Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS One. 2019 Jan 22;14(1):e0210879. doi: 10.1371/journal.pone.0210879. eCollection 2019.
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.
在之前发表的一项研究中，与原发性肿瘤相比，复发性化疗后卵巢癌中的脾酪氨酸激酶 (Syk) 水平更高。研究发现，Syk 抑制可稳定微管并增强紫杉烷耐药卵巢癌细胞模型中的紫杉醇活性。我们进一步研究了 Syk 抑制对紫杉醇活性在 Syk(+)卵巢癌细胞模型和选择用于紫杉烷耐药的变体中的影响。使用 RNAi 和小分子竞争性抑制剂 R406（ fostamatinib 的活性代谢物）来实现 Syk 抑制。R406 或 SYK 特异性 siRNA 池的暴露不会改变我们九个人类卵巢癌细胞系面板中 Syk 含量最多的 OVCAR-3 细胞系中的紫杉醇活性。然而，R406 处理以剂量依赖性方式使多药耐药 (MDR) 变体 MES-SA/Dx5 和 SK-OV-3/TR 对紫杉醇敏感，这是由于 ABCB1/P-糖蛋白 (P-gp) 药物转运蛋白的抑制。这些观察结果是 Syk 独立的，因为这两种 MDR 细胞模型都是 Syk 阴性的。R406 调节了对其他已知 P-gp 底物的耐药性，并且我们观察到用 R406 处理后可诱导 orthovanadate 敏感的 ATP 酶刺激。这些数据表明，先前报道的 R406 在紫杉烷耐药细胞中的化疗增敏作用与 Syk 无关，而是由于 P-gp 介导的 MDR 的调节所致。
