Document Type : Original Article


1 Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 2. Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Rayan Pars Pharmacutical Industry, shiraz, Iran



Thyroid cancer is a malignant disease with poor prognosis. The PI3K/Akt/mTOR and Cyclin-Dependent Kinase 4 (CDK4) pathways are vital regulators of tumor cell proliferation and survival. Therefore the present study was designed to use dual inhibition of such pathways to kill thyroid cancer cells.
Methods and materials
The effects of each inhibitors on human ATC and BCPAP cell lines were evaluated by MTT assay. The suitable concentrations of inhibitors were determined and synergistic effects of such inhibitors were evaluated by bax/bcl-2 mRNA ratio, Caspase-3, and Caspase-9 activity assay as well as Akt, mTOR, and CDK4.
Our finding showed that both ATC and BCPAP cell proliferation is significantly inhibited by PD-332991(PD) and NVP-BEZ235 (NVP) in a time and concentration-dependent manner (P


Ahmed, H. (2005). Principles and reactions of protein extraction, purification, and characterization: CRC press New York.
Ansari, A, Gheysarzadeh, A, Mofid, MR. (2017).The interaction of insulin-like growth factor binding protein 3 (IGFBP-3) in insulin-like growth factor (IGF)-independent system.J. Isfahan Med. School, 35(451):1452-1461.
Ashton, JC. (2015). Drug Combination Studies and Their Synergy Quantification Using the Chou–Talalay Method.Cancer Res., 75(11):400-446.
Brown, RL, de Souza, JA, Cohen, EE. (2011). Thyroid cancer: burden of illness and management of disease. J. Cancer, 2:193-199.
Brown, KK, Toker, A. (2015). The phosphoinositide 3-kinase pathway and therapy resistance in cancer.F1000prime Rep., 7:13-21.
del Alcazar, CRG, Hardebeck, MC, Mukherjee, B, Tomimatsu, N, Gao, X, Yan, J, Xie, XJ, Bachoo, R, Li, L, Habib, AA, Burma, S. (2014). Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin. Cancer Res., 20(5):1235-1248.
Elkabets, M, Vora, S, Juric, D, Morse, N, Mino-Kenudson, M, Muranen, T, Tao, J, Campos, AB, Rodon, J, Ibrahim, YH, Serra, V, Rodrik-Outmezguine, V, Hazra, S, Singh, S, Kim, P, Quadt, C, Liu, M, Huang, A, Rosen, N, Engelman, JA, Scaltriti, M, Baselga, J. (2013). mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci. Translat. Med., 5(196):1-28.
Gheysarzadeh, A, Yazdanparast, R. (2012).Inhibition of H2O2-induced cell death through FOXO1 modulation by EUK-172 in SK-N-MC cells.Eur. J. Pharmacol., 697(1):47-52.
Gheysarzadeh, A, Ansari, A, Emami, MH, Razavi, AE, Mofid, MR. (2019). Over-expression of low-density lipoprotein receptor-related Protein-1 is associated with poor prognosis and invasion in pancreatic ductal adenocarcinoma. Pancreatology, 19:429-435.
Gheysarzadeh, A, Bakhtiari, H, Ansari, A, EmamiRazavi, A, Emami, MH, Mofid, MR. (2019).The insulin‐like growth factor binding protein‐3 and its death receptor in pancreatic ductal adenocarcinoma poor prognosis. J. Cell. Physiol., 234:23537-23546.
Gheysarzadeh, A, Sadeghifard, N, Afraidooni, L, Pooyan, F, Mofid, MR, Valadbeigi, H, Bakhtiari, H, Keikhavani, S. (2018). Serum-based microRNA biomarkers for major depression: MiR-16, miR-135a, and miR-1202. J. Res. Med. Sci., 23:69-81.
Hamzeloo-Moghadam, M, Aghaei, M, Fallahian, F, Jafari, SM, Dolati, M, Abdolmohammadi, MH, Hajiahmadi, S, Esmaeili, S. (2015). Britannin, a sesquiterpene lactone, inhibits proliferation and induces apoptosis through the mitochondrial signaling pathway in human breast cancer cells. Tumor Biology., 36(2):1191-1198.
Hedinger, C, Dillwyn Williams, E, Sobin, LH. (1989). The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer, 63(5):908-911.
Hou, P, Liu, D, Shan, Y, Hu, S, Studeman, K, Condouris, S, Wang, Y, Trink, A, El-Naggar, AK, Tallini, G, Vasko, V, Xing, M. (2007).Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer.Clin. Cancer Res., 13(4):1161-1170.
