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Hesperetin Induces the Apoptosis of Gastric Cancer Cells via Activating Mitochondrial Pathway by Increasing Reactive Oxygen Species

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Abstract

Background

Hesperetin, has been shown to exert biological activities on various types of human cancers. However, few related studies on gastric cancer are available.

Aim

In this study, we sought to investigate the effect of hesperetin on gastric cancer and clarify its specific mechanism.

Materials and Methods

Cell Counting Kit-8, 2′,7′-dichlorofluorescin diacetate, JC-1, Hoechst 33258 staining, and western bolt were used to detect cell viability, levels of intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (△ψ m), cell apoptosis, and expressions of mitochondrial pathway proteins, respectively. Meanwhile, xenograft tumor models in nude mice were made to evaluate the effect of hesperetin on gastric cancer in vivo.

Results

Compared with the control group, the proliferation of gastric cancer cells in hesperetin groups was significantly inhibited (P < 0.05), and dose- and time-dependent effects were observed. Pretreatment with H2O2 (1 mM) or N-acetyl-l-cysteine (5 mM) enhanced or attenuated the hesperetin-induced inhibition of cell viability (P < 0.05). Percentages of apoptotic cells, levels of intracellular ROS, and △ψ m varied with the dose and treatment time of hesperetin (P < 0.05), and hesperetin caused an increase in the levels of AIF, Apaf-1, Cyt C, caspase-3, caspase-9, and Bax and a decrease in Bcl-2 levels (P < 0.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors (P < 0.05).

Conclusion

Our study suggests that hesperetin could inhibit the proliferation and induce the apoptosis of gastric cancer cells via activating the mitochondrial pathway by increasing the ROS.

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References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–E386.

    Article  CAS  PubMed  Google Scholar 

  3. Herszényi L, Tulassay Z. Epidemiology of gastrointestinal and liver tumors. Eur Rev Med Pharmacol Sci. 2010;14:249–258.

    PubMed  Google Scholar 

  4. Yu J, Gao J, Lu Z, Li Y, Shen L. Serum levels of TUBB3 correlate with clinical outcome in Chinese patients with advanced gastric cancer receiving first-line paclitaxel plus capecitabine. Med Oncol. 2012;29:3029–3034.

    Article  CAS  PubMed  Google Scholar 

  5. Seo JH, Jeong ES, Lee KS, Heo SH, Jeong DG, Choi YK. Lentivirus-mediated shRNA targeting of cyclin D1 enhances the chemosensitivity of human gastric cancer to 5-fluorouracil. Int J Oncol. 2013;43:2007–2014.

    CAS  PubMed  Google Scholar 

  6. Xian XS, Park H, Choi MG, Park JM. Cannabinoid receptor agonist as an alternative drug in 5-fluorouracil-resistant gastric cancer cells. Anticancer Res. 2013;33:2541–2547.

    CAS  PubMed  Google Scholar 

  7. Garg A, Garg S, Zaneveld LJ, Singla AK. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. 2001;15:655–669.

    Article  CAS  PubMed  Google Scholar 

  8. Choi EJ. Hesperetin induced G1-phase cell cycle arrest in human breast cancer MCF-7 cells: involvement of CDK4 and p21. Nutr Cancer. 2007;59:115–119.

    Article  CAS  PubMed  Google Scholar 

  9. Cai Y, Luo Q, Sun M, Corke H. Antioxidant activity and phenolic compounds of 112 traditional Chinese medicinal plants associated with anticancer. Life Sci. 2004;74:2157–2184.

    Article  CAS  PubMed  Google Scholar 

  10. Sambantham S, Radha M, Paramasivam A, et al. Molecular mechanism underlying hesperetin-induced apoptosis by in silico analysis and in prostate cancer PC-3 cells. Asian Pac J Cancer Prev. 2013;14:4347–4352.

    Article  PubMed  Google Scholar 

  11. Ye L, Chan FL, Chen S, Leung LK. The citrus flavanone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice. J Nutr Biochem. 2012;23:1230–1237.

