Doxorubicin Expands in Vivo Secretion of Circulating Exosome in Mice
Doxorubicin Expands in Vivo Secretion of Circulating Exosome in Mice
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DOI：
10.1248/bpb.b18-00202
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发表时间：
2018-07-01
影响因子：
2
通讯作者：
Ishida, Tatsuhiro
中科院分区：
文献类型：
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作者：
Emam, Sherif E.;Ando, Hidenori;Ishida, Tatsuhiro
肿瘤免疫的调节是许多化学治疗剂的抗肿瘤活性中的已知因素。外泌体是由几乎所有类型的细胞（包括癌细胞）释放的细胞外纳米囊泡。这些囊泡在肿瘤免疫中起着至关重要的作用。许多体外研究已经再现了用常规抗癌药物治疗后外泌体的侵袭性分泌。然而，包括纳米药物如Doxil（R）在内的化疗剂如何影响外来体的体内分泌尚待阐明。在该研究中，在BALB/c小鼠中评价了静脉内注射游离多柔比星（DXR）或脂质体DXR制剂（Doxil（R））对外泌体分泌的影响。通过使用ExoQuick（TM）试剂盒从血清中分离外来体。游离DXR治疗以注射后时间依赖性方式显著增加血清外泌体水平，而Doxil（R）治疗则没有。研究了外泌体大小分布和标志物蛋白表达（CD 9、CD 63和TSG 101）。处理诱导的外泌体的物理/生物学特征与对照小鼠的那些相当。有趣的是，脾切除术显著抑制了游离DXR诱导的大量外泌体分泌。总的来说，我们的结果表明，常规抗癌剂诱导循环外泌体的分泌，推测是通过刺激脾脏的免疫细胞。据我们所知，这项研究代表了第一份报告表明，传统的化疗药物可能会诱导外泌体分泌，这可能反过来，有助于部分化疗药物的抗肿瘤作用。
Modulation of tumor immunity is a known factor in the antitumor activity of many chemotherapeutic agents. Exosomes are extracellular nanometric vesicles that are released by almost all types of cells, which includes cancer cells. These vesicles play a crucial role in tumor immunity. Many in vitro studies have reproduced the aggressive secretion of exosomes following treatment with conventional anticancer drugs. Nevertheless, how chemotherapeutic agents including nanomedicines such as Doxil (R) affect the in vivo secretion of exosomes is yet to be elucidated. In this study, the effect of intravenous injection of either free doxorubicin (DXR) or liposomal DXR formulation (Doxil (R)) on exosome secretion was evaluated in BALB/c mice. Exosomes were isolated from serum by using an ExoQuick (TM) kit. Free DXR treatment markedly increased serum exosome levels in a post-injection time-dependent manner, while Doxil (R) treatment did not. Exosomal size distribution and marker protein expressions (CD9, CD63, and TSG101) were studied. The physical/biological characteristics of treatment-induced exosomes were comparable to those of control mice. Interestingly, splenectomy significantly suppressed the copious exosomal secretions induced by free DXR. Collectively, our results indicate that conventional anticancer agents induce the secretion of circulating exosomes, presumably via stimulating immune cells of the spleen. As far as we know, this study represents the first report indicating that conventional chemotherapeutics may induce exosome secretion which might, in turn, contribute partly to the antitumor effect of chemotherapeutic agents.