Inhibition of microvesiculation sensitizes prostate cancer cells to chemotherapy and reduces docetaxel dose required to limit tumor growth in vivo

被引:80
作者
Jorfi, Samireh [1 ]
Ansa-Addo, Ephraim A. [1 ]
Kholia, Sharad [1 ]
Stratton, Dan [1 ]
Valley, Shaunelle [1 ]
Lange, Sigrun [2 ]
Inal, Jameel [1 ]
机构
[1] London Metropolitan Univ, Sch Human Sci, Cellular & Mol Immunol Res Ctr, London, England
[2] UCL, Sch Pharm, London WC1N 1AX, England
关键词
MEMBRANE-DERIVED VESICLES; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; C-FOS; CALPAIN; APOPTOSIS; RELEASE; MICROPARTICLES; COMMUNICATION; MODULATION;
D O I
10.1038/srep13006
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 mu M) 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.
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页数:13
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