Jafari, E, Gheysarzadeh, A, Mahnam, K, Shahmohammadi, R, Ansari, A, Bakhtyari, H, Mofid, MR. (2018). In silico interaction of insulin-like growth factor binding protein 3 with insulin-like growth factor 1. Res. Pharm. Sci., 13(4):332-342.
Lee, HJ, Lee, WK, Kang, CW, Ku, CR, Cho, YH, Lee, EJ. (2018). A selective cyclin-dependent kinase 4, 6 dual inhibitor, Ribociclib (LEE011) inhibits cell proliferation and induces apoptosis in aggressive thyroid cancer. Cancer Lett., 417:131-140.
Lopes-Ventura, S, Pojo, M, Matias, A, Moura,M, Marques, I, Leite, V, Cavaco, BM. (2018). The efficacy of HRAS and CDK4/6 inhibitors in anaplastic thyroid cancer cell lines.J. Endocrinol. Investigat.,42(5):527-540.
Maleki, F, Noorkhoda, S, Halabian, R, Behzadi, E, Fooladi, AAI. (2018). The Role of Epidermal Growth Factor Receptor in Cancer and their Application for New Targeted Cancer Therapy. J. Clin. Diag. Res., 12(6):XE01-XE06.
Maleki, F, Sadeghifard, N, Hosseini, HM, Bakhtiyari, S, Goleij, Z, Behzadi, E, Sedighian, H, Imani Fooladi, AA. (2019). Growth-inhibitory effects of TGFαL3-SEB chimeric protein on colon cancer cell line.Biomed.Pharmac.,110:190-196.
Markman, B, Tabernero, J, Krop, I, Shapiro, G, Siu, L, Chen, LC, Mita, M, Melendez Cuero, M, Stutvoet, S, Birle, D, Anak, O, Hackl, W, Baselga, J. (2012). Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann. oncol., 23(9):2399-2408.
Mazzaferri, EL, Kloos, RT. (2001). Current approaches to primary therapy for papillary and follicular thyroid cancer. J. Clin. Endocrinol.Metabolism., 86(4):1447-1463.
Nix, P, Nicolaides, A, Coatesworth, A. (2005). Thyroid cancer review 1: presentation and investigation of thyroid cancer. Int. J. Clin. Pract., 59(11):1340-1344.
Nozhat, Z, Mohammadi-Yeganeh, S, Azizi, F, Zarkesh, M, Hedayati, M. (2018). Effects of metformin on the PI3K/AKT/FOXO1 pathway in anaplastic thyroid Cancer cell lines. DARU J. Pharmac. Sci., 26(2):93-103.
Peyton, J, RodonAhnert, J, Burris, H, Britten, C, Chen, L, Tabernero, J, Duval, V, Rouyrre, N, Silva, AP, Quadt, C, Baselga, J. (2011).A dose-escalation study with the novel formulation of the oral pan-class I PI3K inhibitor BEZ235, solid dispersion system (SDS) sachet, in patients with advanced solid tumors. J.Clin. Oncol., 29(15_suppl):3066-3066.
Pojo, M, Lopes-Ventura, S, Matias, A, Leite, V, Cavaco, B. (2017). Inhibition of hRAS and CDK4/6 leads to an antiproliferative activity, blocks cell cycle and induces cell death in anaplastic thyroid cancer cell lines. 49, GP126, DOI: 10.1530/endoabs.49.GP126
Pópulo, H, Lopes, JM, Soares, P. (2012). The mTORsignalling pathway in human cancer.Int. J. Molecul. Sci., 13(2):1886-918.
Rahib, L, Smith, BD, Aizenberg, R, Rosenzweig, AB, Fleshman, JM, Matrisian, LM. (2014). Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res., 74(11):2913-2921.
Tagliaferri, L, Gobitti, C, Colloca, GF, Boldrini, L, Farina, E, Furlan, C, Paiar, F, Vianello, F, Basso, M, Cerizza, L, Monari, F, Simontacchi, G, Gambacorta, MA, Lenkowicz, J, Dinapoli, N, Lanzotti, V, Mazzarotto, R, Russi, E, Mangoni, M. (2018). A new standardized data collection system for interdisciplinary thyroid cancer management: Thyroid COBRA. Eur. J. Int. Med., 53:73-78.
Vasko, V, Saji, M, Hardy, E, Kruhlak, M, Larin, A, Savchenko, V, Miyakawa, M, Isozaki, O, Murakami, H, Tsushima, T, Burman, KD, De Micco, C, Ringel, MD. (2004). Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer. J. Med. Genet., 41(3):161-170.
Vivanco, I, Sawyers, CL. (2002).The phosphatidylinositol 3-kinase–AKT pathway in human cancer.Nat. Rev. Cancer, 2(7):489-501.
Wartofsky, L, Van Nostrand, D. (2016). Thyroid cancer: a comprehensive guide to clinical management: Springer.
Wu, P, Nielsen, TE, Clausen, MH. (2015). FDA-approved small-molecule kinase inhibitors.Trend.Pharmacol. Sci., 36(7):422-439.
Zarkesh, M, Zadeh-Vakili, A, Akbarzadeh, M, Fanaei, SA, Hedayati, M, Azizi, F. (2018).The role of matrix metalloproteinase-9 as a prognostic biomarker in papillary thyroid cancer. BMC Cancer, 18(1):1199-1210.