The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Chemopreventive potential of goniothalamin in diethylnitrosamine-induced hepatocellular carcinoma through the suppression of P13K/AKT signalling pathway

  • Jie Li (Hepatobiliary and Pancreatic Surgery, Fuyang People's Hospital in Anhui Province) ;
  • Dong Zhan (Human Anatomy Laboratory of Experimental Teaching Centre, School of Basic Medical Sciences, Kunming Medical University) ;
  • Cui Chen (Department of Hepatobiliary Surgery, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People's Hospital) ;
  • Rongfu Li (Department of Hepatobiliary Surgery, Anshun People's Hospital) ;
  • Fang-Qing Zhu (Department of Gastroenterology, Ganzhou People's Hospital)
  • Received : 2023.02.16
  • Accepted : 2023.11.24
  • Published : 2024.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Liver cancer is the most lethal form of cancer and carries a high risk of death around the world. Goniothalamin (GTN) is a styryl-lactone that possesses anti-proliferative and apoptotic activity. The molecular action of GTN is not yet fully evaluated. Thus, our research has been intended to assess the chemopreventive and apoptotic activities of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. Rats were separated into 4 groups: control, DEN only, DEN + GTN (30 mg/kg bw), and GTN (30 mg/kg bw) alone. We evaluated body weight, liver weight, tumor incidence, hepatic toxic markers, antioxidants, inflammatory cytokines, histopathology, immunohistochemistry, and Western blot studies. DEN lessened body weight, antioxidants, and apoptosis, whereas it elevated tumor incidence, toxic markers, cytokines, and Bcl-2 expression. GTN treatment maintains body weight, liver weight, and antioxidant levels, and it also prevents tumor incidence, oxidative stress, toxic markers, pro-inflammatory cytokines, and histological changes. It triggers apoptosis by constraining Bcl-2 and elevating caspase-3 levels. GTN also attenuated the P13K/AKT signaling which enhanced apoptosis. These findings revealed that GTN subdues the P13K/AKT pathway and has auspicious chemopreventive and apoptotic actions in DEN-induced HCC. Therefore, GTN would be suggested as a new medicine in natural remedies for liver cancer.

