Sains Malaysiana 52(12)(2023): 3801-3812

http://doi.org/10.17576/jsm-2023-5212-13

Zerumbone: A Potent Emerging Phytochemical with Anticancer Therapeutic Potential

(Zerumbon: Kemunculan Fitokimia Poten dengan Potensi Terapeutik Antikanser)

NUR AQILAH HUDA AHMAD JAMIL, SYLVIA CHONG HOONGLI, NURUL AKMARYANTI ABDULLAH, NORAINA MOHAMAD ZAKUAN, HAFIZAH ABDUL HAMID, MUHAMMAD ZULFADLI MEHAT, MANRAJ SINGH CHEEMA & NUR FARIESHA MD HASHIM*

Faculty of Medicine and Health Sciences, Department of Biomedical Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

Received: 19 July 2023/Accepted: 1 December 2023

Abstract

Breast cancer is a prevalent cause of global mortality, characterised by abnormal cell growth within the breast. These cells can spread to distant sites in the body through metastasis and one of the mechanisms that breast cancer cells use to metastasise is via invadopodia formation. Accumulated evidence has explained pathways that may contribute to the breast cancer cells metastasis including the ERK, SMAD-3, STAT3 and NF-κB pathways. The hypoxic conditions within tumours enhance their metastatic ability through HIF-1α upregulation. Despite advanced treatments including chemotherapy and radiotherapy, these approaches are expensive and sometimes lack efficacy. Zerumbone, a compound extracted from Zingiber zerumbet, is known for its anti-cancer properties. It counteracts cancer cell metastasis by reducing cell migration, invasion, and proliferation by acting upon multiple signalling pathways. This review recapitulates the metastasis of breast cancer and its biomarkers. In addition, our review will also explore the impact of zerumbone, therapeutic roles and its mechanism of action in reducing breast cancer metastasis.

Keywords: Breast cancer; hypoxia; invadopodia; metastasis; zerumbone

Abstrak

Kanser payudara adalah penyebab lazim kematian global, dicirikan oleh pertumbuhan sel yang tidak normal dalam payudara. Sel-sel ini boleh merebak ke tapak yang jauh dalam badan manusia melalui metastasis dan salah satu mekanisme yang digunakan oleh sel kanser payudara untuk metastasis adalah melalui pembentukan invadopodia. Bukti terkumpul telah menjelaskan mekanisme yang mungkin menyumbang kepada metastasis sel kanser payudara termasuk laluan yang melibatkan ERK, SMAD-3, STAT3 dan NF-κB. Keadaan hipoksik dalam tumor meningkatkan keupayaan metastatik mereka melalui peningkatan HIF-1α. Walaupun dengan kehadiran rawatan lanjutan termasuk kemoterapi dan radioterapi, rawatan ini memerlukan kos yang tinggi dan kadangkala kurang berkesan. Zerumbon, sebatian yang diekstrak daripada Zingiber zerumbet, terkenal dengan sifat anti-kansernya. Ia menentang metastasis sel kanser dengan mengurangkan penghijrahan, pencerobohan dan percambahan sel dengan bertindak melalui pelbagai mekanisme. Kajian ini menyusun semula metastasis kanser payudara dan biopenandanya. Di samping itu, penyelidikan kami juga akan mengkaji kesan zerumbon, peranan pemulihan dan mekanisme tindakannya dalam mengurangkan metastasis kanser payudara.

Kata kunci: Hipoksia; invadopodia; kanser payudara; metastasis; zerumbon

REFERENCES

Al-Amin, M., Sultana, G.N.N. & Hossain, C.F. 2012. Antiulcer principle from Zingiber montanum. Journal of Ethnopharmacology 141(1): 57-60.

