title: Inhibition of microvesiculation sensitizes prostate cancer cells to chemotherapy and reduces docetaxel dose required to limit tumor growth in vivo.
abstract: 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.
authors: Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, U.K.
authors: Samireh
authors: S
authors: Jorfi
authors: Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, U.K.
authors: Ephraim A
authors: EA
authors: Ansa-Addo
authors: Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, U.K.
authors: Sharad
authors: S
authors: Kholia
authors: Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, U.K.
authors: Dan
authors: D
authors: Stratton
authors: Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, U.K.
authors: Shaunelle
authors: S
authors: Valley
authors: University College London School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, U.K.
authors: Sigrun
authors: S
authors: Lange
authors: Cellular and Molecular Immunology Research Centre, School of Human Sciences, London Metropolitan University, U.K.
authors: Jameel
authors: J
authors: Inal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D055252:Cell-Derived Microparticles / Q000187:drug effects* / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D043823:Taxoids; D000077143:Docetaxel; C071482:calpeptin; D002154:Calpain; C527669:CAPNS1 protein, human