Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic
Keywords: 
Selenium
Isoselenourea
Melanoma
STAT3
Apoptosis
Issue Date: 
2019
Publisher: 
MDPI AG
ISSN: 
1422-0067
Note: 
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Citation: 
Alcolea-Devesa, V. (Verónica); Karelia, D.N. (Deepkamal N.); Pandey, M.K. (Manoj K.); et al. "Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic". International Journal of Molecular Sciences. 20 (3), 2019, 521
Abstract
The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032.

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