Zerumbone induces growth inhibition of Burkitt’s lymphoma cell line via apoptosis

Abstract

Zerumbone (ZER), a natural compound has been extracted from Zingiber zerumbet with known pharmacological activities. The aim was to determine the anti-human Burkitt’s lymphoma (Raji) cell effect of ZER. The 3-(4,5-dimethylthiazol-2-yl)-2,5,-diphenyltetrazolium bromide (MTT) assay was used to determine cytotoxic effect while the Annexin-V-fluorescein isothiocyanate/propidium iodide-PI flow cytometric assays was used to determine apoptotic effect of ZER on the human Burkitt’s lymphoma (Raji) cell (ATCC CCL-86) cell line. The expressions of Bax, Bcl-2, and c-Myc genes were determined via real-time PCR. ZER suppressed the proliferation of Raji cells with a 48 h IC50 value of 5.1 μg/mL. Treated Raji cells also underwent late apoptosis especially after treatment with 100 μg/mL ZER. The apoptotic effect of ZER is associated with increase in Bax and decrease in Bcl-2 and c-Myc gene expressions. These results suggest that ZER inhibited the proliferation of Raji cells through the modification of apoptosis-related gene expressions. Therefore, ZER has potential as a candidate for the treatment of Burkitt’s lymphoma.

Keywords

• Cytotoxicity
• Cell Proliferation
• Burkitt Lymphoma
• c-Myc
• Bax

References

1. 1- Al-Attar A, Al-Mondhiry H, Al-Bahrani Z, Al-Saleem T. Burkitt's lymphoma in Iraq. Clinical and pathological study of forty‐seven patients. Int J Cancer. 1979;23(1):14-17.
2. 2- Achmad MH, Horax S, Ramadhany S, Rieuwpassa IE, Sari M, Handayani H, et al.. Anti-cancer and anti-proliferation activity of ethyl asesetat extract from ant nest (Myrmecodia pendans) in Burkitt’s lymphoma cancer cells. Pesqui Bras Odontopediatria Clin Integr. 2019;19(1):e4325.
3. 3- Ling B, Michel D, Sakharkar MK, Yang J . Evaluating the cytotoxic effects of the water extracts of four anticancer herbs against human malignant melanoma cells. Drug Des Devel Ther. 2016;10:3563–3572
4. 4- Sharifi S, Barar J, Hejazi MS, Samadi N. Roles of the Bcl-2/Bax ratio, caspase-8 and 9 in resistance of breast cancer cells to paclitaxel. Asian Pac J Cancer Prev. 2014;15(20):8617-22.
5. 5- Glab J, Mbogo G, Puthalakh H. BH3-only protein in health and disease. Int Rev cell Mol Bio. 2017;328:163-96.
6. 6- Benassi B, Flavin R, Marchionni L, Zanata S, Pan Y, Chowdhury, et al. MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer. Cancer Discov. 2012;2(3):2236-247.
7. 7- Cerquetti L, Sampaoli C, De Salvo, M, Bucci B, Argese N, Chimento A, et al. C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines. Int J Oncol. 2015;46(5):2231-2240.
8. 8- Nguyen L, Papenhausen P, Shao H. (2017). The role of c-MYC in B-cell lymphomas: Ddiagnostic and molecular aspects. Genes, 2017;8(4):E116.

9. 9- Albaayit SFA, Maharjan R. Immunomodulation of zerumbone via decreasing the production of reactive oxygen species from immune cells. Pak J Biol Sci. 2018;21:475-479.
10. 10- Sakinah SS, Handayani ST, Hawariah LA. Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/Bcl-2 ratio. Cancer cell Int. 2007;7(1):4.
11. 11- Haque MA, Jantan I, Arshad L, Bukhari SNA. Exploring the immunomodulatory and anticancer properties of zerumbone. Food Funct. 2017;8(10):3410-431.
12. 12- Girisa S, Shabnam B, Monisha J, Fan L, Halim CE, Arfuso F, et al. Potential of zerumbone as an anti-cancer agent. Molecules. 2019;24(4):734
13. 13- Mohamad NE, Abu N, Rahman HS, Ky H, Ho WY, Lim KL, et al. Nanostructured lipid carrier improved in vivo anti-tumor and immunomodulatory effect of zerumbone in 4T1 challenged mice. RSC Adv. 2015;5(28):22066-74.
14. 14- Abdelwahab SI, Abdul AB, Mohan S, Taha MM, Ibrahim MY, Mariod AA. Zerumbone induces aoptosis in T-acute lymphoblastic leukemia cells. Leuk Res. 2011;35:268-27.
15. 15- Albaayit SFA, Ozaslan M. Cytotoxic and Urease Inhibition Potential of Moringa peregrina Seed Ethanolic Extract. Int J Pharmacol. 2019;15:151-55.
16. 16- Hidayat M, Prahastuti S, Fauziah N, Maesaroh M, Balqis B, Widowati W. Modulation of adipogenesis-related gene expression by ethanol extracts of detam 1 soybean and jati belanda leaf in 3T3-L1 Cells. Bangladesh J Pharmacol. 2016;11(3):697-02.
17. 17- Tonglin H, Gao Y. β-elemene against Burkitt’s lymphoma via activation of PUMA mediated apoptotic pathway. Biomed Pharmacother. 2018;106:1557-62.
18. 18- Ni F, Huang X, Chen Z, Qian W, Tong X. Shikonin exerts antitumor activity in Burkitt’s lymphoma by inhibitin C-MYC and PI3K/AK/mTOR pathway and acts synergistically with doxorubicin. Sci Rep. 2018;8(1):3317.
19. 19- Ni F, Huang X, Chen Z, Qian W, Tong X. Shikonin exerts antitumor activity in Burkitt’s lymphoma by inhibiting C-MYC and PI3K/AKT/mTOR pathway and acts synergistically with doxorubicin. Sci Rep. 2018;8:3317.
20. 20- Jara P, Spies J, Cárcamo C, Arancibia Y, Vargas G, Martin C, et al. The effect of resveratrol on cell viability in the Burkitt’s lymphoma cell line Ramos. Molecules. 2018;23(1):0014.
21. 21- Samad NA, Abdul AB, Abdullah R, Tengku Ibrahim TA, Rahman H, Keong YS. Zerumbone (ZER) induces apoptosis in HepG2 cells via mitochondrial pathway. International Journal of Pharmacy and . Pharm. Sci. 2015;7(5):298-302.
22. 22- Sadhu SK, Khatun A, Ohtsuki T, Ishibashi M. First isolation of sesquiterpenes and flavonoids from Zingiber spectabile and identification of zerumbone as the major cell growth inhibitory component. Nat Prod Res. 2007;21(14):1242-47.
23. 23- Pfeffer C, Singh ATK. Apoptosis: A target for anticancer therapy. Int J Mol Sci. 2018;19:448.
24. 24- Dang CV, O’Donell KA, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc gene network. Semin Cancer Biol. 2006;16:253-64.
25. 25- McMahon SB. MYC and the control of apoptosis. Cold Spring Harb Perspect Med. 2014;4(7): a014407.