Combination of Tangeretin and 5-Fluorouracil Modulates Cell Cycle and Induce Apoptosis on WiDr Cells

Luthfia Indriyani, Adam Hermawan, Riris Istighfari Jenie

Abstract


Co-chemotherapeutics approaches are increasing in cancer treatment in order mainly to suppress the resistence phenomenon of cancer treatment and to enhance the cytotoxic effect of the main chemotherapeutics agent. Tangeretin has been known to have cytotoxic effect to some cancer cells through some pathways in the cells. To explore the potential effect of tangeretin as co-chemotherapeutics agent this research was subjected to study the cytotoxic effect of tangeretin in combination with 5-Fluoro Uracil (5-FU) on WiDr colon cancer cells covering the modulation of cell cycle and apoptosis induction. Cytotoxic effect was examined by using MTT assay while apoptotis induction was determined by annexin-V flowcytometry. Under MTT assay, tangeretin showed weak cytotoxic activity on the cells. However, tangeretin significantly enhanced the cytotoxic effect of 5-FU on the cells. This co-chemotherapeutics effect likely correlated with cell cycle modulation effect, especially in inducing polyploidy phenomenon as expressed in the flowcytometric graph of the DNA content. This combination also increased apoptosis induction. These result suggest that tangeretin is potential to be developed as co-chemotherapeutic agent for 5-Fu on colon cancer and further molecular mechanism need to be explored.

Keywords: Tangeretin, 5-Fluorourasil, WiDr, cell cycle, apoptosis.


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References


Arafa, el-S.A., Zhu, Q., Barakat, B.M., Wani, G., Zhao, Q., El-Mahdy, M.A., et al., 2009, Tangeretin Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells Through Downregulation of Phosphoinositide 3-Kinase/Akt Signaling Pathway, Cancer Res., 69(23), 8910-8917. CrossRef

Bénistant, C., Chapuis, H. and Roche, S., 2000, A Specific Function for Phosphatidylinositol 3-Kinase Alpha (p85alpha-p110alpha) in Cell Survival and for Phosphatidylinositol 3-Kinase Beta (p85alpha-p110beta) in De Novo DNA Synthesis of Human Colon Carcinoma Cells, Oncogene., 19(44), 5083-5090. CrossRef

Choi, S.Y., Ko, H.C., Ko, S.Y., Hwang, J.H., Park, J.G., Kang, S.H., et al., 2007, Correlation Between Flavonoid Content and the NO Production Inhibitory Activity of Peel Extracts from Various Citrus Fruits, Biol. Pharm. Bull., 30(4), 772-778. Link

Giovannetti, E., Backus, H.H.J., Wouters, D., Ferreira, C.G., van Houten, V.M.M., Brakenhoff, R.H., et al., 2007, Changes in The Status of p53 Affect Drug Sensitivity to Thymidylate Synthase (TS) Inhibitors by Altering TS Levels, Br. J. Cancer., 96(5), 769-775. CrossRef

Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J. and Thun, M.J., 2009, Cancer Statistics 2009, CA. Cancer J. Clin., 59(4), 225-249. 10.3322/caac.20006">CrossRef

Liu, H.C., Chen, G.G., Vlantis, A.C., Leung, B.C.S., Tong, M.C.E. and van Hasselt, C.A., 2006, 5-Fluorouracil Mediates Apoptosis and G1/S Arrest in Laryngeal Squamous Cell Carcinoma via a p53-Independent Pathway, Cancer J., 12(6), 482-493. Link

Manthey, J.A. and Guthrie, N., 2002, Antiproliferative Activities of Citrus Flavonoids Against Six Human Cancer Cell Lines, J. Agric. Food Chem., 50(21), 5837-5843. Link

Meyerhardt, J.A. and Mayer, R.J., 2005, Systemic Therapy for Colorectal Cancer, N. Engl. J. Med., 352(5), 476-487. CrossRef

Nogata, Y., Sakamoto, K., Shiratsuchi, H., Ishii, T., Yano, M. and Ohta, H., 2006, Flavonoid Composition of Tissues of Citrus Species, Biosci. Biotechnol. Biochem., 70(1), CrossRef

Noguchi, P., Wallace, R., Johnson, J., Early, E.M., O’Brien, S., Ferrone, S., et al., 1979, Characterization of the WiDr: a Human Colon Carcinoma Cell Line, In Vitro., 15(6), 401-408. Link

Pan, M.H., Chen, W.J., Shiau, S.Y.L., Ho, C.T. and Lin, J.K., 2002, Tangeretin Induces Cell-cycle G1 Arrest Through Inhibiting Cyclin-dependent Kinases 2 and 4 Activities As Well As Elevating Cdk Inhibitors p21 and p27 in Human Colorectal Carcinoma Cells, Carcinogenesis, 23(10), 1677-1684. CrossRef

Yáñez, J., Vicente, V., Alcaraz, M., Castillo, J., Benavente-García, O., Canteras, M., et al., 2004, Cytotoxicity and Antiproliferative Activities of Several Phenolic Compounds Against Three Melanocytes Cell Lines: Relationship Between Structure and Activity, Nutr. Cancer, 49(2), 191–199. CrossRef

Yoshikawa, R., Kusunoki M., Yanagi H., Noda M., Furuyama JI., Yamamura T., et al., 2001, Dual Antitumor Effects of 5-fluorouracil on The Cell Cycle in Colorectal Carcinoma Cells: A Novel Target Mechanism Concept for Pharmacokinetic Modulating Chemotherapy, Cancer Res., 61(3), 1029-1037. Link

Zhang, Z.G., Harstrick, A. and Rustum, Y.M., 1992, Modulation of Fluoropyrimidines: Role of Dose and Schedule of Leucovorin Administration., Semin. Oncol., 19(3), 10-15. Link




DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev3iss1pp364-369

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