdar K, Yanagita T, Choudhury M, Gollahon LS, Rahman SM (2018) The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer. J Steroid Biochem Mol Biol 183:1–9Google Scholar
  68. Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E (2014) Statin use and breast cancer survival: a nationwide cohort study from Finland. PLoS One 9(10):e110231Google Scholar
  69. Nair HK, Rao KV, Aalinkeel R, Mahajan S, Chawda R, Schwartz SA (2004) Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol 11(1):63–69Google Scholar
  70. Nielsen SF, Nordestgaard BG, Bojesen SE (2012) Statin use and reduced cancer-related mortality. N Engl J Med 367(19):1792–1802Google Scholar
  71. Oak C, Khalifa AO, Isali I, Bhaskaran N, Walker E, Shukla S (2018) Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. Int J OncolGoogle Scholar
  72. Ohvo-Rekilä H, Ramstedt B, Leppimäki P, Slotte JP (2002) Cholesterol interactions with phospholipids in membranes. Prog Lipid Res 41(1):66–97Google Scholar
  73. Osman A-M, Ahmed M, Khayyal M, El-Merzabani M (1993) Hyperthermic potentiation of cisplatin cytotoxicity on solid Ehrlich carcinoma. Tumori 79(4):268–272Google Scholar
  74. Osman A-MM, Al-Harthi SE, AlArabi OM, Elshal MF, Ramadan WS, Alaama MN et al (2013) Chemosensetizing and cardioprotective effects of resveratrol in doxorubicin-treated animals. Cancer Cell Int 13(1):52Google Scholar
  75. Panaretakis T, Laane E, Pokrovskaja K, Bjorklund AC, Moustakas A, Zhivotovsky B et al (2005) Doxorubicin requires the sequential activation of caspase-2, protein kinase Cdelta, and c-Jun NH2-terminal kinase to induce apoptosis. Mol Biol Cell 16(8):3821–3831Google Scholar
  76. Park S-Y, Bok S-H, Jeon S-M, Park YB, Lee S-J, Jeong T-S, Choi MS (2002) Effect of rutin and tannic acid supplements on cholesterol metabolism in rats. Nutr Res 22(3):283–295Google Scholar
  77. Perkins GL, Slater ED, Sanders GK, Prichard JG (2003) Serum tumor markers. Am Fam Physician 68(6):1075–1088Google Scholar
  78. Perry S (1969) Reduction of toxicity in cancer chemotherapy. Cancer Res 29(12):2319–2325Google Scholar
  79. Pizer ES, Chrest FJ, DiGiuseppe JA, Han WF (1998) Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res 58(20):4611–4615Google Scholar
  80. Pizer ES, Pflug BR, Bova GS, Han WF, Udan MS, Nelson JB (2001) Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression. Prostate 47(2):102–110Google Scholar
  81. Pompella A, Corti A, Paolicchi A, Giommarelli C, Zunino F (2007) γ-Glutamyltransferase, redox regulation and cancer drug resistance. Curr Opin Pharmacol 7(4):360–366Google Scholar
  82. Ponzone R, Biglia N, Jacomuzzi ME, Mariani L, Dominguez A, Sismondi P (2006) Antihormones in prevention and treatment of breast cancer. Ann N Y Acad Sci 1089(1):143–158Google Scholar
  83. Posey LM (2005) Cancer treatment and chemotherapy, Pharmacotherapy: a pathophysiologic approach. McGraw-Hill, New YorkGoogle Scholar
  84. Pugazhendhi A, Edison T, Velmurugan BK, Jacob JA, Karuppusamy I (2018) Toxicity of doxorubicin (dox) to different experimental organ systems. Life Sci 200:26–30Google Scholar
  85. Ross JA, Kasum CM (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22(1):19–34Google Scholar
  86. Rossi S, Graner E, Febbo P, Weinstein L, Bhattacharya N, Onody T et al (2003) Fatty acid synthase expression defines distinct molecular signatures in prostate cancer1 1 NCI (Director’s Challenge CA84995-04, SPORE in Prostate Cancer CA90381-01A1, and PO1 CA89021-02), Novartis Investigator, and CaPCURE awards. Mol Cancer Res 1(10):707–715Google Scholar
  87. Rouibah H, Kebsa W, Lahouel M, Zihlif M, Ahram M, Aburmeleih B, Mustafa E, el-Amir H (2018) Algerian propolis potentiates doxorubicin mediated anticancer effect against human pancreatic PANC-1 Cancer cell line through cell cycle arrest, apoptosis induction and P-glycoprotein inhibition. Anti Cancer Agents Med Chem 18(3):375–387Google Scholar
