Bioinformatic and Molecular Docking Study of Zerumbone and Its Derivates against Colorectal Cancer
Abstract
The prevalence of colorectal cancer (CRC) is ranked third among all cancer types in both men and women, highlighting the urgency for drug exploration. Zerumbone and its derivatives have gained attention for their ability to inhibit angiogenesis, invasion, and metastasis and have been tested for their efficacy against various cancer cells. This study aimed to investigate the potential targets and mechanism of action of zerumbone derivatives in colon cancer invasion and migration. Bioinformatic analysis was conducted using STITCH and STRING to identify potential target genes, and molecular docking was used to search for anticancer candidates from 20 zerumbone derivatives. The results revealed that six proteins were targeted by zerumbone derivatives, including XIAPBIR3 (1TFT), AKT1 (3O96), JAK2 (6VGL), HASP90AA (2XJX), MDM2 (4MDN), and XIAPBIR2 (4KJU). Compound 4 was found to have a lower binding energy than zerumbone as well as AZD5363 (pan-Akt inhibitor) when interacting with the protein target AKT1. This makes it the most promising candidate among the zerumbone derivatives for treating colorectal cancer. Further development, such as the addition of an amine functional group, is expected to improve the potency of this molecule through the formation of hydrogen bonds and other interactions with lower bond energy.
Keywords: Bioinformatic, molecular docking, zerumbone derivatives, colorectal cancer.
Full Text:
PDFReferences
Asadi, M., Shanehbandi, D., Kermani, T.A., Sanaat, Z., Zafari, V., and Hashemzadeh, S., 2018, Expression level of caspase genes in colorectal cancer, Asian Pacific Journal of cancer prevention, 19(5), 1277-1280. CrossRef
Antolin, A.A., Workman, P., Mestres, J., and Al-Lazikani, B., 2016, Polypharmacology in Precision Oncology: Current Applications and Future Prospects, Curr Pharm Des., 22(46), 6935-6945. CrossRef
Chen, J-S., Hsu, Y-M., Chen, C-C., Chen, L-L., Lee, C-C., and Huang, T-S., 2010, Secreted heat shock protein 90α induces colorectal cancer cell invasion through CD91/LRP-1 and NF-κB-mediated integrin αV expression, Journal of Biological Chemistry, 285(33), 25458-25466. CrossRef
Chinh. V.T., Loan, P.T., Duong, V.X., Vu, T.K., and Chinh, L.V., 2020, Synthesis of New Zerumbone Derivatives and Their In vitro Anti-cancer Activity, Chiang Mai Journal of Sciences, 47(1), 181-194.
Danielsen, S.A., Eide, P.W., Nesbakken, A., Guren, T., Leithe, E., and Lothe, R.A., 2015, Portrait of the PI3K/AKT pathway in colorectal cancer, Biochim Biophys Acta, 1855(1), 104-121. CrossRef
Dolgin, E., 2017, The most popular genes in the human genome, Nature, 551(7681), 427-432. CrossRef
Drecoll, E., Nitsche, U., Bauer, K., Berezowska, S., Slotta-Huspenina, J., Rosenberg, R., and Langer, R., 2014, Expression analysis of heat shock protein 90 (HSP90) and Her2 in colon carcinoma, International Journal of Colorectal Disease, 29(6), 663-671. CrossRef
Edi, E., 2017, Bioinformatika: Komputer, Statistika, Matematika, Biologi, Jurnal TIMES, 6(1), 23–25.
Elshazli, R.M., Toraih, E.A., Elgaml, A., Kandil, E., and Fawzy, M.S., 2020, Genetic polymorphisms of TP53 (rs1042522) and MDM2 (rs2279744) and colorectal cancer risk: An updated meta-analysis based on 59 case-control studies, Gene, 734, 144391. CrossRef
Girisa, S., Shabnam, B., Monisha, J., Fan, L., Halim, C.E., Arfuso, F., et al., 2019, Potential of Zerumbone as an Anti-Cancer Agent, Molecules, 24(4), 734. CrossRef
Hemmings, B.A., and Restuccia, D.F., 2012, PI3K-PKB/Akt pathway, Cold Spring Harbor Perspectives in Biology, 4(9), a011189.
Hermawan, A., Khumaira, A., Ikawati, M., Putri, H., Jenie, R.I., Angraini, S.M., and Muflikhasari, H.A., 2021, Identification of key genes of hesperidin in inhibition of breast cancer stem cells by functional network analysis, Computational Biology and Chemistry, 90, 107427.
Hou, H., Sun, D., and Zhang, X., 2019, The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors, Cancer cell international, 19, 216. CrossRef
Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., and Sarkar, S., 2014, Drug resistance in cancer: an overview, Cancers (Basel), 6(3), 1769-1792. CrossRef
Hua, H., Zhang, H., Chen, J., Wang, J., Liu, J., and Jiang, Y., 2021, Targeting Akt in cancer for precision therapy, Journal of Hematology & Oncology, 14, 128. CrossRef
Kitayama, T., Nakahira. M., Yamasaki. K, Inoue. H., Imada. C., Yonekura. Y., Awata. M., et al., 2013, Novel synthesis of zerumbone-pendant derivatives and their biological activity, Tetrahedron, 69(47), 10152-10160.
