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Ouabain Exhibited Strong Anticancer Effects in Melanoma Cells via Induction of Apoptosis, G2/M Phase Arrest, and Migration Inhibition

Authors Wang L, Cai W, Han B, Zhang J, Yu B, Chen M

Received 23 September 2020

Accepted for publication 27 January 2021

Published 25 February 2021 Volume 2021:14 Pages 1261—1273

DOI https://doi.org/10.2147/OTT.S283548

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Sanjeev Srivastava


Lei Wang,1 Wei Cai,2 Bing Han,1 Jue Zhang,1 Bing Yu,1 Ming Chen1

1Burn and Plastic Surgery, Zhongda Hospital Affiliated Southeast University, Nanjing, 210009, People’s Republic of China; 2Burn and Plastic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, People’s Republic of China

Correspondence: Wei Cai
Burn and Plastic Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of China
Email [email protected]

Background: Malignant melanoma was characterized by insensitive chemotherapy, drug resistance, and high metastatic ability, which resulted in the main reason for the mortality among skin-related cancers. The current agents were not sufficient to improve the treatment status of melanoma patients, and it was still needed to develop new chemotherapeutic drugs for melanoma. Our study aimed to study the anticancer effects and potential mechanisms of ouabain on melanoma cells.
Methods: The inhibitory effects of ouabain were determined by CCK8 and colony formation assays, and the morphological changes of melanoma cells were observed by inverted microscope. The apoptosis induction and cell cycle distribution were detected by annexin V/PI double staining and PI staining, respectively. The expression of the biomarker proteins in apoptosis and G2/M phase were determined by Western blotting analysis. The effects of ouabain on the migration of melanoma cells were measured by transwell migration assay and wound closure analysis. The potential mechanisms of ouabain in melanoma cells were analyzed by transcriptome sequencing.
Results: Our present study demonstrated that ouabain exhibited strong inhibitory effects on cell proliferation and triggered dramatical morphological changes of melanoma cells. Moreover, ouabain induced significant apoptosis in A375 rather than SK-Mel-28 cells via upregulation of bax expression and downregulation of bcl-2 expression. Consistently, ouabain treatment induced cell cycle arrest at G2/M phase in both A375 and SK-Mel-28 cells via upregulation of cyclin B1 and downregulation of cdc2 and cdc25c. Importantly, ouabain suppressed the migration of A375 and SK-Mel-28 cells. Furthermore, the transcriptome sequencing demonstrated that p53 and MAPK signaling pathway might play important roles in the inhibitory effects of ouabain.
Conclusion: Our study revealed that ouabain exhibited dramatical anticancer effects, which provided a novel application for cardiac glycoside drugs in the clinical treatment of melanoma.

Keywords: melanoma, ouabain, apoptosis, cell cycle, migration

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