  88. Roy A, Sarker S, Upadhyay P, Pal A, Adhikary A, Jana K, Ray M (2018) Methylglyoxal at metronomic doses sensitizes breast cancer cells to doxorubicin and cisplatin causing synergistic induction of programmed cell death and inhibition of stemness. Biochem Pharmacol 156:322–339Google Scholar
  89. Sabaa M, HM EL, Elshazly S, Youns M, Barakat W (2017) Anticancer activity of salicin and fenofibrate. Naunyn Schmiedeberg's Arch Pharmacol 390(10):1061–1071Google Scholar
  90. Sadzuka Y, Sugiyama T, Suzuki H, Sawanishi H, Miyamoto K-i (2004) Increased effects of MPDAX, a novel xanthine derivative, on antitumor activity of doxorubicin. Toxicol Lett 150(3):341–349Google Scholar
  91. Sadzuka Y, Hatakeyama H, Daimon T, Sonobe T (2008) Screening of biochemical modulator by tumor cell permeability of doxorubicin. Int J Pharm 354(1):63–69Google Scholar
  92. Salazar AT, Hoheisel J, Youns M, Wink M (2011) Anti-inflammatory and anti-cancer activities of essential oils and their biological constituents. Int J Clin Pharmacol Ther 49(1):93–95Google Scholar
  93. Sato Y, Sasaki N, Saito M, Endo N, Kugawa F, Ueno A (2015) Luteolin attenuates doxorubicin-induced cytotoxicity to MCF-7 human breast cancer cells. Biol Pharm Bull 38(5):703–709Google Scholar
  94. Sazuka Y, Tanizawa H, Takino Y (1989) Effect of adriamycin on the activities of superoxide dismutase, glutathione peroxidase and catalase in tissues of mice. Jpn J Cancer Res 80(1):89–94Google Scholar
  95. Schwedhelm E, Maas R, Troost R, Böger RH (2003) Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress. Clin Pharmacokinet 42(5):437–459Google Scholar
  96. Seo C-W, Um IC, Rico CW, Kang MY (2011) Antihyperlipidemic and body fat-lowering effects of silk proteins with different fibroin/sericin compositions in mice fed with high fat diet. J Agric Food Chem 59(8):4192–4197Google Scholar
  97. Sharma S, Ali A, Ali J, Sahni JK, Baboota S (2013) Rutin: therapeutic potential and recent advances in drug delivery. Expert Opin Investig Drugs 22(8):1063–1079Google Scholar
  98. Sheu J-R, Hsiao G, Chou P-H, Shen M-Y, Chou D-S (2004) Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets. J Agric Food Chem 52(14):4414–4418Google Scholar
  99. Shimada R, Matsunaga K, YAMADA Y, SHIMIZU M (1999) Inhibition of azoxymethane-induced aberrant crypt foci in rats by natural compounds, caffeine, quercetin and morin. Oncol Rep 6:1333–1340Google Scholar
  100. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics. CA Cancer J Clin 66(1):7–30Google Scholar
  101. Sokolowska E, Presler M, Goyke E, Milczarek R, Swierczynski J, Sledzinski T (2017) Orlistat reduces proliferation and enhances apoptosis in human pancreatic cancer cells (PANC-1). Anticancer Res 37(11):6321–6327Google Scholar
  102. Sugiyama T, Sadzuka Y (1998) Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma. Cancer Lett 133(1):19–26Google Scholar
  103. Sundvall J, Leiviskأ¤ J, Alfthan G, Vartiainen E (2007) Serum cholesterol during 27 years: assessment of systematic error and affecting factors and their role in interpreting population trends. Clin Chim Acta 378(1):93–98Google Scholar
  104. Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97(11):2869–2879Google Scholar
  105. Swinnen JV, Roskams T, Joniau S, Van Poppel H, Oyen R, Baert L et al (2002) Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer 98(1):19–22Google Scholar
  106. Takahashi T (2011) Studies on molecular mechanism of toxicity of anticancer drugs. Yakugaku Zasshi: J Pharm Soc Jpn 131(3):355–358Google Scholar
  107. Tang S, Zhou F, Sun Y, Wei L, Zhu S, Yang R, Huang Y, Yang J (2016) CEA in breast ductal secretions as a promising biomarker for the diagnosis of breast cancer: a systematic review and meta-analysis. Breast Cancer 23(6):813–819Google Scholar
