Therapeutic efficacy of a Dioscorea membranacea extract in a rat model of hepatocellular carcinoma: Histopathological aspects

10.1016/j.jtcme.2021.02.001

Vichununt Kerdput；Cheng Nilbu-nga；Nattpawit Kaewnoonual；Arunporn Itharat；Suriya Pongsawat；Wisuit Pradidarcheep

Hua-Khao-Yen ； Liver cancer ； Traditional medicine ； glypican3 ； Reticulin

Journal of Traditional and Complementary Medicine

11卷5期（2021 / 09 / 01）

400 - 408

英文

Hepatocellular carcinoma (HCC) is most common in adults and has a high mortality rate because of a lack of effective treatment options. We investigated the effect of a medicinal plant as a potential source of drugs against HCC. The rhizomes of Dioscorea membranacea Pierre (DM), Hua-Khao-Yen in Thai, are commonly used as ingredients for alternative treatment of cancer in Thailand. In this study, the anticancer effects of DM extract in HCC-bearing rats were evaluated with respect to gross morphology, histopathology, and leakage of liver enzymes. In untreated HCCs, typical features of liver cancer, including hepatic nodules, thick-cell cords, and pseudoglandular cell arrangements, were observed. In addition, the HCCs showed abnormal reticulin patterns and a high glypican3 expression. In HCC-bearing rats treated with DM the cancer areas and reticulin expression were significantly reduced compared to the untreated group (p ＜ 0.01). Sorafenib, the standard drug to treat HCC, reduced the cancer area further, but increased leakage of liver enzymes and decreased serum albumin concentration, indicating liver toxicity. These findings suggest that DM has an anticancer effect on HCCs in an animal model in vivo with potentially less severe side effects than sorafenib. Therefore, further studies of DM’s mechanism of action in HCC should be carried out.

