Sains Malaysiana 47(9)(2018): 1953–1959

http://dx.doi.org/10.17576/jsm-2018-4709-02

Cytotoxic Effect of Polyisoprenoids from Rhizophora mucronata and Ceriops tagal Leaves against WiDr Colon Cancer Cell Lines

(Kesan Sitotoksik Poliisoprenoid daripada Daun Rhizophora mucronata dan Ceriops tagal terhadap Titisan Sel Kanser Kolon WiDr)

DINI PERMATA SARI¹, MOHAMMAD BASYUNI^2*, POPPY ANJELISA ZAITUN HASIBUAN¹, RIDHA WATI² & SUMARDI³

¹Faculty of Pharmacy, Universitas Sumatera Utara Jl. Tri Dharma No. 5, Pintu 4 USU Campus, Medan 20155, Indonesia

²Department of Forestry, Faculty of Forestry, Universitas Sumatera Utara, Jl. Tri Dharma Ujung No. 1, Medan, North Sumatra, 20155, Indonesia

³Faculty of Pharmacy, Universitas Tjut Nyak Dhien, Jl. Rasmi No. 28, Medan, 20123

Indonesia

Received: 15 December 2017/Accepted: 16 May 2018

ABSTRACT

The mangrove plant is known to produce secondary metabolite compounds, mainly isoprenoids. Polyisoprenoids (dolichol and polyprenol) are known to have antimicrobial, anticancer and antiviral activity. Therefore, this study aimed to determine the cytotoxic effects of polyisoprenoids from Rhizophora mucronata and Ceriops tagal leaves by evaluating the induction of apoptosis and cell cycle arrest and the inhibition of the expression of Bcl-2 and cyclin D1 in WiDr colon cancer cells. Cell death was determined based on IC₅₀ values in MTT assays. The induction of apoptosis and alterations in the cell cycle were observed by flow cytometry. The expression of Bcl-2 and cyclin D1 proteins, which play a role in apoptosis and cell cycle regulation, was observed by immunocytochemistry. The results showed that polyisoprenoids from R. mucronata and C. tagal leaves exhibited toxicity against the WiDr cell line, with IC₅₀ values of 278 ± 5.77 and 276 ± 9.54 μg/mL, respectively. Polyisoprenoids from R. mucronata and C. tagal leaves significantly induced apoptosis and caused cell cycle arrest in G0/G1 phase, while also decreasing the expression of Bcl-2 and cyclin D1. Our results confirmed that polyisoprenoids from R. mucronata and C. tagal leaves have the potential to be developed as anticancer agents for colon cancer.

Keywords: Apoptosis; Ceriops tagal; cytotoxic; dolichol; Rhizophora mucronata

ABSTRAK

Tumbuhan bakau diketahui menghasilkan sebatian metabolit sekunder, terutamanya isoprenoid. Poliisoprenoid (dolichol dan poliprenol) diketahui mempunyai aktiviti antimikrob, antikanser dan antivirus. Oleh itu, kajian ini bertujuan untuk menentukan kesan sitotoksik poliisoprenoid daripada daun Rhizophora mucronata dan Ceriops tagal dengan menilai induksi apoptosis tangkapan kitaran sel serta kesan ekpresi Bcl-2 dan siklin D1 dalam titisan sel kanser kolon WiDr. Kematian sel ditentukan berdasarkan nilai IC₅₀ dalam asai MTT. Induksi apoptosis dan perubahan dalam kitaran sel diperhatikan dengan aliran sitometri. Ekpresi Bcl-2 dan protein siklin D1 yang memainkan peranan dalam apoptosis dan kawal-selia kitaran sel diperhatikan melalui imunositokimia. Keputusan menunjukkan bahawa poliisoprenoid daripada daun R. mucronata dan C. tagal mengeluarkan ketoksikan terhadap titisan sel WiDr, masing-masing dengan nilai IC₅₀ 278 ± 5.77 dan 276 ± 9.54 μg/mL. Poliisoprenoid daripada daun R. mucronata dan C. tagal dengan ketara mengaruh apoptosis dan menyebabkan tangkapan kitaran sel dalam fasa G0/G1, selain menurunkan ekspresi Bcl-2 dan siklin D1. Keputusan kami mengesahkan bahawa poliisoprenoid daripada daun R. mucronata dan C. tagal mempunyai potensi untuk dibangunkan sebagai agen anti-kanser untuk kanser kolon.

Kata kunci: Apoptosis; Ceriops tagal; dolichol; Rhizophora mucronata; sitotoksik

REFERENCES

Arifiyanto, D., Basyuni, M., Sumardi, Putri, L.A.P., Siregar, E.S., Risnasari, I. & Syahputra, I. 2017. Occurrence and cluster analysis of palm oil (Elaeis guineensis) fruit type using two-dimensional thin layer chromatography. Biodiversitas 18: 1487-1492.