    Article  CAS  PubMed  Google Scholar 

  12. Alshatwi AA, Ramesh E, Periasamy VS, Subash-Babu P. The apoptotic effect of hesperetin on human cervical cancer cells is mediated through cell cycle arrest, death receptor, and mitochondrial pathways. Fundam Clin Pharmacol. 2013;27:581–592.

    Article  CAS  PubMed  Google Scholar 

  13. Aranganathan S, Nalini N. Antiproliferative efficacy of hesperetin (citrus flavonoid) in 1,2-dimethylhydrazine-induced colon cancer. Phytother Res. 2013;27:999–1005.

    Article  CAS  PubMed  Google Scholar 

  14. Yang Y, Wolfram J, Shen H, Fang X, Ferrari M. Hesperetin: an inhibitor of the transforming growth factor-β (TGF-β) signaling pathway. Eur J Med Chem. 2012;58:390–395.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Yang Y, Wolfram J, Boom K, Fang X, Shen H, Ferrari M. Hesperetin impairs glucose uptake and inhibits proliferation of breast cancer cells. Cell Biochem Funct. 2013;31:374–379.

    Article  CAS  PubMed  Google Scholar 

  16. Patel PN, Yu XM, Jaskula-Sztul R, Chen H. Hesperetin activates the Notch1 signaling cascade, causes apoptosis, and induces cellular differentiation in anaplastic thyroid cancer. Ann Surg Oncol. 2014;21:S497–S504.

    Article  PubMed  Google Scholar 

  17. Zarebczan B, Pinchot SN, Kunnimalaiyaan M, Chen H. Hesperetin, a potential therapy for carcinoid cancer. Am J Surg. 2011;201:329–332; discussion 333.

  18. Haidari F, Ali Keshavarz S, Reza Rashidi M, Mohammad Shahi M. Orange juice and hesperetin supplementation to hyperuricemic rats alter oxidative stress markers and xanthine oxidoreductase activity. J Clin Biochem Nutr. 2009;45:285–291.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Yang HL, Chen SC, Senthil Kumar KJ, et al. Antioxidant and anti-inflammatory potential of hesperetin metabolites obtained from hesperetin-administered rat serum: an ex vivo approach. J Agric Food Chem. 2012;60:522–532.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang H, Gomez AM, Wang X, Yan Y, Zheng M, Cheng H. ROS regulation of microdomain Ca(2+) signalling at the dyads. Cardiovasc Res. 2013;98:248–258.

    Article  CAS  PubMed  Google Scholar 

  21. Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012;48:158–167.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Finkel T. Signal transduction by reactive oxygen species. J Cell Biol. 2011;194:7–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Grivennikova VG, Vinogradov AD. Mitochondrial production of reactive oxygen species. Biochemistry (Mosc). 2013;78:1490–1511.

    Article  CAS  PubMed  Google Scholar 

  24. Starkov AA. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann NY Acad Sci. 2008;1147:37–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Chang MC, Chang HH, Chan CP, et al. p-Cresol affects reactive oxygen species generation, cell cycle arrest, cytotoxicity and inflammation/atherosclerosis-related modulators production in endothelial cells and mononuclear cells. PLoS One. 2014;9:e114446.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Rehman AU, Dugic E, Benham C, Lione L, Mackenzie LS. Selective inhibition of NADPH oxidase reverses the over contraction of diabetic rat aorta. Redox Biol. 2013;2C:61–64.

    PubMed  Google Scholar 

  27. Prasad K, Dhar I. Oxidative stress as a mechanism of added sugar-induced cardiovascular disease. Int J Angiol. 2014;23:217–226.

    Article  PubMed  Google Scholar 

  28. Dhillon H, Chikara S, Reindl KM. Piperlongumine induces pancreatic cancer cell death by enhancing reactive oxygen species and DNA damage. Toxicol Rep. 2014;1:309–318.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Udensi UK, Tchounwou PB. Dual effect of oxidative stress on leukemia cancer induction and treatment. J Exp Clin Cancer Res. 2014;33:106.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Wang P, Xie K, Wang C, Bi J. Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur Neurol. 2014;72:249–254.

