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Eriocitrin from lemon suppresses the proliferation of human hepatocellular carcinoma cells through inducing apoptosis and arresting cell cycle

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Abstract

Hepatocellular carcinoma is a lethal cancer with high recurrence ratio and lacks effective therapeutics. In the past few years, it has been reported that increased intake of vegetables and fruits could reduce the cancer incidence, which suggests dietary agents might possess anticancer effects. Eriocitrin is a flavonoid isolated from lemon, which is known as a strong antioxidant agent. We here for the first time demonstrated that eriocitrin could inhibit the proliferation of hepatocellular carcinoma cell lines by arresting cell cycle in S phase through up-regulation of p53, cyclin A, cyclin D3 and CDK6. Furthermore, we found that eriocitrin could trigger apoptosis by activating mitochondria-involved intrinsic signaling pathway. Thus, eriocitrin might be regarded as a potential chemopreventive natural product to inhibit the early malignant transformation of hepatocellular carcinoma.

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References

  1. World Health Organization (WHO) (2014) Global battle against cancer won’t be won with treatment alone effective prevention measures urgently needed to prevent cancer crisis. Cent Eur J Publ Health 22(23):28

    Google Scholar 

  2. Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet 379:1245–1255

    Article  PubMed  Google Scholar 

  3. Llovet JM, Bruix J (2008) Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48:1312–1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lu SC (2010) Where are we in the chemoprevention of hepatocellular carcinoma? Hepatology 51:734–736

    PubMed  Google Scholar 

  5. Song MJ (2015) Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma. World J Gastroenterol 21:3843–3849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Key TJ (2010) Fruit and vegetables and cancer risk. Br J Cancer 104:6–11

    Article  PubMed  PubMed Central  Google Scholar 

  7. Reddy L, Odhav B, Bhoola KD (2003) Natural products for cancer prevention: a global perspective. Pharmacol Ther 99:1–13

    Article  CAS  PubMed  Google Scholar 

  8. Lee KW, Bode AM, Dong Z (2011) Molecular targets of phytochemicals for cancer prevention. Nat Rev Cancer 11:211–218

    Article  CAS  PubMed  Google Scholar 

  9. Gonzalez-Molina E, Dominguez-Perles R, Moreno DA, Garcia-Viguera C (2010) Natural bioactive compounds of Citrus limon for food and health. J Pharm Biomed Anal 51:327–345

    Article  CAS  PubMed  Google Scholar 

  10. Li C, Zug C, Qu H, Schluesener H, Zhang Z (2015) Hesperidin ameliorates behavioral impairments and neuropathology of transgenic APP/PS1 mice. Behav Brain Res 281:32–42

    Article  CAS  PubMed  Google Scholar 

  11. Bacanli M, Basaran AA, Basaran N (2015) The antioxidant and antigenotoxic properties of citrus phenolics limonene and naringin. Food Chem Toxicol 81:160–170

    Article  CAS  PubMed  Google Scholar 

  12. Banjerdpongchai R, Wudtiwai B, Khaw-On P, Rachakhom W, Duangnil N, Kongtawelert P (2016) Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways. Tumour Biol 37(1):227–237

  13. Miyake Y, Yamamoto K, Tsujihara N, Osawa T (1998) Protective effects of lemon flavonoids on oxidative stress in diabetic rats. Lipids 33:689–695

    Article  CAS  PubMed  Google Scholar 

  14. K-i Minato, Miyake Y, Fukumoto S, Yamamoto K, Kato Y, Shimomura Y et al (2003) Lemon flavonoid, eriocitrin, suppresses exercise-induced oxidative damage in rat liver. Life Sci 72:1609–1616

    Article  Google Scholar 

  15. Hiramitsu M, Shimada Y, Kuroyanagi J, Inoue T, Katagiri T, Zang L et al (2014) Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep 4:3708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang Y, Yu H, Zhang J, Gao J, Ge X, Lou G (2015) Hesperidin inhibits HeLa cell proliferation through apoptosis mediated by endoplasmic reticulum stress pathways and cell cycle arrest. BMC Cancer 15:682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schrödinger Release 2015-2 (2015) Maestro, version 10.2, Schrödinger, LLC, New York