Bandaranayake, W.M. 1998. Traditional and medicinal uses of mangroves. Mangroves and Salt Marshes 2: 133-148.

Basyuni, M., Wati, R., Sagami, H., Sumardi, Baba, S. & Oku, H. 2018. Diversity and abundance of polyisoprenoid composition in coastal plant species from North Sumatra, Indonesia. Biodiversitas 19: 1-11.

Basyuni, M., Sagami, H., Baba, S. & Oku, H. 2017. Distribution and occurrence of new polyprenyl acetone and other polyisoprenoids in Indonesian mangroves. Dendrobiology 78: 18-31.

Basyuni, M., Sagami, H., Baba, S., Iwasaki, H. & Oku, H. 2016. Diversity of polyisoprenoids in ten Okinawan Mangroves. Dendrobiology 75: 167-175.

Bishayee, A., Ahmed, S., Brankov, N. & Perloff, M. 2011. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Frontiers in Bioscience: A Journal and Virtual Library 16: 980-986.

Corley, D.A., Jensen, C.D., Marks, A.R., Zhao, W.K., Lee, J.K., Doubeni, C.A., Zauber, A.G., Boer, J.D., Fireman, B.H., Schottinger, J.E., Quinn, V.P., Ghai, N.R., Levin, T.R. & Quesenberry, C.P. 2014. Adenoma detection rate and risk of colorectal cancer and death. New England Journal of Medicine 370: 1298-1306.

Dhas, S.P., Mukherjee, A.M.I.T.A.V.A. & Chandrasekaran, N. 2013. Photosynthesis of silver nanoparticles using Ceriops tagal and its antimicrobial potential against human pathogens. International Journal of Pharmacy and Pharmaceutical Sciences 5: 349-352.

Elson, C.E., Peffley, D.M., Hentosh, P. & Mo, H. 1999. Isoprenoid-mediated inhibition of mevalonate synthesis: Potential application to cancer. Proceedings of the Society for Experimental Biology and Medicine 221: 294-311.

Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.W., Forman, D. & Bray, F. 2015. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 136: 359-386.

Harvey, A.L., Edrada-Ebel, R. & Quinn, R.J. 2015. The re-emergence of natural products for drug discovery in the genomics era. Nature Reviews Drug Discovery 14: 111-129.

He, L., Wang, Y.S. & Wang, Q.J. 2007. In vitro antitumor activity of triterpenes from Ceriops tagal. Natural Product Research 21: 1228-1233.

Holstein, S.A. & Hohl, R.J. 2004. Isoprenoids: Remarkable diversity of form and function. Lipids 39: 293-309.

Howlader, M., Islam, S., Ahmed, M., Kabir, A.N.M., Uddin, M. & Hossain, M. 2013. Antibacterial, cytotoxic, analgesic and diuretic activities of Rhizophora mucronata Lam. bark. Indian Journal of Natural Products and Resources 4: 229-232.

Iwamoto, T. 2013. Clinical application of drug delivery systems in cancer chemotherapy: Review of the efficacy and side effects of approved drugs. Biological and Pharmaceutical Bulletin 36: 715-718.

Jakobisiak, M. & Golab, J. 2003. Potential antitumor effects of statins. International Journal of Oncology 23: 1055-1069.

Jiang, P., Mukthavaram, R., Chao, Y., Nomura, N., Bharati, I.S., Fogal, V., Pastorino, S., Teng, D., Cong, X., Pingle, S.C., Kapoor, S., Shetty, K., Aggrawal, A., Vali, S., Abbasi, T., Chien, S. & Kesari, S. 2014. In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells. British Journal of Cancer 111: 1562-1571.

Kuznecovs, S., Jegina, K. & Kuznecovs, I. 2007. Inhibition of P-glycoprotein by polyprenol in human breast cancer cells. The Breast 16: 515-521.

Larsson, O. 1994. Effects of isoprenoids on growth of normal human mammary epithelial cells and breast cancer cells in vitro. Anticancer Research 14: 123-128.

Laszczyk, M.N. 2009. Pentacyclic. Triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Medica 75: 1549-1560.

Leonard, R.C.F., Williams, S., Tulpule, A., Levine, A.M. & Oliveros, S. 2009. Improving the therapeutic index of anthracycline chemotherapy: Focus on liposomal doxorubicin (Myocet™). The Breast 18: 218-224.

Liby, K.T., Yore, M.M. & Sporn, M.B. 2007. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nature Reviews Cancer 7: 357-369.

