Sains Malaysiana 50(1)(2021): 181-189

http://dx.doi.org/10.17576/jsm-2021-5001-18

The Anticancer Compound Dolichol from Ceriops tagal and Rhizophora mucronata Leaves Regulates Gene Expressions in WiDr Colon Cancer

(Sebatian Anti-kanser Dolikol daripada Daun Ceriops tagal dan Rhizophora mucronatauntuk Mengawal Pengekspresan Gen Sel Kanser Kolon WiDr)

MEIGHINA ATIKA ISTIQOMAH¹, POPPY ANJELISA ZAITUN HASIBUAN¹, ARIF NURYAWAN^2,3, SUMAIYAH SUMAIYAH¹, ETTI SARTINA SIREGAR⁴ & MOHAMMAD BASYUNI^2,3*

¹Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, North Sumatra, Indonesia

²Department of Forestry, Faculty of Forestry, Universitas Sumatera Utara, Medan, North Sumatera, Indonesia

³Center of Excellence for Mangrove, Universitas Sumatera Utara, Medan, North Sumatra, Indonesia

⁴Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sumatera Utara, Medan, North Sumatra, Indonesia

Received: 16 February 2020/Accepted: 22 June 2020

ABSTRACT

Mangrove plants produce polyisoprenoid alcohol. The polyisoprenoid consists of polyprenol and dolichol, which in pharmacological activity act as anticancer agents. The major polyisoprenoid compound of mangrove plants Ceriops tagal and Rhizophora mucronata was reported as dolichol. The present study was conducted to examine the anticancer effects of dolichol from C. tagal and R. mucronata leaves on WiDr cells and cell cycle-related cancer for 24 h and to evaluate the regulation of five genes, p53, EGFR, PI3K, Akt, and mTOR. The inhibited cell cycle was analysed by flow cytometry and the gene expression of p53, EGFR, PI3K, Akt, and mTOR was determined using reverse transcription-polymerase chain reaction (RT-PCR) method. Dolichol from C. tagal was more effective than that from R. mucronata, where it worked on the G0/G1 cycle for 87.94% and 82.36%, respectively, and regulated positive control 5-FU on the G0/G1 cycle (88.12%), S (9.52%) and G2-M (6.42%). The upregulation (p53) and downregulation (EGFR) contributed to the contracting cell cycle of colon cancer cells (WiDr) in PI3K, Akt and mTOR genes. To summarise, the current study suggests significant pharmacological properties of dolichols in C. tagal and R. mucronata leaves, which worked explicitly in the G0/G1 phase.

Keywords: Anticancer; Ceriops tagal; mangrove; polyisoprenoid; Rhizophora mucronata

ABSTRAK

Tumbuhan bakau menghasilkan alkohol poliisoprenoid. Poliisoprenoid terdiri daripada poliprenol dan dolikol yang bertindak sebagai agen anti-kanser dalam aktiviti farmakologi. Dolikol telah didapati sebagai sebatian poliisoprenoid utama dalam tanaman bakau Ceriops tagal dan Rhizophora mucronata. Kajian ini dijalankan untuk mengkaji kesan anti-kanser dolikol daripada daun C. tagal dan R. mucronata pada sel WiDr dan kanser yang berkaitan dengan kitaran sel selama 24 jam untuk menilai pengawalan lima gen, p53, EGFR, PI3K, Akt dan mTOR. Kitaran sel yang direncat telah dianalisis dengan sitometri aliran dan pengekspresan gen p53, EGFR, PI3K, Akt dan mTOR ditentukan menggunakan kaedah tindak balas polimerase berantai transkripsi berbalik (RT-PCR). Dolikol daripada C. tagal lebih berkesan daripada R. mucronata, kerana ia bertindak balas pada kitaran G0/G1, masing-masing dengan 87.94% dan 82.36% keberkesanan serta mengatur kawalan positif 5-FU pada kitaran G0/G1 (88.12%), S (9.52%) dan G2-M (6.42%). Pengawalan-atas (p53) dan pengawalan-bawah (EGFR) menyumbang kepada pengurangan kitaran sel barah kolon (WiDr) pada gen PI3K, Akt dan mTOR. Sebagai kesimpulan, kajian semasa menunjukkan sifat farmakologi dolikol yang signifikan pada daun C. tagal dan R. mucronata, yang berfungsi secara berkesan dalam fasa G0/G1.

Kata kunci: Anti-kanser; bakau; Ceriops tagal; poliisoprenoid; Rhizophora mucronata

REFERENCES

Ajay, A.K., Upadhyay, A.K., Singh, S., Vijayakumar, M.V., Kumari, R., Pandey, V., Boppana, R. & Bhat, M.K. 2010. Cdk5 phosphorylates non-genotoxically overexpressed p53 following inhibition of PP2A to induce cell cycle arrest/apoptosis and inhibits tumor progression. Molecular Cancer 9: 204-218.

Andersen, Q.M. & Markham, K.R. 2006. Flavonoid: Chemistry, biochemistry, and applications. Angewandte Chemie 45(41): 6787-6787.

Arung, E.T., Wicaksono, B.D., Handoko, Y.A., Kusuma, I.Y., Yulia, D. & Sandra, F. 2009. Anticancer properties of diethyl ether extract of wood from sukun (Artocarpus altilis) in human breast cancer (T47D) cells. Tropical Journal of Pharmaceutical Research 8(4): 317-324.

Baeriswyl, V. & Christofori, G. 2009. The angiogenic switch in carcinogenesis. Seminars in Cancer Biology 19(5): 329-337.