  18. Whitfield ML, George LK, Grant GD, Perou CM (2006) Common markers of proliferation. Nat Rev Cancer 6:99–106

    Article  CAS  PubMed  Google Scholar 

  19. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11:558–572

    Article  CAS  PubMed  Google Scholar 

  20. Lee J, Kim SS (2009) The function of p27 KIP1 during tumor development. Exp Mol Med 41:765–771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen J (2016) The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Med 6(3):a026104

  22. Shalini S, Dorstyn L, Dawar S, Kumar S (2014) Old, new and emerging functions of caspases. Cell Death Differ 22:526–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Delbridge AR, Grabow S, Strasser A, Vaux DL (2016) Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 16:99–109

    Article  CAS  PubMed  Google Scholar 

  24. Liu K, Cho YY, Yao K, Nadas J, Kim DJ, Cho EJ et al (2011) Eriodictyol inhibits RSK2-ATF1 signaling and suppresses EGF-induced neoplastic cell transformation. J Biol Chem 286:2057–2066

    Article  CAS  PubMed  Google Scholar 

  25. Bruix J, Han KH, Gores G, Llovet JM, Mazzaferro V (2015) Liver cancer: approaching a personalized care. J Hepatol 62:S144–S156

    Article  PubMed  PubMed Central  Google Scholar 

  26. Demain AL, Vaishnav P (2011) Natural products for cancer chemotherapy. Microb Biotechnol 4:687–699

    Article  PubMed  PubMed Central  Google Scholar 

  27. O’Leary B, Finn RS, Turner NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 13(7):417–430

  28. Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30:630–641

    Article  CAS  PubMed  Google Scholar 

  29. Mateo F, Vidal-Laliena M, Canela N, Busino L, Martinez-Balbas MA, Pagano M et al (2009) Degradation of cyclin A is regulated by acetylation. Oncogene 28:2654–2666

    Article  CAS  PubMed  Google Scholar 

  30. Hydbring P, Malumbres M, Sicinski P (2016) Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol 17(5):280-292

  31. Inoue S, Browne G, Melino G, Cohen GM (2009) Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway. Cell Death Differ 16:1053–1061

    Article  CAS  PubMed  Google Scholar 

  32. Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947

    Article  CAS  PubMed  Google Scholar 

  33. Manson MM (2003) Cancer prevention—the potential for diet to modulate molecular signalling. Trends Mol Med 9:11–18

    Article  CAS  PubMed  Google Scholar 

  34. Henderson AJ, Ollila CA, Kumar A, Borresen EC, Raina K, Agarwal R et al (2012) Chemopreventive properties of dietary rice bran: current status and future prospects. Adv Nutr: Int Rev J 3:643–653

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by National Natural Science Foundation of China (31170676, 81300398), Natural Science Foundation of Guangdong Province, China (2015A030313518), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (2014-1685) and Scientific Research Foundation for Returned Overseas Scholars of Guangdong Medical College, China (B2012082). This work was also supported by the funds from 2013 Sail Plan “the introduction of the Shortage of Top-Notch Talent” Project (YueRenCai-Ban [2014] 1), Science and Technology Planning Project (2013B021800072) and Education Discipline Construction Project (2013KJCX0090) of Guangdong Province, China.

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Correspondence to Zunnan Huang.

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The authors have declared that there are no conflict of interests to disclose.

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Ziyou Wang and Hua Zhang have contributed equally to this work.

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Wang, Z., Zhang, H., Zhou, J. et al. Eriocitrin from lemon suppresses the proliferation of human hepatocellular carcinoma cells through inducing apoptosis and arresting cell cycle. Cancer Chemother Pharmacol 78, 1143–1150 (2016). https://doi.org/10.1007/s00280-016-3171-y

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  • DOI: https://doi.org/10.1007/s00280-016-3171-y

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