Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

General Research Article

Cyclosporine A Suppresses the Malignant Progression of Oral Squamous Cell Carcinoma in vitro

Author(s): Ling Gao*, Jianwei Dong, Nanyang Zhang, Zhanxian Le, Wenhao Ren*, Shaoming Li, Fan Li, Jianzhong Song, Qibo Wang, Zhichao Dou, Soo Y. Park and Keqian Zhi*

Volume 19, Issue 2, 2019

Page: [248 - 255] Pages: 8

DOI: 10.2174/1871520618666181029170605

Price: $65

Abstract

Background: The Oral Squamous Cell Carcinoma (OSCC) is one of the most frequent cancer types. Failure of treatment of OSCC is potentially lethal because of local recurrence, regional lymph node metastasis, and distant metastasis. Chemotherapy plays a vital role through suppression of tumorigenesis. Cyclosporine A (CsA), an immunosuppressant drug, has been efficiently used in allograft organ transplant recipients to prevent rejection, and also has been used in a subset of patients with autoimmunity related disorders. The present study aims to investigate novel and effective chemotherapeutic drugs to overcome drug-resistance in the treatment of OSCC.

Methods: Cells were incubated in the standard way. Cell viability was assayed using the MTT assay. Cell proliferation was determined using colony formation assay. The cell cycle assay was performed using flow cytometry. Apoptosis was assessed using fluorescence-activated cell sorting after stained by the Annexin V-fluorescein isothiocyanate (FITC). Cell migration and invasion were analyzed using wound healing assay and tranwell. The effect of COX-2, c-Myc, MMP-9, MMP-2, and NFATc1 protein expression was determined using Western blot analysis while NFATc1 mRNA expression was determined by RT-PCR.

Results: In vitro studies indicated that CsA inhibited partial OSCC growth by inducing cell cycle arrest, apoptosis, and the migration and invasion of OSCC cells. We also demonstrated that CsA could inhibit the expression of NFATc1 and its downstream genes COX-2, c-Myc, MMP-9, and MMP-2 in OSCC cells. Furthermore, we analyzed the expression of NFATc1 in head and neck cancer through the Oncomine database. The data was consistent with the experimental findings.

Conclusion: The present study initially demonstrated that CsA could inhibit the progression of OSCC cells and can mediate the signal molecules of NFATc1 signaling pathway, which has strong relationship with cancer development. That explains us CsA has potential to explore the possibilities as a novel chemotherapeutic drug for the treatment of OSCC.

Keywords: Oral squamous cell carcinoma, cyclosporine A, NFATc1, cell growth, apoptosis, migration, invasion.