Petronelli, A., Pannitteri, G. & Testa, U. 2009. Triterpenoids as new promising anticancer drugs. Anti-Cancer Drugs 20: 880-892.

Mo, H. & Elson, C.E. 2004. Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention. Experimental Biology and Medicine 229: 567-585.

Nebula, M., Harisankar, H.S. & Chandramohanakumar, N. 2013. Metabolites and bioactivities of Rhizophoraceae mangroves. Natural Products and Bioprospecting 3: 207-232.

Otto, T. & Sicinski, P. 2017. Cell cycle proteins as promising targets in cancer therapy. Nature Reviews Cancer 17: 93-115.

Premanathan, M., Nakashima, H., Kathiresan, K., Rajendran, N. & Yamamoto, N. 1996. In vitro anti human immunodeficiency virus activity of mangrove plants. Indian Journal of Medical Research 103: 278-281.

Qui, P., Guan, H., Dong, P., Li, S., Ho, C.T., Pan, M.S., McClements, D.J. & Xiao, H. 2011. The p53-, Bax- and p21-dependent inhibition of colon cancer cell growth by 5-hydroxy polymethoxyflavones. Molecular Nutrition Food Research 55: 613-22.

Reddy, L., Odhav, B. & Bhoola, K.D. 2003. Natural products for cancer prevention: A global perspective. Pharmacology & Therapeutics 99: 1-13.

Safatov, A.S., Boldyrev, A.N., Bulychev, L.E., Buryak, G.A, Kukina, T.P., Poryvaev, V.D., P’Yankov, O.V., Raldugin, V.A., Ryzhikov, A.B., Sergeev, A.N., Shishkina, L.N., Tolstikov, G.A. & Zhukov, V.A. 2005. A prototype prophylactic anti-influenza preparation in aerosol form on the basis of Abiessibirica polyprenols. Journal of Aerosol Medicine 18: 55-62.

Sakagami, H., Jiang, Y., Kusama, K., Atsumi, T., Ueha, T., Toguchi, M., Iwakura, I., Satoh, K., Fukai, T. & Nomura, T. 2000. Induction of apoptosis by flavones, flavonols (3-hydroxyflavones) and isoprenoid-substituted flavonoids in human oral tumor cell lines. Anticancer Research 20: 271-277.

Setzer, W.N. & Setzer, M.C. 2003. Plant-derived triterpenoids as potential antineoplastic agents. Mini-Reviews in Medicinal Chemistry 3: 540-556.

Siegel, R.L., Miller, K.D., Fedewa, S.A., Ahnen, D.J., Meester, R.G., Barzi, A. & Jemal, A. 2017. Colorectal cancer statistics. 2017. CA: Cancer Journal for Clinicians 67: 177-193.

Singh, G., Gupta, P., Rawat, P., Puri, A., Bhatia, G. & Maurya, R. 2007. Antidyslipidemic activity of polyprenol from Cocciniagrandis in high-fat diet fed hamster model. Phytomedicine 14: 792-798.

Sudheer, N.S., Philip, R. & Singh, I.B. 2011. In vivo screening of mangrove plants for anti WSSV activity in Penaeus monodon, and evaluation of Ceriops tagal as a potential source of antiviral molecules. Aquaculture 311: 36-41.

Tiwari, P., Tamrakar, A.K., Ahmad, R., Srivastava, M.N., Kumar, R., Lakshmi, V. & Srivastava, A.K. 2008. Antihyperglycaemic activity of Ceriops tagal in normoglycaemic and streptozotocin-induced diabetic rats. Medicinal Chemistry Research 17: 74-84.

Ulukaya, E., Ozdikicioglu, F., Oral, A.Y. & Demirci, M. 2008. The MTT assay yields a relatively lower result of growth inhibition than the ATP assay depending on the chemotherapeutic drugs tested. Toxicology in Vitro 22: 232-239.

Vermuelen, K., Van Bockstaele, D.R. & Berneman, Z.N. 2003. The cell cycle: A review of regulation, deregulation and therapeutic targets in cancer. Cell Proliferation 36: 131-149.

Wiemer, A.J., Hohl, R.J. & Wiemer, D.F. 2009. The intermediate enzymes of isoprenoid metabolism as anticancer targets. Anticancer Agents in Medisinal Chemistry 9: 525-542.

Zhang, C.X., Yan, S.J., Zhang, G.W., Lu, W.G., Su, J.Y. & Zeng, L.M. 2005. Cytototxic diterpenoid from soft coral Sinularia microclavata. Journal of Natural Products 68: 1087-1089.

*Corresponding author; email: m.basyuni@usu.ac.id