The Syk inhibitor R406 is a modulator of P-glycoprotein (ABCB1)-mediated multidrug resistance

PLoS One. 2019 Jan 22;14(1):e0210879. doi: 10.1371/journal.pone.0210879. eCollection 2019.

Abstract

In a previously published study, higher levels of spleen tyrosine kinase (Syk) were observed in recurrent post-chemotherapy ovarian cancers compared to primary tumors. Syk inhibition was found to stabilize microtubules and potentiate paclitaxel activity in cellular models of taxane-resistant ovarian cancers. We further studied the effects of Syk inhibition on paclitaxel activity in Syk(+) ovarian cancer cell models and in variants selected for taxane resistance. Syk inhibition was accomplished using RNAi and by exposure to the small molecule competitive inhibitor R406, the active metabolite of fostamatinib. Exposure to R406 or to a SYK-specific pool of siRNAs did not alter taxane activity in the OVCAR-3 cell line, which has the most Syk content in our panel of nine human ovarian cancer cell lines. However, treatment with R406 sensitised the multidrug resistant (MDR) variants MES-SA/Dx5 and SK-OV-3/TR to paclitaxel in a dose-dependent manner resulting from the inhibition of the ABCB1/P-glycoprotein (P-gp) drug transporter. These observations are Syk-independent since both MDR cell models are Syk negative. R406 modulated resistance to other known P-gp substrates, and we observed orthovanadate-sensitive ATPase stimulation resulting from treatment with R406. These data indicate that the chemo-sensitizing effect of R406 in taxane-resistant cells previously reported was not associated with Syk but resulted from the modulation of P-gp-mediated MDR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Adenosine Triphosphatases / metabolism
  • Antineoplastic Agents / pharmacology
  • Bridged-Ring Compounds / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Multiple / genetics*
  • Drug Resistance, Multiple / physiology
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics*
  • Drug Resistance, Neoplasm / physiology
  • Female
  • Gene Expression / drug effects
  • Humans
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Oxazines / pharmacology*
  • Paclitaxel / pharmacology
  • Pyridines / pharmacology*
  • RNA, Small Interfering / genetics
  • Syk Kinase / antagonists & inhibitors*
  • Syk Kinase / genetics
  • Taxoids / pharmacology

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • Bridged-Ring Compounds
  • N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
  • Oxazines
  • Pyridines
  • RNA, Small Interfering
  • Taxoids
  • taxane
  • SYK protein, human
  • Syk Kinase
  • Adenosine Triphosphatases
  • Paclitaxel