Keywords

References

  1. El-Kassas M, Elbadry M. Hepatocellular carcinoma in Africa: challenges and opportunities. Front Med (Lausanne). 2022;9:899420.
  2. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245-1255.
  3. Sivaramakrishnan V, Shilpa PN, Praveen Kumar VR, Niranjali Devaraj S. Attenuation of N-nitrosodiethylamine-induced hepatocellular carcinogenesis by a novel flavonol-Morin. Chem Biol Interact. 2008;171:79-88.
  4. Liao DJ, Blanck A, Eneroth P, Gustafsson JA, Hallstrom IP. Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat. Environ Health Perspect. 2001;109:943-947.
  5. Bartsch H, Montesano R. Relevance of nitrosamines to human cancer. Carcinogenesis. 1984;5:1381-1393.
  6. Ramakrishnan G, Raghavendran HR, Vinodhkumar R, Devaki T. Suppression of N-nitrosodiethylamine induced hepatocarcinogenesis by silymarin in rats. Chem Biol Interact. 2006;161:104-114.
  7. Chodon D, Banu SM, Padmavathi R, Sakthisekaran D. Inhibition of cell proliferation and induction of apoptosis by genistein in experimental hepatocellular carcinoma. Mol Cell Biochem. 2007;297:73-80.
  8. Gey KF. Prospects for the prevention of free radical disease, regarding cancer and cardiovascular disease. Br Med Bull. 1993;49:679-699.
  9. Marra M, Sordelli IM, Lombardi A, Lamberti M, Tarantino L, Giudice A, Stiuso P, Abbruzzese A, Sperlongano R, Accardo M, Agresti M, Caraglia M, Sperlongano P. Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: an overview. J Transl Med. 2011;9:171.
  10. Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:360-369.
  11. Pang Y, Zheng B, Fan LW, Rhodes PG, Cai Z. IGF-1 protects oligodendrocyte progenitors against TNFalpha-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway. Glia. 2007;55:1099-1107.
  12. Bishayee A, Dhir N. Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis. Chem Biol Interact. 2009;179:131-144.
  13. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control. 1991;2:325-357.
  14. Demain AL, Vaishnav P. Natural products for cancer chemotherapy. Microb Biotechnol. 2011;4:687-699.
  15. Saunders RMK. A synopsis of Goniothalamus species (Annonaceae) in Peninsular Malaysia, with a description of a new species. Bot J Lin Soc. 2003;142:321-339.
  16. Vendramini-Costa DB, Francescone R, Posocco D, Hou V, Dmitrieva O, Hensley H, de Carvalho JE, Pilli RA, Grivennikov SI. Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis. Carcinogenesis. 2017;38:51-63.
  17. King J. Practical clinical enzymology. Van Nostrand; 1965.
  18. Rosalki SB, Rau D. Serum γ-glutamyl transpeptidase activity in alcoholism. Clin Chim Acta. 1972;39:41-47.
  19. Vendramini-Costa DB, de Castro IB, Ruiz AL, Marquissolo C, Pilli RA, de Carvalho JE. Effect of goniothalamin on the development of Ehrlich solid tumor in mice. Bioorg Med Chem. 2010;18:6742-6747.
  20. Inayat-Hussain SH, Wong LT, Chan KM, Rajab NF, Din LB, Harun R, Kizilors A, Saxena N, Mourtada-Maarabouni M, Farzaneh F, Williams GT. RACK-1 overexpression protects against goniothalamin-induced cell death. Toxicol Lett. 2009;191:118-122.
  21. Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys. 1984;21:130-132.
  22. Takahara S, Hamilton HB, Neel JV, Kobara TY, Ogura Y, Nishimura ET. Hypocatalasemia: a new genetic carrier state. J Clin Invest. 1960;39:610-619.
  23. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973;179:588-590.
  24. Carlberg I, Mannervik B. Glutathione reductase. Methods Enzymol. 1985;113:484-490.
  25. Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta. 1979;582:67-78.
  26. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of proteindye binding. Anal Biochem. 1976;72:248-254.
  27. Park DH, Shin JW, Park SK, Seo JN, Li L, Jang JJ, Lee MJ. Diethylnitrosamine (DEN) induces irreversible hepatocellular carcinogenesis through overexpression of G1/S-phase regulatory proteins in rat. Toxicol Lett. 2009;191:321-326.
  28. Borbath I, Leclercq IA, Sempoux C, Abarca-Quinones J, Desaeger C, Horsmans Y. Efficacy of lanreotide in preventing the occurrence of chemically induced hepatocellular carcinoma in rats. Chem Biol Interact. 2010;183:238-248.
  29. Amat N, Upur H, Blazekovic B. In vivo hepatoprotective activity of the aqueous extract of Artemisia absinthium L. against chemically and immunologically induced liver injuries in mice. J Ethnopharmacol. 2010;131:478-484.
  30. Dorai T, Aggarwal BB. Role of chemopreventive agents in cancer therapy. Cancer Lett. 2004;215:129-140.
  31. Sheikh BY, Elsaed WM, Samman AH, Ladin AMMB. Ajwa dates as a protective agent against liver toxicity in rat. Eur Sci J. 2014;3:358-368.
  32. Lippert M, Papadopoulos N, Javadpour N. Role of lactate dehydrogenase isoenzymes in testicular cancer. Urology. 1981;18:50-53.
  33. Bulle F, Mavier P, Zafrani ES, Preaux AM, Lescs MC, Siegrist S, Dhumeaux D, Guellaen G. Mechanism of gamma-glutamyl trans-peptidase release in serum during intrahepatic and extrahepatic cholestasis in the rat: a histochemical, biochemical and molecular approach. Hepatology. 1990;11:545-550.
  34. Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol. 2001;35:297-306.
  35. Kweon S, Park KA, Choi H. Chemopreventive effect of garlic powder diet in diethylnitrosamine-induced rat hepatocarcinogenesis. Life Sci. 2003;73:2515-2526.
  36. Grivennikov SI, Karin M. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis. 2011;70 Suppl 1:i104-i108.
  37. Moore MA, Tsuda H. Chronically elevated proliferation as a risk factor for neoplasia. Eur J Cancer Prev. 1998;7:353-385.
  38. Bravo R, Frank R, Blundell PA, Macdonald-Bravo H. Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature. 1987;326:515-517.
  39. Shuang L, Aihua Z, Xiaoxin H, Yujiang R. Expression and significance of proliferating cell nuclear antigen in resistance of lithium carbonate to aflatoxin B_1-induced hepatocarcinogenesis in rats. Teratog Carcinog Mutagen. 2002;14:84-86.
  40. Karamitopoulou E, Cioccari L, Jakob S, Vallan C, Schaffner T, Zimmermann A, Brunner T. Active caspase 3 and DNA fragmentation as markers for apoptotic cell death in primary and metastatic liver tumours. Pathology. 2007;39:558-564.
  41. Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008;27:6194-6206.
  42. Yu HP, Yang SC, Lau YT, Hwang TL. Role of Akt-dependent upregulation of hemeoxygenase-1 in resveratrol-mediated attenuation of hepatic injury after trauma hemorrhage. Surgery. 2010;148:103-109.