1. El-Lakkany, NM,El-Maadawy, WH,Seifel-Din, SH(2019).Antifibrotic effects of gallic acid on hepatic stellate cells: in vitro and in vivo mechanistic study.J Tradit Complement Med,9(1),45-53.
   連結：
2. Allegretta, M,Filmus, J.(2012).Therapeutic potential of targeting glypican-3 in heap-tocellular carcinoma.Anticancer Agents Med Chem,11(6),543-548.
3. Alzahrani, FA,El-Magd, MA,Abdelfattah-Hassan, A(2018).Potential effect of exosomes derived from cancer stem cells and MSCs on progression of DEN-induced HCC in rats.Stem Cell Int,2018,8058979.
4. Ataide, EC,Perales, SR,Silva, MG(2017).Immunoexpression of heat shock protein 70, glypican 3, glutamine synthetase, and β -catenin in hepatocellular carcinoma after liver transplantation: association between positive glypican 3 and b-catenin with the presence of larger nodules.Transplant Proc,49(4),858-862.
5. Bray, F,Ferlay, J,Soerjomataram, I,Siegel, RL,Torre, LA,Jemal, A(2001).Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.Ca-Cancer J Clin,68(6),394-424.
6. Chilakapati, J,Shankar, K,Korrapati, MC,Hill, RA,Mehendale, HM(2005).Saturation toxicokinetics of thioacetamide: role in initiation of liver injury.Drug Metab Dispos,33(12),1877-1885.
7. El-Ashmawy, NE,El-Bahrawy, HA,Shamloula, MM,El-Feky, OA(2014).Biochemical/metabolic changes associated with hepatocellular carcinoma development in mice.Tumour Biol J Int Soc Oncodevelopmental Biol Med,35(6),5459-5466.
8. El-Magd, MA,Mohamed, Y,El-Shetry, ES(2019).Melatonin maximizes the therapeutic potential of non-preconditioned MSCs in a DEN-induced rat model of HCC.Biomed Pharmacother,114,108732.
9. Gao, W,Kim, H,Feng, M(2014).Inactivation of Wnt signaling by a human anti-body that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy.Hepatology,60(2),576-587.
10. Gauthier, A,Ho, M(2013).Role of sorafenib in the treatment of advanced hepatocellular carcinoma: an update.Hepatol Res,43(2),147-154.
11. Ghouri, YA,Mian, I,Rowe, JH(2017).Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis.J Carcinog,16(1),1-8.
12. Gowda, S,Desai, PB,Hull, VV,Math, AAK,Vernekar, SN,Kulkarni, SS(2009).A review on laboratory liver function tests.Pan Afr Med J.,3,17.
13. Gu, FM,Li, QL,Gao, Q(2011).Sorafenib inhibits growth and metastasis of heap-tocellular carcinoma by blocking STAT3.World J Gastroenterol,17(34),3922-3932.
14. Guo, M,Zhang, H,Zheng, J,Liu, Y(2020).Glypican-3: a new target for diagnosis and treatment of hepatocellular carcinoma.J Canc,11(8),2008-2021.
15. Hong, H,Patonay, B,Finley, J(2011).Unusual reticulin staining pattern in well-differentiated hepatocellular carcinoma.Diagn Pathol,6,15.
16. Itharat, A,Houghton, PJ,Eno-Amooquaye, E,Burke, PJ,Sampson, JH,Raman, A(2004).In vitro cytotoxic activity of Thai medicinal plants used traditionally to treat cancer.J Ethnopharmacol,90(1),33-38.
17. Itharat, A,Ooraikul, B(2007).Research on Thai medicinal plants for cancer treatment.Advances in Medicinal Plant Research,India:
18. Itharat, A,Plubrukan, A,Kaewpradub, N,Chuchom, T,Ratanasuwan, P,Houghton, PJ(2007).Selective cytotoxicity and antioxidant effects of compounds from Dioscorea membranacea rhizomes.Nat Prod Commun,2(6),643-648.
19. Itharat, A,Plubrukarn, A,Kongsaeree, P,Bui, T,Keawpradub, N,Houghton, PJ(2003).Dioscorealides and dioscoreanone, novel cytotoxic naphthofuranoxepins, and 1,4-phenanthraquinone from Dioscorea membranacea Pierre.Org Lett,5(16),2879-2882.
20. Itharat, A,Thongdeeying, P,Ruangnoo, S(2014).Isolation and characterization of a new cytotoxic dihydrophenanthrene from Dioscorea membranacea rhizomes and its activity against five human cancer cell lines.J Ethnopharmacol,156,130-134.
21. Kaewnoonual, N,Itharat, A,Pongsawat, S,Nilbu-Nga, C,Kerdput, V,Pradidarcheep, W(2020).Anti-angiogenic and anti-proliferative effects of benja-ummarit extract in rats with hepatocellular carcinoma.Biomed Reports,12(3),109-120.
22. Kalaiselvan, A,Gokulakrishnan, K,Anand, T,Akhilesh, U,Velavan, S(2013).Preventive effect of shorea robusta bark extract against diethylnitrosamine-Induced hepatocellular carcinoma in rats.Int Res J Med Sci.,1(1),2-9.
23. Kim, WR,Flamm, SL,Di Bisceglie, AM,Bodenheimer, HC(2008).Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease.Hepatology,47(4),136-e1370.
24. Kuroda, D,Hayashi, H,Nitta, H(2016).Successful treatment for sorafenib-induced liver dysfunction: a report of case with liver biopsy.Surg Case Reports,2(1)
25. Li, QL,Gu, FM,Wang, Z(2012).Activation of PI3K/AKT and MAPK pathway through a PDGFRβ-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma.PloS One,7(3),e33379.
26. Llovet, JM,Bruix, J(2008).Molecular targeted therapies in hepatocellular carcinoma.Hepatology,48(4),1312-1327.