Casey, S.C., Amedei, A., Aquilano, K., Azmi, A.S., Benencia, F., Bhakta, D., Bilsland, A.E., Boosani, C.S., Chen, S., Ciriolo, M.R., Crawford, S., Fujii, H., Georgakilas, A.G., Guha, G., Halicka, D., Helferich, W.G., Heneberg, P., Honoki, K., Keith, W.N., Kerkar, S.P., Mohammed, S.I., Niccolai, E., Nowsheen, S., Vasantha Rupasinghe, H.P., Samadi, A., Singh, N., Talib, W.H., Venkateswaran, V., Whelan, R.L., Yang, X. & Felsher, D.W. 2015. Cancer prevention and therapy through the modulation of the tumor microenvironment. Seminars in Cancer Biology 35: S199-S223.

Castaneda, S.A. & Strasser, J. 2017. Updates in the treatment of breast cancer with radiotherapy. Surgical Oncology Clinics of North America 26(3): 371-382.

Dattachoudhury, S., Sharma, R., Kumar, A. & Jaganathan, B.G. 2020. Sorafenib inhibits proliferation, migration and invasion of breast cancer cells. Oncology (Switzerland) 98(7): 478-486.

Eddy, R.J., Weidmann, M.D., Sharma, V.P. & Condeelis, J.S. 2017. Tumor cell invadopodia: Invasive protrusions that orchestrate metastasis. Trends in Cell Biology 27(8): 595-607.

Edwards, A. & Brennan, K. 2021. Notch signalling in breast development and cancer. Frontiers in Cell and Developmental Biology 9: 692173.

El Fagie, R.M.H., Yusoff, N.A., Lim, V., Kamal, N.N.S.N.M. & Samad, N.A. 2021. Anti-cancer and anti-angiogenesis activities of zerumbone isolated from Zingiber zerumbet – A systematic review. Current Research in Nutrition and Food Science 9(2): 353-374.

Elaraj, D.M., Weinreich, D.M., Varghese, S., Puhlmann, M., Hewitt, S.M., Carroll, N.M., Feldman, E.D., Turner, E.M. & Alexander, H.R. 2006. The role of interleukin 1 in growth and metastasis of human cancer xenografts. Clinical Cancer Research 12(4): 1088-1096.

Eom, Y.H., Kim, H.S., Lee, A., Song, B.J. & Chae, B.J. 2016. BCL2 as a subtype-specific prognostic marker for breast cancer. Journal of Breast Cancer 19(3): 252-260.

Fadhel Abbas Albaayit, S., Maharjan, R., Abdullah, R. & Mohd Noor, M.H. 2022. Evaluation of anti-methicillin-resistant Staphylococcus aureus property of zerumbone. J. Appl. Biomed. 20: 15-21.

Girisa, S., Shabnam, B., Monisha, J., Fan, L., Halim, C.E., Arfuso, F., Ahn, K.S., Sethi, G. & Kunnumakkara, A.B. 2019. Potential of zerumbone as an anti-cancer agent. Molecules 24(4): 734.

Guo, F., Wang, Y., Liu, J., Mok, S.C., Xue, F. & Zhang, W. 2016. CXCL12/CXCR4: A symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene 35(7): 816-826.

Guo, Y.J., Pan, W.W., Liu, S.B., Shen, Z.F., Xu, Y. & Hu, L.L. 2020. ERK/MAPK signalling pathway and tumorigenesis. Experimental and Therapeutic Medicine 19(3): 1997-2007.

Hamad, H.A., Gopalsamy, B., Kqueen, C.Y. & Hashim, N.F.M. 2019. Potential ability of phytochemical in inhibition of invadopodia formation and HIF-1α in cancer metastasis. Malaysian Journal of Medicine and Health Sciences 15: 71-80.

Han, J., Bae, S.Y., Oh, S.J., Lee, J., Lee, J.H., Lee, H.C., Lee, S.K., Kil, W.H., Kim, S.W., Nam, S.J., Kim, S. & Lee, J.E. 2014. Zerumbone suppresses IL-1β-induced cell migration and invasion by inhibiting IL-8 and MMP-3 expression in human triple-negative breast cancer cells. Phytotherapy Research 28(11): 1654-1660.