  108. Tomankova K, Polakova K, Pizova K, Binder S, Havrdova M, Kolarova M, Kriegova E, Zapletalova J, Malina L, Horakova J, Malohlava J, Kolokithas-Ntoukas A, Bakandritsos A, Kolarova H, Zboril R (2015) In vitro cytotoxicity analysis of doxorubicin-loaded/superparamagnetic iron oxide colloidal nanoassemblies on MCF7 and NIH3T3 cell lines. Int J Nanomedicine 10:949–961Google Scholar
  109. Trumbeckaite S, Bernatoniene J, Majiene D, Jakstas V, Savickas A, Toleikis A (2006) The effect of flavonoids on rat heart mitochondrial function. Biomed Pharmacother 60(5):245–248Google Scholar
  110. Tsou SH, Chen TM, Hsiao HT, Chen YH (2015) A critical dose of doxorubicin is required to alter the gene expression profiles in MCF-7 cells acquiring multidrug resistance. PLoS One 10(1):e0116747Google Scholar
  111. van Putten M, de Winter C, van Roon-Mom W, van Ommen G-J, Hoen P, Aartsma-Rus A (2010) A 3 months mild functional test regime does not affect disease parameters in young mdx mice. Neuromuscul Disord 20(4):273–280Google Scholar
  112. Verma AK, Johnson JA, Gould MN, Tanner MA (1988) Inhibition of 7, 12-dimethylbenz (a) anthracene-and N-nitrosomethylurea-induced rat mammary cancer by dietary flavonol quercetin. Cancer Res 48(20):5754–5758Google Scholar
  113. Vincent HK, Innes KE, Vincent KR (2007) Oxidative stress and potential interventions to reduce oxidative stress in overweight and obesity. Diabetes Obes Metab 9(6):813–839Google Scholar
  114. Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M et al (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91(5):710–717Google Scholar
  115. Wang JC (1996) DNA topoisomerases. Annu Rev Biochem 65(1):635–692Google Scholar
  116. Wu C-H, Lin M-C, Wang H-C, Yang M-Y, Jou M-J, Wang C-J (2011) Rutin inhibits oleic acid induced lipid accumulation via reducing lipogenesis and oxidative stress in hepatocarcinoma cells. J Food Sci 76(2):T65–T72Google Scholar
  117. Wysham WZ, Roque DR, Han J, Zhang L, Guo H, Gehrig PA et al (2016) Effects of fatty acid synthase inhibition by orlistat on proliferation of endometrial cancer cell lines. Target Oncol:1–7Google Scholar
  118. Xia J, Chen J, Zhang Z, Song P, Tang W, Kokudo N (2014) A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo. Drug Discov Ther 8(4):139–153Google Scholar
  119. Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD (2012) The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol 36(3):237–248Google Scholar
  120. Youns M, Efferth T, Jr R, Fellenberg K, Bauer A, Hoheisel JD (2009) Gene expression profiling identifies novel key players involved in the cytotoxic effect of artesunate on pancreatic cancer cells. Biochem Pharmacol 78(3):273–283Google Scholar
  121. Youns M, Efferth T, Hoheisel JD (2011) Transcript profiling identifies novel key players mediating the growth inhibitory effect of NS-398 on human pancreatic cancer cells. Eur J Pharmacol 650(1):170–177Google Scholar
  122. Zheng S, Wang X, Weng YH, Jin X, Ji JL, Guo L, Hu B, Liu N, Cheng Q, Zhang J, Bai H, Yang T, Xia XH, Zhang HY, Gao S, Huang Y (2018) siRNA knockdown of RRM2 effectively suppressed pancreatic tumor growth alone or synergistically with doxorubicin. Mol Ther Nucleic Acids 12:805–816Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology & Toxicology, Faculty of PharmacyZagazig UniversityZagazigEgypt
  2. 2.Department of Pharmacology & Toxicology, Faculty of PharmacySinai UniversityIsmailiaEgypt
  3. 3.Department of Biochemistry and Molecular Biology, Faculty of PharmacyHelwan UniversityHelwanEgypt
  4. 4.Department of Biochemistry, Oman Pharmacy InstituteMinistry of HealthMuscatOman
  5. 5.Department of Pharmacology & Toxicology, Faculty of PharmacyTabuk UniversityTabukKingdom of Saudi Arabia

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