27. Mangipudy, RS,Chanda, S,Mehendale, HM(1995).Tissue repair response as a function of dose in thioacetamide hepatotoxicity.Environ Health Perspect,103(3),260-267.
28. Marisi, G,Cucchetti, A,Ulivi, P(2018).Ten years of sorafenib in hepatocellular carcinoma: are there any predictive and/or prognostic markers?.World J Gas-troenterol,24(36),4152-4163.
29. Mukherjee, B,Kumar, M,Mobaswar, C(2012).Chemically induced hepatocellular carcinoma and stages of development with biochemical and genetic modulation: a special reference to insulin-like-growth factor II and raf gene signaling.Hepatocellular Carcinoma-Basic Research
30. Panthong, S,Ruangnoo, S,Thongdeeying, P,Sriwanthana, B,Itharat, A(2014).Immunomodulatory activity of Dioscorea membranacea Pierre rhizomes and of its main active constituent dioscorealide B.BMC Compl Alternative Med,14,403.
31. Poonthananiwatkul, B,Lim, RHM,Howard, RL,Pibanpaknitee, P,Williamson, EM(2015).Traditional medicine use by cancer patients in Thailand.J Ethnopharmacol,168,100-107.
32. Reanmongkol, W,Itharat, A,Bouking, P(2007).Investigation of the anti-inflammatory, analgesic and antipyretic activities of the extracts from the rhizome of Dioscorea membranacea Pierre in experimental animals.Songklanakarin J Sci Technol,29(SUPPL. 1),49-57.
33. Rodniem, S,Tiyao, V,Nilbu-Nga, C,Poonkhum, R,Pongmayteegul, S,Pradidarcheep, W(2019).Protective effect of alpha-mangostin on thioacetamide-induced liver fibrosis in rats as revealed by morpho-functional analysis.Histol Histopathol,34(4),419-430.
34. Saetung, A,Itharat, A,Dechsukum, C,Wattanapiromsakul, C,Keawpradub, N,Ratanasuwan, P(2005).Cytotoxic activity of Thai medicinal plant for cancer treatment.Songklanakarin J Sci Technol,27,469-478.
35. Schlageter, M,Terracciano, LM,D’Angelo, S,Sorrentino, P(2014).Histopathology of hepatocellular carcinoma.World J Gastroenterol,20(43),15955-15964.
36. Sekine, S,Lan, BYA,Bedolli, M,Feng, S,Hebrok, M(2006).Liver-specific loss of β-catenin blocks glutamine synthesis pathway activity and cytochrome P450 expression in mice.Hepatology,43(4),817-825.
37. Shirakawa, H,Kuronuma, T,Nishimura, Y(2009).Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer.Int J Oncol.,34(3),649-656.
38. Sirikatitham, A,Chuchom, T,Itharat, A(2007).Development of the chromatographic fingerprint analysis of dioscorealides and dioscoreanone from Dioscorea membranacea Pierre.Songklanakarin J Sci Technol,29(SUPPL. 1),101-107.
39. Sukkarn, B,Itharat, A(2009).Development of the HPLC quantitative analysis of dioscorealide B from Dioscorea memebranacea Pierre.Thammasat Med J.,9,156-163.
40. Tewtrakul, S,Itharat, A(2006).Anti-allergic substances from the rhizomes of Dioscorea membranacea.Bioorg Med Chem,14(24),8707-8711.
41. Tewtrakul, S,Itharat, A(2007).Nitric oxide inhibitory substances from the rhizomes of Dioscorea membranacea.J Ethnopharmacol,109(3),412-416.
42. Thongdeeying, P,Itharat, A,Umehara, K,Ruangnoo, S(2016).A novel steroid and cytotoxic constituents from Dioscorea membranacea Pierre against hepatocellular carcinoma and cholangiocarcinoma cells.J Ethnopharmacol,194,91-97.
43. Van Hootegem, A,Verslype, C,Van Steenbergen, W(2011).Sorafenib-induced liver failure: a case report and review of the literature.Case Reports Hepatol,2011,941395.
44. Vauthey, J-N(ed.),Brouquet, Antoine(ed.)(2013).Multidisciplinary Treatment of Hepatocellular Carcinoma.Springer-Verlag Berlin Heidelberg.
45. Verna, L,Whysner, J,Williams, GM(1996).N-Nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation.Pharmacol Ther,71(1-2),57-81.
46. Vogel, A,Cervantes, A,Chau, I(2018).Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol,29,iv238-iv255.
47. Wang, B,Zhao, L,Fish, M,Logan, CY,Nusse, R(2015).Self-renewing diploid Axin2 + cells fuel homeostatic renewal of the liver.Nature,524(7564),180-185.
48. Wang, HL,Anatelli, F,Zhai, Q,Adley, B,Chuang, ST,Yang, XJ(2008).Glypican-3 as a useful diagnostic marker that distinguishes hepatocellular carcinoma from benign hepatocellular mass lesions.Arch Pathol Lab Med,132(11),1723-1728.
49. Wang, Q-L,Li, X-J,Yao, Z-C(2017).Sorafenib-induced acute-on-chronic liver failure in a patient with hepatocellular carcinoma after transarterial chemo-embolization and radiofrequency ablation: a case report.Mol Clin Oncol,7(4),693-695.
50. Yao, S,Zhang, J,Chen, H(2013).Diagnostic value of immunohistochemical staining of GP73, GPC3, DCP, CD34, CD31, and reticulin staining in hepatocellular carcinoma.J Histochem Cytochem,61(9),639-648.
51. Zhang, X,Yu, H(2016).Matrine inhibits diethylnitrosamine-induced HCC proliferation in rats through inducing apoptosis via p53, bax-dependent caspase-3 activation pathway and down-regulating MLCK overexpression.Iran J Pharm Res,15(2),491-499.