Haque, M.A., Jantan, I., Arshad, L. & Bukhari, S.N.A. 2017. Exploring the immunomodulatory and anticancer properties of zerumbone. Food and Function 8(10): 3410-3431.

Hashimoto, T. & Shibasaki, F. 2015. Hypoxia-inducible factor as an angiogenic master switch. Frontiers in Pediatrics 3: 33.

Jeannot, P. & Besson, A. 2020. Cortactin function in invadopodia. Small GTPases 11(4): 256-270.

Jeon, M., Han, J., Nam, S.J., Lee, J.E. & Kim, S. 2016. Elevated IL-1β expression induces invasiveness of triple negative breast cancer cells and is suppressed by zerumbone. Chemico-Biological Interactions 258: 126-133.

Karamanou, K., Franchi, M., Vynios, D. & Brézillon, S. 2020. Epithelial-to-mesenchymal transition and invadopodia markers in breast cancer: Lumican a key regulator. Seminars in Cancer Biology 62: 125-133.

Khera, S. & Gupta, S. 2020. Zerumbone: A magical phytochemical. International Journal of Health Sciences and Research 10: 73-79.

Khoshakhlagh, M., Soleimani, A., Binabaj, M.M., Avan, A., Ferns, G.A., Khazaei, M. & Hassanian, S.M. 2019. Therapeutic potential of pharmacological TGF-β signaling pathway inhibitors in the pathogenesis of breast cancer. Biochemical Pharmacology 164: 17-22.

Kim, S., Lee, J., Jeon, M., Lee, J.E. & Nam, S.J. 2015. Zerumbone suppresses the motility and tumorigenecity of triple negative breast cancer cells via the inhibition of TGF-β1 signaling pathway. Oncotarget 7(2): 1544-1558.

Kim, S., Kil, W.H., Lee, J., Oh, S.J., Han, J., Jeon, M., Jung, T., Lee, S.K., Bae, S.Y., Lee, H.C., Lee, J.H., Yi, H.W., Kim, S.W., Nam, S.J. & Lee, J.E. 2014. Zerumbone suppresses EGF-induced CD44 expression through the inhibition of STAT3 in breast cancer cells. Oncology Reports 32(6): 2666-2672.

Kiyama, R. 2020. Nutritional implications of ginger: chemistry, biological activities and signaling pathways. Journal of Nutritional Biochemistry 86: 108486.

Lambert, A.W., Pattabiraman, D.R. & Weinberg, R.A. 2017. Emerging biological principles of metastasis. Cell 168(4): 670-691.

Li, Y., Zhao, L. & Li, X.F. 2021. Hypoxia and the tumor microenvironment. Technology in Cancer Research and Treatment 20: 15330338211036304.

Li, Y.M., Pan, Y., Wei, Y., Cheng, X., Zhou, B.P., Tan, M., Zhou, X., Xia, W., Hortobagyi, G.N., Yu, D. & Hung, M.C. 2004. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6(5): 459-469.

Linderholm, B.K., Hellborg, H., Johansson, U., Elmberger, G., Skoog, L., Lehtiö, J. & Lewensohn, R. 2009. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Annals of Oncology 20(10): 1639-1646.

Liu, Z.J., Semenza, G.L. & Zhang, H.F. 2015. Hypoxia-inducible factor 1 and breast cancer metastasis. Journal of Zhejiang University: Science B 16(1): 32-43.

Lobry, C., Oh, P., Mansour, M.R., Thomas Look, A. & Aifantis, I. 2014. Notch signaling: Switching an oncogene to a tumor suppressor. Blood 123(16): 2451-2459.

Meirson, T. & Gil-Henn, H. 2018. Targeting invadopodia for blocking breast cancer metastasis. Drug Resistance Updates 39: 1-17.

Moses, H. & Barcellos-Hoff, M.H. 2011. TGF-β Biology in mammary development and breast cancer. Cold Spring Harbor Perspectives in Biology 3(1): a003277.