Basyuni, M., Sagami, H., Baba, S. & Oku, H. 2017. Distribution, occurrence, and cluster analysis of new polyprenyl acetones and other polyisoprenoids in North Sumatran mangroves. Dendrobiology 78: 18-31.

Doležel, J. 1991. Flow cytometric analysis of nuclear DNA content in higher plants. Phytochemical Analysis 2(4): 143-154.

Dong, M., Yang, G., Liu, H., Liu, X., Lin, S. & Sun, D. 2014. Aged black garlic extract inhibits HT29 colon cancer cell growth via the PI3K/Akt signaling pathway. Biomedical Reports 2(2): 250-254.

Elmore, S. 2007. Apoptosis: A review of programmed cell death. Toxicologic Pathology 35(4): 495-516.

Fosslien, E. 2001. Molecular pathology of cyclooxygenase-2 in cancer induced angiogenesis. Annals of Clinical & Laboratory Science 31(4): 325-348.

Hassan, Z.K., Elamin, M.H., Daghestani, M.H., Omer, S.A., Al-Olayan, E.M., Elobeid, M.A., Virk, P. & Mohammed, O.B. 2012. Oleuropein induces anti-metastatic effects in breast cancer. Asian Pacific Journal of Cancer Prevention 13(9): 4555-4559.

Hogg, R.W. & Gillan, FT. 1984. Fatty acids, sterols and hydrocarbons in the leaves from eleven species of mangrove. Phytochemistry 23(1): 93-97.

Illian, D.N., Hasibuan, P.A.Z., Sumardi, S., Nuryawan, A., Wati, R. & Basyuni, M. 2019. Anticancer activity of polyisoprenoids from Avicennia alba blume in WiDr cells. Iranian Journal of Pharmaceutical Research 18(3): 1477-1487.

Illian, D.N., Basyuni, M., Wati, R. & Hasibuan, P.A.Z. 2018. Polyisoprenoids from Avicennia marina and Avicennia lanata inhibit WiDr cells proliferation. Pharmacognosy Magazine 14(58): 513-518.

Kamal, A., Reddy, K.S., Khan, M.N. & Shetti, R.V. 2010. Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole–pyrrolo [2,1–c][1,4] benzodiazepine conjugates. Bioorganic and Medicinal Chemistry 18(13): 4747-4761.

Kuznecovs, S., Jegina, K. & Kuznecovs, I. 2007. Inhibition of P-glycoprotein by polyprenol in human breast cancer cells. The Breast Journal 16(1): 515-521.

Matsumoto, K., Arao, T., Tanaka, K., Kaneda, H., Kudo, K., Fujita, Y., Tamura, D., Aomatsu, K., Tamura, T., Yamada, Y., Saijo, N. & Nishio, K. 2009. mTOR signal and hypoxia-inducible factor-1α regulate CD133 expression in cancer cells. Cancer Research 69(18): 7160-7164.

Nomani, A., Fouladdel, S., Haririan, I., Rahimnia, R., Ruponen, M. & Gazori, T. 2012. Poly (amidoamine) dendrimer silences the expression of epidermal growth factor receptor and p53 gene in vitro. African Journal of Pharmacy and Pharmacology 6(8): 530-537.

Sari, D.P., Basyuni, M., Hasibuan, P.A.Z., Wati, R. & Sumardi. 2018a. Cytotoxic effect of polyisoprenoids from Rhizophora mucronata and Ceriops tagal leaves against WiDr colon cancer cell lines. Sains Malaysiana 47(9): 1953-1959.

Sari, D.P., Basyuni, M., Hasibuan, P.A., Sumardi, S., Nuryawan, A. & Wati, R. 2018b. Cytotoxic and antiproliferative activity of polyisoprenoids in seventeen mangroves species against WiDr colon cancer cells. Asian Pacific Journal of Cancer Prevention 19(12): 3393-3400.

Singh, B., Sahu, P.M. & Sharma, M.K. 2002. Anti-inflammatory and anti-microbial activities of triterpenoids from Strobilanthes callosus nees. Phytomedicine 9(4): 355-359.

Sobolewski, C., Cerella, C., Dicato, M., Ghibelli, L. & Diederich, M.M. 2010. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. International Journal of Cell Biology 2010: 1-21.

Swiezewska, E. & Danikiewicz, W. 2005. Polyisoprenoids: Structure, biosynthesis, and function. Progress in Lipid Research 44(4): 235-258.

Vogelstein, B. & Kinzler, K.W. 1992. P53 function and dysfunction. Cell 70(4): 523-526.

Wang, D. & Dubois, N.R. 2004. Cyclooxygenase-2 derived prostaglandin E2 regulates the angiogenic switch. Proceedings of the National Academy of Sciences of the United States of America 101(2): 415-416.

Wang, H., Duan, L., Zou, Z., Li, H., Yuan, S., Chen, X., Zhang, Y., Li, X., Sun, H., Zha, H., Zhang, Y. & Zhou, L. 2014. Activation of the PI3K/Akt/mTOR/p70S6K pathway is involved in S100A4-induced viability and migration in colorectal cancer cells. International Journal of Medical Sciences 11(8): 841-849.

Zhang, Y., Dong, B., Guan, X.Y. & Zhao, M. 2011. Expression of MMP-9 and WAVE3 in colorectal cancer and its relationship to clinicopathological features. Journal of Cancer Research and Clinical Oncology 138(12): 2035-2044.

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