Inhibition of microvesiculation sensitizes prostate cancer cells to chemotherapy and reduces docetaxel dose required to limit tumor growth in vivo.
Inhibition of microvesiculation sensitizes prostate cancer cells to chemotherapy and reduces docetaxel dose required to limit tumor growth in vivo.
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DOI：
10.1038/srep13006
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发表时间：
2015-08-25
影响因子：
4.6
通讯作者：
Inal J
中科院分区：
文献类型：
--
作者：
Jorfi S;Ansa-Addo EA;Kholia S;Stratton D;Valley S;Lange S;Inal J
从细胞脱落的微泡携带细胞质的成分，包括肿瘤细胞试图外排的药物，这在癌症化疗的多药耐药性中很重要。为了了解这些药物是否可以在较低浓度下使用而具有相同的功效，首先显示前列腺癌（PCa）细胞PC 3的微泡形成可以用钙蛋白酶（calpeptin）（钙蛋白酶抑制剂）和siRNA（CAPNS 1）抑制。在用多西他赛（DTX）处理的细胞中，这种抑制导致DTX的细胞内浓度增加三倍。因此，在钙肽酶（20 μM）存在下，可使用比单独使用100 nM DTX低20倍的浓度的DTX（5 nM），在PC 3细胞中48 h后诱导相同程度的凋亡。抑制微泡形成同样改善了联合化疗（DTX和甲氨蝶呤）。在PCa的小鼠异种移植物模型中，腹膜内施用DTX（0.1mg/kg）连同钙肽酶（10 mg/kg），与单独的DTX（0.1mg/kg）相比，显著降低了肿瘤体积，并带来了与单独的10 mg/kg DTX相同的肿瘤生长降低。除了进一步减少血管形成外，它还增加了肿瘤异种移植物中PC 3细胞的凋亡和增殖。
Microvesicles shed from cells carry constituents of the cell cytoplasm, including, of importance in multidrug resistance to cancer chemotherapy, drugs that the tumor cell attempts to efflux. To see whether such drugs could be used at lower concentrations with the same efficacy, it was first shown that microvesiculation of prostate cancer (PCa) cells, PC3, could be inhibited pharmacologically with calpeptin (calpain inhibitor) and by siRNA (CAPNS1). In cells treated with docetaxel (DTX), this inhibition resulted in a third-fold increase in intracellular concentrations of DTX. As a result, 20-fold lower concentrations of DTX (5 nM) could be used, in the presence of calpeptin (20 μM) inducing the same degree of apoptosis after 48 h in PC3 cells, as 100 nM of DTX alone. Inhibition of microvesiculation similarly improved combination chemotherapy (DTX and methotrexate). In a mouse xenograft model of PCa, DTX (0.1 mg/kg) together with calpeptin (10 mg/kg), administered i.p., significantly reduced tumor volumes compared to DTX alone (0.1 mg/kg) and brought about the same reductions in tumor growth as 10 mg/kg of DTX alone. As well as further reducing vascularization, it also increased apoptosis and reduced proliferation of PC3 cells in tumor xenografts.