    CAS  PubMed  Google Scholar 

  31. Nijland PG, Witte ME, van Het Hof B, et al. Astroglial PGC-1alpha increases mitochondrial antioxidant capacity and suppresses inflammation: implications for multiple sclerosis. Acta Neuropathol Commun. 2014;2:170.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Sivagami G, Vinothkumar R, Bernini R, et al. Role of hesperetin (a natural flavonoid) and its analogue on apoptosis in HT-29 human colon adenocarcinoma cell line—a comparative study. Food Chem Toxicol. 2012;50:660–671.

    Article  CAS  PubMed  Google Scholar 

  33. Choi EJ, Ahn WS. Neuroprotective effects of chronic hesperetin administration in mice. Arch Pharm Res. 2008;31:1457–1462.

    Article  CAS  PubMed  Google Scholar 

  34. Aranganathan S, Selvam JP, Nalini N. Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: a dose-dependent study. J Pharm Pharmacol. 2008;60:1385–1392.

    Article  CAS  PubMed  Google Scholar 

  35. Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA. Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. Biotechniques. 2011;50:98–115.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Ly JD, Grubb DR, Lawen A. The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis. 2003;8:115–128.

    Article  CAS  PubMed  Google Scholar 

  37. Solaini G, Sgarbi G, Lenaz G, Baracca A. Evaluating mitochondrial membrane potential in cells. Biosci Rep. 2007;27:11–21.

    Article  CAS  PubMed  Google Scholar 

  38. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004;305:626–629.

    Article  CAS  PubMed  Google Scholar 

  39. Chen Q, Lesnefsky EJ. Blockade of electron transport during ischemia preserves bcl-2 and inhibits opening of the mitochondrial permeability transition pore. FEBS Lett. 2011;585:921–926.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Halestrap AP, Doran E, Gillespie JP, O’Toole A. Mitochondria and cell death. Biochem Soc Trans. 2000;28:170–177.

    Article  CAS  PubMed  Google Scholar 

  41. Kim JY, Jung KJ, Choi JS, Chung HY. Hesperetin: a potent antioxidant against peroxynitrite. Free Radic Res. 2004;38:761–769.

    Article  CAS  PubMed  Google Scholar 

  42. Chen ZT, Chu HL, Chyau CC, Chu CC, Duh PD. Protective effects of sweet orange (Citrus sinensis) peel and their bioactive compounds on oxidative stress. Food Chem. 2012;135:2119–2127.

    Article  CAS  PubMed  Google Scholar 

  43. Jung HA, Jung MJ, Kim JY, Chung HY, Choi JS. Inhibitory activity of flavonoids from Prunus davidiana and other flavonoids on total ROS and hydroxyl radical generation. Arch Pharm Res. 2003;26:809–815.

    Article  CAS  PubMed  Google Scholar 

  44. Parhiz H, Roohbakhsh A, Soltani F, Rezaee R, Iranshahi M. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res. 2015;29:323–331.

    Article  CAS  PubMed  Google Scholar 

  45. Palit S, Kar S, Sharma G, Das PK. Hesperetin induces apoptosis in breast carcinoma by triggering accumulation of ROS and activation of ASK1/JNK pathway. J Cell Physiol. 2014. doi:10.1002/jcp.24818.

  46. Liu L, Fu J, Li T, et al. NG, a novel PABA/NO-based oleanolic acid derivative, induces human hepatoma cell apoptosis via a ROS/MAPK-dependent mitochondrial pathway. Eur J Pharmacol. 2012;691:61–68.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Weiguo Dong.

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Zhang, J., Wu, D., Vikash et al. Hesperetin Induces the Apoptosis of Gastric Cancer Cells via Activating Mitochondrial Pathway by Increasing Reactive Oxygen Species. Dig Dis Sci 60, 2985–2995 (2015). https://doi.org/10.1007/s10620-015-3696-7

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  • DOI: https://doi.org/10.1007/s10620-015-3696-7

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