Molecular Therapeutic Potency of Metformin by Targeting p53-Related Molecules in Mutant p53 Colon Cancer Cell Line

Dyah R. Budiani, Melani R. Mahanani, Yohanes C. Wibowo, Ari Probandari, Diding H. Prasetyo, Ambar Mudigdo


Colon cancer is a malignancy in gastrointestinal tract. It causes high mortality rate in global cancer population. However, chemotherapy as its first option therapy is still controversial due to its effectiveness and its adverse effects. Finding supportive and alternative drugs to cure cancer is one of focus in cancer research. A drug which also has anticancer effects is metformin. Metformin is a biguanide antidiabetic which show its potential anticancer benefit in metabolic-related cancers including colon cancer. To investigate anticancer potency of metformin in targeting p53-related molecules. Metformin treatment were divided into 4 groups by 0, 5, 10 and 20 mM concentrations and incubated in 37o C and 5 % CO2 condition for 48 hours. Immunohistochemistry were conducted to asses level of expression of Bax, p21, cyclin D1 and E2F1, respectively. Level of expression were measured by H-SCORE using percentage and intensity calculation. Comparisons of H-SCORE between groups were performed by ANOVA for parametrical data and Kruskal-Wallis for non-parametrical data. Growth inhibition were observed after metformin treatment. Metformin increases Bax expression significantly at all concentrations. p21 expression was also increased after metformin treatment but is not statistically significant. Subsequently, metformin decreases cyclin D1 expression at 10 and 20 mM concentration thus decreased E2F1 expression at 5 and 10 mM concentration. These data suggest that metformin may have potential therapeutic effects in mutant p53 colon cancer cell line by targeting p53-related molecules.

Keywords: Colon cancer; p53; Biguanide; Metformin; p53-mutant cell line

Full Text:



Alimova, I.N., Liu, B., Fan, Z., Edgerton, S.M., Dillon, T., Lind, S.E., et al., 2009, Metformin inhibits breast cancer cell growth, Colony Formation and Induces Cell Cycle Arrest in vitro, Cell Cycle, 8(6),909-915. CrossRef

Buzzai, M., Jones, R.G., Amaravadi, R.K., Lum, J.J., DeBerardinis, R.J., Zhao, F., et al., 2007, Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007; 67(14):6745-6752. CrossRef

Fradley, M.G., Barrett, C.D., Clark, J.R. and Francis, S.A., 2013, Ventricular Fibrillation Cardiac Arrest Due to 5-fluorouracil Cardiotoxicity, Tex. Heart Inst. J., 40(4),472-476. Link

Hosono, K., Endo, H., Takahashi, H., Sugiyama, M., Sakai, E., Uchiyama, T., et al., Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial, Cancer Prev. Res., 3(9),1077-1083.

Hardie, D.G., 2013, The LKB1-AMPK Pathway-friend or Foe in Cancer?, Cancer Cell, 23(2), 131-132. 10.1016/j.ccr.2013.01.009">CrossRef

Harper, J.W., Elledge, S.J., Keyomarsi, K., Dynlacht, B., Tsai, L.H., Zhang, P., et al., 1995, Inhibition of Cyclin-Dependent Kinases by p21, Mol. Biol. Cell, 6(4), 387-400. Link

Harris, S.L. and Levine, A.J., 2005, The p53 Pathway: Positive and Negative Feedback Loops, Oncogene, 24(17), 2899-2908. CrossRef

Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E. and Forman, D., 2001, Global Cancer Statistics, CA Cancer J. Clin., 61(2), 69-90. CrossRef

Labianca, R., Nordlinger, B., Beretta, G.D., Brouquet, A., Cervantes, A. and On behalf of the ESMO Guidelines Working Group, 2010, Primary Colon Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Adjuvant Treatment and Follow-up, Ann. Oncol., 215, v70-v77. CrossRef

Iacopetta, B., 2003, TP53 Mutation in Colorectal Cancer, Hum. Mutat., 21(3),271-276.

Landman, G.W., Kleefstra, N., van Hateren, K.J., Groenier, K.H., Gans, R.O. and Bilo, H.J., 2010, Metformin Associated with Lower Cancer Mortality in Type 2 Diabetes: ZODIAC-16, Diabetes Care, 33(2), 322-326. CrossRef

Lee, M.H. and Yang, H.Y., 2003, Regulators of G1 Cyclin-Dependent Kinases and Cancers, Cancer Metastasis Rev., 22(4),435-449. Link

O’Connor, E.S., Greenblatt, D.Y., LoConte, N.K., Gangnon, R.E., Liou, J.I., Heise, C.P., et al., 2011, Adjuvant Chemotherapy for Stage II Colon Cancer with Poor Prognostic Features, J. Clin. Oncol., 29(25), 3381-3388. CrossRef

Queiroz, E.A., Puukila, S., Eichler, R., Sampaio, S.C., Forsyth, H.L., Lees, S.J., et al., 2014, Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress, AMPK and FOXO3a in MCF-7 Breast Cancer Cells, PLoS One, 9(5), e98207. CrossRef

Shackelford, D.B. and Shaw, R.J., 2009, The LKB1-AMPK Pathway: Metabolism and Growth Control in Tumour Suppression, Nat. Rev. Cancer, 9(8), 563-567. CrossRef

Stanelle, J., Stiewe, T., Theseling, C.C., Peter, M. and Pützer, B.M., 2002, Gene Expression Changes in Response to E2F1 Activation, Nucleic Acids Res., 30(8), 1859-1867. Link

Suzuki, H., Kurita, M., Mizumoto, K., Nishimoto, I., Ogata, E. and Matsuoka, M., 2003, p19ARF-induced p53-Independent Apoptosis Largely Occurs Through BAX, Biochem. Biophys. Res. Commun., 312(4), 1273-1277. Link

Takahashi, A., Kimura, F., Yamanaka, A., Takebayashi, A., Kita, N., Takahashi, K., et al., 2014, Metformin Impairs Growth of Endometrial Cancer Cells Via Cell Cycle Arrest and Concomitant Autophagy and Apoptosis, Cancer Cell Int., 14, 53. CrossRef

Zakikhani, M., Dowling, R.J., Sonenberg, N. and Pollak, M.N., 2008, The Effects of Adiponectin and Metformin On Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase, Cancer Prev. Res., 1(5), 369-375. 1CrossRef

Zhang, Z.J., Zheng, Z.J., Kan, H., Song, Y., Cui, W., Zhao, G., et al., 2011, Reduced Risk of Colorectal Cancer with Metformin Therapy in Patients With Type 2 Diabetes: a Meta-Analysis, Diabetes Care, 34(10), 2323-2328. CrossRef

Zhuang, Y. and Miskimins, W.K., 2008, Cell Cycle Arrest in Metformin Treated Breast Cancer Cells Involves Activation of AMPK, Downregulation of Cyclin D1, and Requires p27Kip1 or p21Cip1, J. Mol. Signal, 3, 18. CrossRef


Copyright (c) 2017 Indonesian Journal of Cancer Chemoprevention

Indexed by:




Indonesian Society for Cancer Chemoprevention