Pentagamavunone-0 (PGV-0), a Curcumin Analog, Enhances Cytotoxicity of 5-Fluorouracil and Modulates Cell Cycle in WiDr Colon Cancer Cells
Abstract
The use of 5-fluorouracil (5-FU) in colon cancer as the primary chemotherapy has not been meet satisfactory effectiveness. Therefore, the development of new chemicals as a chemopreventive agent and a combination agent (co-chemotherapeutic agent) for colon cancer is important. Pentagamavunone-0 (2,5-bis-(4'-hydroxy-3'-methoxybenzylidine) cyclopentanone) (PGV-0), one of curcumin analogs, exhibits cytotoxic effect and apoptosis induction in various cancer cell lines, including colon cancer cell, better than curcumin. This study aimed to investigate the cytotoxic potency of PGV-0 in combination with 5-FU and their effects, in single or in combination, on cell cycle toward WiDr colon cancer cell line. The cells were treated with combination concentrations of PGV-0 and 5-FU, and examined by MTT cell viability assay. The value of combination index (CI) as a parameter of cytotoxic combination assay was measured by a combination index method. Cells were stained with propidium iodide and the cell cycle distribution was determined by flowcytometry. CI calculation showed additive effects between PGV-0 and 5-FU. Combination of PGV-0 and 5-FU gave synergism on cell cycle. Single treatment of PGV-0 increased apoptosis, illustrated as subG1-phase accumulation, stronger than single treatment of 5-FU. Meanwhile, combination of PGV-0 and 5-FU demonstrated S-phase arrest. Based on these results, it can be concluded that PGV-0 has the potential to be developed as a co-chemotherapeutic agent for colon cancer but still requires further tracking of its molecular mechanisms.
Keywords: Pentagamavunone-0 (PGV-0), 5-fluorouracil (5-FU), colon cancer,combination, cell cycle
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Aggarwal, B.B., Kumar, A., Aggarwal, M.S. and Shishodia, S., 2005, Curcumin Derived from Turmeric (Curcuma longa): A Spicefor All Seasons, In: Ravindran, P.N., Babu, K.N. and Sivaraman, K., editors., 2005, Turmeric the genus Curcuma, Boca Raton: CRC Press. pp. 349-387.
Arkenau, H.T., Rettig, K. and Porschen, R., 2005, Adjuvant Chemotherapy in Curative Resected Colon Carcinoma: 5-fluorouracil/leucovorin versus High-dose 5-fluorouracil 24-h Infusion, Int. J. Colorectal Dis., 20(3), 258-261. CrossRef
Backus, H.H.J., Pinedo, H.M., Wouters, D., Kuiper, C.M., Jansen, G. and van Groeningen, C.J., 2001, Differences in the Induction of DNA Damage, Cell Cycle Arrest, and Cell Death by 5-dluorouracil and Antifolates, Oncol. Res., 12(5), 231-239. Link
Da’i, M., Margono, S.A., Meiyanto, E. and Jenie, U.A., 2007, Geometric Isomers and Cytotoxic Effect on T47D Cells of Curcumin Analogues PGV-0 and PGV-1, Indones. J. Pharm., 18(1), 40-47. CrossRef
Da’i, M., 2003, Antiproliferative Effects of Pentagamavunon-0 on Raji, HeLa, and Myeloma Cells, Thesis, Universitas Gadjah Mada, Yogyakarta.
De Angelis, P.M., Svendsrud, D.H., Kravik, K.L. and Stokke, T., 2006, Cellular Response to 5-fluorouracil (5-FU) in 5-FU-resistant Colon Cancer Cell Lines During Treatment and Recovery, Mol. Cancer, 5(20), 1-25. CrossRef
Doyle, A. and Griffiths, J.B., 2000, Cell and Tissue Culture for Medical Research, New York: John Willey and Sons.
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. Can., 96(5), 769-775. CrossRef
Hermawan, A., Fitriasari, A., Junedi, S., Ikawati, M., Haryanti, S., Widaryanti, B., et al., 2011, PGV-0 and PGV-1 Increased Apoptosis Induction of Doxorubicin on MCF-7 Breast Cancer Cells, Pharmacon, 12(2), 55-59. Link
Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., Smigal, C., et al., 2006, Cancer Statistics 2006, Cancer J. Clin., 56(2), 106-130. Link
Meiyanto, E., Margono, S.A. and Da’i, M., 2003, Antiproliferative Effect of PGV-0 (A Curcumin Analogue) Against HeLa Cells, Gama Sains, 5(3), 200-206.
Meiyanto, E., Agustina, D., Margono, S.A. and Da’i, M., 2006, PGV-0 Induces Apoptosis on T47D Breast Cancer Cell Line Through Caspace-3 Activation, Yarsi Medical J., 15(2), 75-79. Link
Meiyanto, E., Putri, D.D.P.P., Susidarti, R.A., Murwanti, R., Sardjiman, Fitriasari, A., et al., 2014, Curcumin and Its Analogues (PGV-0 and PGV-1) Enhance Sensitivity of Resistant MCF-7 Cells to Doxorubicin Through Inhibition of HER2 and NF-κB Activation, Asian Pac. J. Cancer Prev., 15(1), 179-184. Link
Meiyanto, E., Septisetyani, E.P., Larasatim Y.A. and Kawaichi, M., 2018, Curcumin Analog Pentagamavunone-1 (PGV-1) Sensitizes WiDr Cells to 5-fluorouracil Through Inhibition of NF-κB Activation, Asian Pac. J. Cancer Prev., 19(1), 49-56. Link
Mosmann, T., 1983, Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays, J. Immunol. Methods, 65(1-2), 55-63. Link
National Molecule Team, 2001a, Research Report: Acute Toxicity, Teratogenicity, and Ulcerogenicity of PGV-0, PGV-1, and HGV-1 in Rats dan Rabbits, Yogyakarta: Universitas Gadjah Mada.
National Molecule Team, 2001b, Research Report: Subhronic Toxicity Assay of PGV-0, PGV-1, and HGV-1 in Rats dan Rabbits, Yogyakarta: Universitas Gadjah Mada.
Nurulita, N.A. and Meiyanto, E., 2006, The Anticancer Effects of Pentagamavunon-0 (PGV-0) to T47D Cell Line Induces by 17-b-estradiol Thorugh Apoptosis Induction and Angiogenesis Suppression Mechanisms, Sains Kesehatan, 19(1), 109-117. Link
Palozza, P., Serini, S., Maggiano, N., Giuseppe, T., Navarra, P., Ranelletti, F.O., et al., 2005, β-carotene Downregulates the Steady-state and Heregulin-α-induced COX-2 Pathways in Colon Cancer Cells, J. Nutr., 135(1), 129-136. Link
Reksohadiprodjo, M.S., Timmerman, H., Sardjiman, Margono, S.A., Martono, S., Hakim, L.R., et al., 2004, Derivatives of Benzylidenecyclohexanone, Benzylidenecyclopentanone, and Benzylidene Acetone, and Therapeutic Uses Thereof, USA: United States Patent.
Reynolds, C.P. and Maurer, B.J., 2005, Evaluating Response to Antineoplastic Drug Combinations in Tissue Culture Models, Methods Mol. Medicine., 110, 173-183. CrossRef
Septisetyani, E.P., Ikawati, M., Widaryanti, B. and Meiyanto, E., 2008, Apoptosis Mediated Cytotoxicity of Curcumin Analogues PGV-0 and PGV-1 in WiDr Cell Line, Proceeding, Yogyakarta: Molecular Targeted Therapy Symposium, ISBN: 978-979-95107-6-1, pp. 48-56.
Shah, M.A. and Schwartz, G.K., 2001, Cell Cycle-mediated Drug Resistance: An Emerging Concept in Cancer Therapy, Clin. Can. Res., 7(8), 2168-2181. Link
Sharma R.A., Euden S.A., Platton S.L., Cooke D.N., Shafayat A. and Hewitt H.R., 2004, Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and Compliance, Clin. Can. Res., 10(20), 6847-6854. CrossRef
Sigmond J., Backus H.H., Wouters D., Temmink O.H., Jansen, G. and Peters, G.J., 2003, Induction of Resistance to the Multi Targeted Antifolate Pemetrexed (ALIMTA) in WiDr Human Colon Cancer Cells is Associated with Thymidylate Synthase Overexpression, Biochem. Pharmacol., 66(3), 431-438. Link
Suwaldi and Oetari., 2004, Research Report: An Attempt to Increase PGV-0 Absorption in vitro by An Inverted Intestine Method, Yogyakarta: Universitas Gadjah Mada.
DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev9iss1pp23-31
Copyright (c) 2018 Muthi Ikawati, Endah Puji Septisetyani
Indexed by:
Indonesian Society for Cancer Chemoprevention