Murakami, A., Matsumoto, K., Koshimizu, K. & Ohigashi, H. 2003. Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide- and interferon-γ-induced IκB degradation in RAW264.7 macrophages. Cancer Letters 195(1): 17-25.

Nair, S. & Dhodapkar, M.V. 2017. Natural killer T cells in cancer immunotherapy. Frontiers in Immunology 8: 1178.

Nakamura, Y., Yoshida, C., Murakami, A., Ohigashi, H., Osawa, T. & Uchida, K. 2004. Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes. FEBS Letters 572(1-3): 245-250.

O’Neill, C.F., Urs, S., Cinelli, C., Lincoln, A., Nadeau, R.J., León, R., Toher, J., Mouta-Bellum, C., Friesel, R.E. & Liaw, L. 2007. Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. American Journal of Pathology 171(3): 1023-1036.

O’Reilly, E.A., Gubbins, L., Sharma, S., Tully, R., Guang, M.H.Z., Weiner-Gorzel, K., McCaffrey, J., Harrison, M., Furlong, F., Kell, M. & McCann, A. 2015. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clinical 3: 257-275.

Om Alblazi, K.M. & Siar, C.H. 2015. Cellular protrusions - Lamellipodia, filopodia, invadopodia and podosomes - and their roles in progression of orofacial tumours: Current understanding. Asian Pacific Journal of Cancer Prevention 16(6): 2187-2191.

Padilla, J. & Lee, J. 2021. A novel therapeutic target, BACH1, regulates cancer metabolism. Cells 10(3): 634.

Padmanaban, V., Krol, I., Suhail, Y., Szczerba, B.M., Aceto, N., Bader, J.S. & Ewald, A.J.  2019. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 573(7774): 439-444.

Prasannan, R., Kalesh, K.A., Shanmugam, M.K., Nachiyappan, A., Ramachandran, L., Nguyen, A.H., Kumar, A.P., Lakshmanan, M., Ahn, K.S. & Sethi, G. 2012. Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer. Biochemical Pharmacology 84(10): 1268-1276.

Rajabi, S., Maresca, M., Yumashev, A.V., Choopani, R. & Hajimehdipoor, H. 2021. The most competent plant‐derived natural products for targeting apoptosis in cancer therapy. Biomolecules 11(4): 534.

Rizvi, Z.A., Puri, N. & Saxena, R.K. 2015. Lipid antigen presentation through CD1d pathway in mouse lung epithelial cells, macrophages and dendritic cells and its suppression by poly-dispersed single-walled carbon nanotubes. Toxicology in Vitro 29(6): 1275-1282.

Sakinah, S.A.S., Tri Handayani, S. & Hawariah, L.P.A. 2007. Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/ Bcl-2 ratio. Cancer Cell International 7: 4.

Salminen, A., Lehtonen, M., Suuronen, T., Kaarniranta, K. & Huuskonen, J. 2008. Terpenoids: Natural inhibitors of NF-κB signaling with anti-inflammatory and anticancer potential. Cellular and Molecular Life Sciences 65(19): 2979-2999.

Sarkar, D.K., Jana, D., Patil, P.S., Chaudhari, K.S., Chattopadhyay, B.K., Chikkala, B.R., Mandal, S. & Chowdhary, P. 2013. Role of NF-κB as a prognostic marker in breast cancer: A pilot study in Indian patients. Indian Journal of Surgical Oncology 4(3): 242-247.

Schioppa, T., Uranchimeg, B., Saccani, A., Biswas, S.K., Doni, A., Rapisarda, A., Bernasconi, S., Saccani, S., Nebuloni, M., Vago, L., Mantovani, A., Melillo, G. & Sica, A. 2003. Regulation of the chemokine receptor CXCR4 by hypoxia. Journal of Experimental Medicine 198(9): 1391-1402.

