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Research Article Open access CC BY 4.0

Digoxin Inhibits Retinoblastoma through Suppressing a Non-canonical TGFβ Signaling Pathway

Maryam Sheikhzade, Abolfazl Akbari, Reza Karkhaneh, Fariba Ghassemi, Abdolrahim Sadeghi, Mahshid Shahrzad Kavakani, Gholam Reza Mobini, Masoumeh Mohebbi, Mansour Heidari

Journal of Advances in Medicine and Medical Research · pp. 1–10 · Published 28 Apr 2016

10.9734/BJMMR/2016/25709

Abstract

Aims: Retinoblastoma is a childhood ocular tumor rapidly developing from the immature cells of the retina due to loss of functional retinoblastoma protein. Digoxin, a cardiac glycoside, has been reported to be effective in inducing apoptosis, cell cycle arrest, and cytotoxic effects on human cancers. In this regard, the present study aims to investigate whether digoxin could suppress retinoblastoma cancer through the regulation of transforming growth factor-β (TGF-β) signaling pathway. Methodology: The effects of digoxin on Y-79 cells, retinoblastoma cancer cell line, were investigated using MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazoli-umbromide) and BrdU (bromodeoxyuridine) assays to measure cellular cytotoxicity effects and cell apoptosis, respectively. Also, a qPCR assay was employed to analyze the mRNA expression levels of TGFβ signaling pathway including C-MYC, P21, P15, TGFβRI, TGFβRII, and SMAD2, 3, and 4 genes. Results: The results of the cell function assays revealed that digoxin inhibited the cell viability and proliferation of Y-79 cells. In addition, it was found that digoxin significantly suppressed C-MYC expression and enhanced the expression of P21, P15, SMAD2 and SMAD4 genes in a dose-and time-dependent manner. However, the obtained results could not detect any significant effect of digoxin on TGFβRI, TGFβRII and SMAD3 genes. Conclusion: Taken together, the findings of the present study suggest that digoxin could be a potential therapeutic agent in the treatment of retinoblastoma by regulating the cell cycle genes via a non-canonical TGF-β signaling pathway.

c-Myc eye cancer gene expression P21 P15 real-time PCR.

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