Graphical Abstract
[1]
Napier, S.S.; Speight, P.M. Natural history of potentially malignant oral lesions and conditions: An overview of the literature. J. Oral Pathol. Med., 2008, 37(1), 1-10.
[2]
Marocchio, L.S.; Lima, J.; Sperandio, F.F.; Corrêa, L.; de Sousa, S.O.M. Oral squamous cell carcinoma: An analysis of 1,564 cases showing advances in early detection. J. Oral Sci., 2010, 52(2), 267-273.
[3]
Massano, J.; Regateiro, F.S.; Januário, G.; Ferreira, A. Oral squamous cell carcinoma: Review of prognostic and predictive factors. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 2006, 102(1), 67-76.
[4]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. Cancer J. Clin, 2011, 61, 69-90.
[5]
Sambandam, Y.; Sakamuri, S.; Balasubramanian, S.; Haque, A. rank ligand modulation of autophagy in oral squamous cell carcinoma tumor cells. J. Cell. Biochem., 2016, 117(1), 118-125.
[6]
Pisani, B.; Bray, F.; Parkin, D.M. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int. J. Cancer, 2002, 97, 72-81.
[7]
Kiyosue, T.; Kawano, S.; Matsubara, R.; Goto, Y.; Hirano, M.; Jinno, T.; Toyoshima, T.; Kitamura, R.; Oobu, K.; Nakamura, S. Immunohistochemical location of the p75 neurotrophin receptor (p75NTR) in oral leukoplakia and oral squamous cell carcinoma International. Int. J. Clin. Oncol., 2013, 18(1), 154-163.
[8]
Watts, R.; Clunie, G.; Hall, F.; Marshall, T. Rheumatology; Oxford University Press: New York, 2009, p. 558.
[9]
WHO Model Formulary 2008 (PDF). World Health Organization. 2009, 221.
[10]
The American Society of Health-System Pharmacists. Retrieved 8 December. 2016.
[11]
Liu, J.; Farmer, J.D., Jr; Lane, W.S.; Friedman, J.; Weissman, I.; Schreiber, S.L. Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP–FK506 complexes. Cell, 1991, 66(1991), 807-815.
[12]
Ram, B.M.; Ramakrishna, G. Endoplasmic reticulum vacuolation and unfolded protein response leading to paraptosis like cell death in cyclosporine A treated cancer cervix cells is mediated by cyclophilin B inhibition. Biochim. Biophys. Acta, 2014, 1843(11), 2497-2512.
[13]
Shou, J.; You, L.; Yao, J.; Xie, J.; Jing, J.; Jing, Z.; Jiang, L.; Sui, X.; Pan, H.; Han, W. Cyclosporine A sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of STAT3. Cancer Lett., 2016, 379(1), 124-133.
[14]
Zupanska, A.; Dziembowska, M.; Ellert-Miklaszewska, A.; Gaweda-Walerych, K.; Kaminska, B. Cyclosporine a induces growth arrest or programmed cell death of human glioma cells. Neurochem. Int., 2005, 47(6), 430-441.
[15]
Jiang, K.; He, B.; Lai, L.; Chen, Q.; Liu, Y.; Guo, Q.; Wang, Q. Cyclosporine A inhibits breast cancer cell growth by downregulating the expression of pyruvate kinase subtype M2. Int. J. Mol. Med., 2012, 30(2), 302-308.
[16]
Ponticelli, C.; Tarantino, A.; Campise, M.; Montagnino, G.; Aroldi, A.; Passerini, P. From cyclosporine to the future. Transplant. Proc., 2004, 36, 557S-560S.
[17]
Flanagan, W.M.; Corthesy, B.; Bram, R.J.; Crabtree, G.R. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature, 1991, 352, 803-807.
[18]
Crabtree, G.R.; Olson, E.N. NFAT signaling: choreographing the social lives of cells. Cell, 2002, 109(Suppl. 2), S67-S79.
[19]
Hogan, P.G.; Chen, L.; Nardone, J.; Rao, A. Transcription regulation by calcium, calcineurin, and NFAT. Genes Dev., 2003, 17, 2205-2232.
[20]
Greenhough, A.; Smartt, H.J.; Moore, A.E.; Roberts, H.R.; Williams, A.C.; Paraskeva, C.; Kaidi, A. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis, 2009, 30, 377-386.
[21]
Buchholz, M.; Schatz, A.; Wagner, M.; Michl, P.; Linhart, T.; Adler, G.; Gress, T.M.; Ellenrieder, V. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J., 2006, 25(15), 3714-3724.
[22]
Kawahara, T.; Kashiwagi, E.; Ide, H.; Li, Y.; Zheng, Y.; Miyamoto, Y.; Netto, G.J.; Ishiguro, H.; Miyamoto, H. Cyclosporine A and tacrolimus inhibit bladder cancer growth through down-regulation of NFATc1. Oncotarget, 2015, 6(3), 1582-1593.
[23]
Johansson, N.; Ahonen, M.; Kähäri, V.M. Matrix metalloproteinases in tumor invasion. Cell. Mol. Life Sci., 2000, 57(1), 5-15.
[24]
Li, X.; Zhu, L.; Yang, A.; Lin, J.; Tang, F.; Jin, S.; Wei, Z.; Li, J.; Jin, Y. Calcineurin-NFAT signaling critically regulates early lineage specification in mouse embryonic stem cells and embryos. Cell Stem Cell, 2011, 8, 46-58.
[25]
Sachinidis, A.; Schwengberg, S.; Hippler-Altenburg, R.; Mariappan, D.; Kamisetti, N.; Seelig, B.; Berkessel, A.; Hescheler, J. Identification of small signalling molecules promoting cardiacspecific differentiation of mouse embryonic stem cells. Cell. Physiol. Biochem., 2006, 18, 303-314.
[26]
Shou, J.; You, L.; Yao, J.; Xie, J.; Jing, J.; Jing, Z.; Jiang, L.; Sui, X.; Pan, H.; Han, W. Cyclosporine A sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of STAT3. Cancer Lett., 2016, 379, 124-133.
[27]
Kawahara, T.; Kashiwagi, E.; Li, Y.; Zheng, Y.; Miyamoto, Y.; Netto, G.J.; Ishiguro, H.; Miyamoto, H. Cyclosporine A and tacrolimus inhibit urothelial tumorigenesis. Mol. Carcinog., 2016, 55(2), 161-169.
[28]
Wang, S.; Kang, X.; Cao, S.; Cheng, H.; Wang, D.; Geng, J. Calcineurin/NFATc1 pathway contributes to cell proliferationin hepatocellular carcinoma. Dig. Dis. Sci., 2012, 57, 3184-3188.
[29]
Kawahara, T.; Kashiwagi, E.; Ide, H.; Li, Y.; Zheng, Y.; Ishiguro, H.; Miyamoto, H. The role of NFATc1 inprostate cancer progression: Cyclosporine A and tacrolimusinhibit cell proliferation, migration, and invasion. Prostate, 2014, 75(6), 573-584.
[30]
Pham, L.V.; Tamayo, A.T.; Li, C.; Bueso-Ramos, C.; Ford, R.J. An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas. Blood, 2010, 116(19), 3899-3906.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy