Antimetastatic effect of the pharmacological inhibition of serine/arginine-rich protein kinases (SRPK) in murine melanoma

Toxicol Appl Pharmacol. 2018 Oct 1:356:214-223. doi: 10.1016/j.taap.2018.08.012. Epub 2018 Aug 20.

Abstract

The Serine/arginine-rich protein kinases (SRPK) are involved in pre-mRNA splicing control through the phosphorylation of the SR protein family of splicing factors. Over the last years, several studies have shown the relevance of SRPK for human cancers and their potential as promising drug targets. In this context, we have previously selected three trifluoromethyl arylamides (named here as SRVIC24, SRVIC30 and SRVIC36) with improved in vitro antileukemia effect and ability of impairing the cellular activity of SRPK. Given the increasing amount of reports on the implication of these kinases in metastatic cancers, in this study, we have evaluated the antimetastatic effect of these compounds and the known SRPK inhibitor (SRPIN340) on a murine model of metastatic melanoma. The compounds were able to impact the melanoma cell metastatic behavior by decreasing migration, invasion, adhesion, and colony formation in in vitro assays. Also, they presented antimetastatic in vivo activity, without apparent signs of systemic toxicity after treatments, as revealed by the histology of organs and analysis of key serum biochemical markers. Moreover, the effect of the treatments on SRPK1 nuclear translocation and SR protein phosphorylation was observed. Finally, molecular docking studies were carried out to gain structural information on the SRPK-compound complexes. Together, these data suggest that SRPK pharmacological inhibition should be considered as an interesting therapeutic strategy against metastatic cancers.

Keywords: Melanoma; Metastasis; Protein kinases; SRVIC compounds; Serine/Arginine-rich.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Neoplasm Invasiveness
  • Neoplasm Metastasis / prevention & control*
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Tumor Stem Cell Assay

Substances

  • Antineoplastic Agents
  • Piperidines
  • SRPIN340
  • Niacinamide
  • Protein Serine-Threonine Kinases