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

Date Published: January 22, 2019

Publisher: Public Library of Science

Author(s): George E. Duran, Branimir I. Sikic, Arun Rishi.

http://doi.org/10.1371/journal.pone.0210879

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.

Partial Text

The taxanes, paclitaxel (Taxol), docetaxel (Taxotere), and the second-generation taxane cabazitaxel (Jevtana), are used to treat breast, ovarian, lung, prostate and other cancers. These potent anticancer agents stabilize microtubules, blocking cells in the late G2/M phase of the cell cycle [1]. Pre-existing or acquired drug resistance during the course of therapy affects their clinical efficacy. A major determinant of taxane activity is the multidrug resistance transporter P-gp, and in vitro drug selections with taxanes alone result in the activation of the ABCB1 gene [2]. This resistance can be modulated in the presence of known transport inhibitors such as the PSC-833 (valspodar) and LY335979 (zosuquidar), among others [3, 4].

Activation of the ABCB1 gene is a predominant mechanism of resistance in response to selection with taxanes in vitro [1–3, 16–19]. In cell models co-selected with P-gp inhibitors, non-MDR mechanisms of taxane resistance emerge including elevated class III beta-tubulin (TUBB3) expression [3, 20–22], altered expression of cell cycle regulators such as CDKN1A/p21 and BRCA1 [3, 23–26] and apoptotic regulators [27, 28], and epithelial to mesenchymal transition [3, 29–31].

Our data indicate that neither R406 nor anti-SYK siRNA have any direct antitumor activity against the Syk-expressing ovarian cancer lines. Any effect resulting from R406 treatment added to paclitaxel would result from P-gp modulation and not Syk function.

 

Source:

http://doi.org/10.1371/journal.pone.0210879

 

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