The effect of nanomicelle curcumin, sorafenib, and combination of the two on the cyclin D1 gene expression of the hepatocellular carcinoma cell line (HUH7)

Document Type: Original Article

Authors

1 Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Biology, Faculty of Sciences, Islamic Azad University-Mashhad Branch, Mashhad, Iran

3 Student Research Committee, School of Para Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Modern Sciences & Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

5 Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Hepatocellular carcinoma (HCC) is one of the most significant health condition around the world. As the only curative therapies, liver transplantation and surgical resection are the clinical treatments of HCC. Due to the systemic toxicity and severe side effects of these treatments, it is vital to establish new therapeutic approaches. The present study aimed to compare cyclin D1 (CCN D1) gene expression in hepatocellular carcinoma cell line (HUH7) when it is treated with nanomicelle curcumin and sorafenib. The purpose was to identify toxicity risk and antioxidant activity of these drugs.
Materials and Methods: The toxic dose (IC50) of nanomicelle curcumin and sorafenib were detected after treatment of HUH7 cell lines with different dose of mentioned agents followed by MTT assay. CCN D1 gene expression was evaluated using real-time PCR. Following the Tukey’s multiple comparison tests, statistical analysis is done through Student’s t-test or ANOVA.
Results: The expression of the CCN D1 gene was statistically significant (P<0.001) at 289.31, 128 and 152.36 for sorafenib, nanomicelle curcumin and SNC (sorafenib-nanomicelle curcumin) respectively. The finding of this study revealed that, in comparison to sorafenib alone, the treatment of HUH7 with a nanomicelle curcumin IC50 dose, in combination with sorafenib, might down-regulate CCN D1 gene expression.
Conclusion: The present research indicates that the treatment of the cell line with only nanomicelle curcumin results in the down-regulation of cyclin D1. To further decrease cyclin D1 expression, the co-delivery of curcumin and sorafenib appears to induce the apoptotic process. As a result, the effect of sorafenib cytotoxicity and CCN D1 gene expression decreases twofold.

Keywords

Main Subjects


1. Cheng A, Kang Y, Chen Z, Tsao C, Qin S, Kim J, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10:25-34.

2. Parkin D, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005 Mar-Apr;55:74-108.

3. Villanueva A, Llovet J. Targeted therapies for hepatocellular carcinoma. Gastro J. 2011;140:1410-1426

4. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepato J. 2005;42:1208-1236.

5. Cao H, Wang Y, He X, Zhang Z, Yin Q, Chen Y, et al. Codelivery of sorafenib and curcumin by directed self-assembled nanoparticles enhances therapeutic effect on hepatocellular carcinoma. Mol Pharma J. 2015;12:922-931.

6. Usmani A, Mishra A, Ahmad M. Nanomedicines: a theranostic approach for hepatocellular carcinoma. Artificial Cells, Nanomed Biotech J. 2018;46:680-690

7. De Jong W, Borm P. Drug delivery and nanoparticles: applications and hazards. Int J Nanomed. 2008;3:133-149.

8. Steichen S, Caldorera-Moore M, Peppas N. A review of current nanoparticle and targeting moieties for the delivery of cancer therapeutics. Euro J Pharma Sci. 2013;48:416-427.

9. Rahimi H, Mohammadpour A, Dastani M, Jaafari M, Abnous K, Mobarhan M, et al. The effect of nano-curcumin on HbA1c, fasting blood glucose, and lipid profile in diabetic subjects: a randomized clinical trial. Avicenna J Phytomed. 2016;6:567-577.

10. Rahimi H, Kazemi Oskuee R. Curcumin from traditional Iranian medicine to molecular medicine. Razavi Int J Med. 2014;2:1-2.