Scully, O.J., Bay, B-H., Yip, G. & Yu, Y. 2012. Breast cancer metastasis. Cancer Genomics & Proteomics 9(5): 311-320.

Sehrawat, A., Arlotti, J.A., Murakami, A. & Singh, S.V. 2012. Zerumbone causes Bax- and Bak-mediated apoptosis in human breast cancer cells and inhibits orthotopic xenograft growth in vivo. Breast Cancer Research and Treatment 136(2): 429-441.

Sehrawat, A., Sakao, K. & Singh, S.V. 2014. Notch2 activation is protective against anticancer effects of zerumbone in human breast cancer cells. Breast Cancer Res. Treat 146(3): 543-555.

Semenza, G.L. 2001. HIF-1 and mechanisms of hypoxia sensing. Current Opinion in Cell Biology 13(2): 167-171.

Shrestha, Y., Schafer, E.J., Boehm, J.S., Thomas, S.R., He, F., Du, J., Wang, S., Barretina, J., Weir, B.A., Zhao, J.J., Polyak, K., Golub, T.R., Beroukhim, R. & Hahn, W.C. 2012. PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling. Oncogene 31(29): 3397-3408.

Shyanti, R.K., Sehrawat, A., Singh, S.V., Mishra, J.P.N. & Singh, R.P. 2017. Zerumbone modulates CD1d expression and lipid antigen presentation pathway in breast cancer cells. Toxicology in Vitro 44: 74-84.

Smith, D. 2011. Synthetic and endogenous cannabinoids inhibit breast cancer cell growth and metastasis. Honors research thesis. The Ohio State University (Unpublished).

Sulaiman, M.R., Perimal, E.K., Akhtar, M.N., Mohamad, A.S., Khalid, M.H., Tasrip, N.A., Mokhtar, F., Zakaria, Z.A., Lajis, N.H. & Israf, D.A. 2010. Anti-inflammatory effect of zerumbone on acute and chronic inflammation models in mice. Fitoterapia 81(7): 855-858.

Sung, B., Jhurani, S., Kwang, S.A., Mastuo, Y., Yi, T., Guha, S., Liu, M. & Aggarwal, B.B.  2008. Zerumbone down-regulates chemokine receptor CXCR4 expression leading to inhibition of CXCL12-induced invasion of breast and pancreatic tumor cells. Cancer Research 68(21): 8938-8944.

Tan, A.R., Alexe, G. & Reiss, M. 2009. Transforming growth factor-β signaling: Emerging stem cell target in metastatic breast cancer? Breast Cancer Research and Treatment 115(3): 453-495.

Wang, M., Niu, J., Gao, L., Gao, Y. & Gao, S. 2019. Zerumbone inhibits migration in ESCC via promoting Rac1 ubiquitination. Biomedicine and Pharmacotherapy 109: 2447-2455.

Wertheimer, E., Gutierrez-Uzquiza, A., Rosemblit, C., Lopez-Haber, C., Sosa, M.S. & Kazanietz, M.G. 2012. Rac signaling in breast cancer: A tale of GEFs and GAPs. Cellular Signalling 24(2): 353-362.

Whiteside, T.L. 2008. The tumor microenvironment and its role in promoting tumor growth. Oncogene 27(45): 5904-5912.

Woźniak, M., Krajewski, R., Makuch, S. & Agrawal, S. 2021. Phytochemicals in gynecological cancer prevention. International Journal of Molecular Sciences 22(3): 1219.

Yin, L., Duan, J.J., Bian, X.W. & Yu, S.C. 2020. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Research 22(1): 61.

Zhao, F., Ma, B., Lv, Z., Chen, J., Cai, Y., Xu, C. & Cai, Y. 2020. Zerumbone decreases BACH1 levels by upregulating miR-708 to inhibit breast cancer cell proliferation and invasion. Tropical Journal of Pharmaceutical Research 19(7): 1411-1416.

*Corresponding author; email: nurfariesha@upm.edu.my