Kung, C-P., and Weber, J.D., 2022, It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy, Frontiers in Cell and Developmental Biology, 10, 818744. CrossRef
Martorana, F., Motta, G., Pavone, G., Motta, L., Stella, S., Vitale, S.R., et al., 2021, AKT inhibitors: new weapons in the fight against breast cancer?, Frontiers in Pharmacology, 12, 662232. CrossRef
Menin, C., Scaini, M.C., De Salvo, G.L., Biscuola, M., Quaggio, M., Esposito, G., et al., 2006, Association between MDM2–SNP309 and age at colorectal cancer diagnosis according to p53 mutation status, Journal of the National Cancer Institute, 98(4), 285-288. CrossRef
Moser, C., Lang, S.A., and Stoeltzing, O., 2009, Heat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancer, Anticancer Research, 29(6), 2031-2042.
Mudde, A.C.A., Booth, C., and Marsh, R.A., 2021, Evolution of our understanding of XIAP deficiency, Frontiers in Pediatrics, 9, 660520. CrossRef
El-Hachem, N., Haibe-Kains, B., Khalil, A., Kobeissy, F.H., and Nemer, G., 2017, AutoDock and AutoDockTools for Protein-Ligand Docking: Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1(BACE1) as a Case Study, Methods in Molecular Biology, 1598, 391–403.
National Cancer Institute (NCI), 2019, Akt Inhibitor MK2206 in Treating Patients With Previously Treated Colon or Rectal Cancer That is Metastatic or Locally Advanced and Cannot Be Removed by Surgery. https://beta.clinicaltrials.gov/study/NCT01802320
Nurgali, K., Rudd, J.A., Was, H., and Abalo, R., 2022, Cancer therapy: The challenge of handling a double-edged sword, Frontiers in Pharmacology, 13, 1007762.
Qureshy, Z., Johnson, D.E., and Grandis, J.R., 2020, Targeting the JAK/STAT pathway in solid tumors, Journal of cancer metastasis and treatment, 6, 27.
Rahman, H.S., Rasedee, A., Abdul, A.B., Zeenathul, N.A., Othman, H.H., Yeap, S.K., et al., 2014, Zerumbone-loaded nanostructured lipid carrier induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in a human lymphoblastic leukemia cell line, Int. J. Nanomedicine, 9, 527–538.
Sahlberg, S.H., Mortensen, A.C., Haglöf, J., Engskog, M.K.R., Arvidsson, T., Pettersson, C., et al., 2017, Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells, International Journal of Oncology, 50(1), 5-14.
Shi, Y., Liu, X., Lou, J., Han, X., Zhang, L., Wang, Q., et al., 2014, Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses, Clinical cancer research, 20(23), 6016-6022.
Songsiang, U., Pitchuanchom, S., Boonyarat, C., Hahnvajanawong, C., and Yenjai, C., 2010, Cytotoxicity against cholangiocarcinoma cell lines of zerumbone derivatives, Eur J Med Chem., 45(9), 3794-3802.
Tang, S., Yuan, X., Song, J., Chen, Y., Tan, X., and Li, Q., 2019, Association analyses of the JAK/STAT signaling pathway with the progression and prognosis of colon cancer, Oncology letters, 17(1), 159-164.
The Global Cancer Observatory, 2020. Cancer Incident in Indonesia [WWW Document]. URL https://gco.iarc.fr/today/data/factsheets/populations/360indonesia-fact-sheets.pdf (accessed 22.12.22).
WHO, 2022. Cancer [WWW Document]. URL https://www.who.int/news-room/factsheets/detail/cancer (accessed 22.12.22).
Wilkening, S., Bermejo, J.L., and Hemminki, K., 2007, MDM2 SNP309 and cancer risk: a combined analysis, Carcinogenesis, 28(11), 2262-2267.
Xiang, G., Wen, X., Wang, H., Chen, K., and Liu, H., 2009, Expression of X‐linked inhibitor of apoptosis protein in human colorectal cancer and its correlation with prognosis, Journal of Surgical Oncology, 100(8), 708-712.
Xiong, H., Zhang, Z-G., Tian, X-Q., Sun, D-F., Liang, Q-C., Zhang, Y-J., et al., 2008, Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells, Neoplasia, 10(3), 287-297.
Xu, Q.R., Liu, X., Yao, Y.M., and Liu, Q.G., 2014, Expression of HSP90 and HIF-1α in human colorectal cancer tissue and its significance., Asian pacific journal of tropical medicine, 7(9), 720-724.
DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev14iss1pp39-48
Copyright (c) 2023 Indonesian Journal of Cancer Chemoprevention
Indexed by:
Indonesian Society for Cancer Chemoprevention