11. Tønnesen H, Karlsen J. Studies on curcumin and curcuminoids. Z Lebensm Unters Forsch. 1985 May;180:402-404.

12. Subramani P, Panati K, Narala V. Curcumin nanotechnologies and its anticancer activity. Nutr Cancer. 2017 Apr;69(3):381-393.. 2017;69:381-393

13. Rahimi H, Nedaeinia R, Shamloo A, Nikdoust S, Oskuee R. Novel delivery system for natural products: Nano-curcumin formulations. Avicenna J Phytomed. 2016;6:383-398.

14. Schiborrl C, Alexa Kosher DB, Jandasek J, Toeistede S, Frank J. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. Mol Nutr Food Res. 2014;58:516-527.

15. Weinstein I. Disorders in cell circuitry during multistage carcinogenesis: the role of HomeoCarcino. Carcinogenesis. 2000;21:857-864.

16. Deane N, Parker M, Aramandla R, Diehl L, Lee W, Washington M, et al. Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice. Canc Res. 2001;61:5389-5395.

17. Ahangari N, Kargozar S, Ghayour‐Mobarhan M, Baino F, Pasdar A, Sahebkar A, et al. Curcumin in tissue engineering : A traditional remedy for modern medicine. Biofactors. 2018;45:135-151.

18. Rahimi H, Jaafari M, Mohammadpour A, Abnous K, Ghayour Mobarhan M, Ramezanzadeh E, et al. Curcumin: reintroduced therapeutic agent from traditional medicine for alcoholic liver disease. Asia Pacific J of Med Tox. 2015;4:25-30.

19. Zhang Y, Jiang W, Chen C, Lee C, Kahn S, Santella R, et al. Amplification and overexpression of Cyclin D1 in human hepatocellular carcinoma. Biochem and Biophys Res Communication. 1993;196:1010-1016.

20. Nishida N, Fukuda Y, Komeda T, Kita R, Sando T, Furukawa M, et al. Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res. 1994;54:3107-3110.

21. Ikeda K, Marusawa H, Osaki Y, Nakamura T, Kitajima N, Yamashita Y, et al. Antibody to hepatitis b core antigen and risk for hepatitis c–related hepatocellular carcinoma: A prosp study. Annals Int Med. 2007;146:649-656.

22. Abou-Alfa G, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clinical Onc. 2006;24:4293-4300.

23. Cai X, Wang J, Xiao-Dong L, Wang G, Liu F, Cheng M, et al. Curcumin suppresses proliferation and invasion in human gastric cancer cells by down-regulation of PAK1 activity and cyclin D1 expression. Cancer Bio Therapy. 2009;8:1360-1368.

24. Hosseini S, Chamani J, Rahimi H, Azmoodeh N, Ghasemi F, Abadi P. An in vitro study on curcumin delivery by nano-micelles for esophageal squamous cell carcinoma (KYSE-30). Rep Biochem Mol Biol. 2018 ;6:137-143.

25. Mukhopadhyay A, Banerjee S, Stafford L, Xia C, Liu M, Aggarwal B. Curcumin-induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression and CDK4-mediated retinoblastoma protein phosphorylation. Oncogene. 2002;21:8852-8861.

26. Plastaras J, Kim S, Liu Y, Dicker D, Dorsey J, McDonough J, et al. Cell cycle–dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res. 2007;67:9443-9454.

27. Zhang Y, Jiang W, Chen C, Lee C, Kahn S, Santella R, et al. Amplification and overexpression of cyclin D1 in human hepatocellular carcinoma. Biochem Biophys Res Commun. 1993;196:1010-1016.

28. Hsu C, Lin L, Cheng Y, Feng Z, Shao Y, Cheng A, et al. Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression. Clin Cancer Res.  2016;22:2555-2564.

29. Hosseini S, Chamani J, Hadipanah MR, Ebadpour N, Hojjati AS, Mohammadzadeh MH, et al. Nano-curcumin's suppression of breast cancer cells (MCF7) through the inhibition of cyclinD1 expression. Breast Cancer (Dove Med Press). 2019;11:137-142.