Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic

Verónica Alcolea, Deepkamal N. Karelia, Manoj K. Pandey, Daniel Plano, Parvesh Singh, Juan Antonio Palop, Shantu Amin, Carmen Sanmartín, Arun Sharma

Research output: Contribution to journalArticle

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-RAF V600E -mutant and wild-type (WT) cells. Compound 1 (IC 50 range 0.8–3.8 µM) showed lower IC 50 values than compound 3 (IC 50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC 50 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.

Original languageEnglish (US)
Article number521
JournalInternational journal of molecular sciences
Volume20
Issue number3
DOIs
StatePublished - Feb 1 2019

Fingerprint

quinoxalines
STAT3 Transcription Factor
Quinoxalines
Transcription
Transducers
Melanoma
transducers
Cell death
apoptosis
metastasis
Apoptosis
ureas
Urea
inhibitors
Therapeutics
cells
Cells
Neoplasm Metastasis
Derivatives
phosphorylation

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Alcolea, Verónica ; Karelia, Deepkamal N. ; Pandey, Manoj K. ; Plano, Daniel ; Singh, Parvesh ; Palop, Juan Antonio ; Amin, Shantu ; Sanmartín, Carmen ; Sharma, Arun. / Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic. In: International journal of molecular sciences. 2019 ; Vol. 20, No. 3.
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Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic. / Alcolea, Verónica; Karelia, Deepkamal N.; Pandey, Manoj K.; Plano, Daniel; Singh, Parvesh; Palop, Juan Antonio; Amin, Shantu; Sanmartín, Carmen; Sharma, Arun.

In: International journal of molecular sciences, Vol. 20, No. 3, 521, 01.02.2019.

Research output: Contribution to journalArticle

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T1 - Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic

AU - Alcolea, Verónica

AU - Karelia, Deepkamal N.

AU - Pandey, Manoj K.

AU - Plano, Daniel

AU - Singh, Parvesh

AU - Palop, Juan Antonio

AU - Amin, Shantu

AU - Sanmartín, Carmen

AU - Sharma, Arun

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AB - 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-RAF V600E -mutant and wild-type (WT) cells. Compound 1 (IC 50 range 0.8–3.8 µM) showed lower IC 50 values than compound 3 (IC 50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC 50 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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