title: In vivo chemoresistance of prostate cancer in metronomic cyclophosphamide therapy.
abstract: A human prostate cancer (PC3) xenograft model was established which reflects acquired in vivo resistance towards metronomic cyclophosphamide (CPA) treatment. Cell cultures of two in vivo resistant PC3 tumors were established which maintain chemoresistant phenotypes upon xenografting into mice. A comparative proteome analysis of the two resistant cell lines PC3-D3 and -D4 versus the non-resistant parental PC3 cell line by 2D-DIGE approach followed by MALDI-TOF-TOF analysis revealed a total of 25 differently expressed proteins. Validation of protein candidates by Western blot analysis of the corresponding in vivo tumor xenografts identified three differentially expressed proteins (thioredoxin containing protein 5, cathepsin B, and annexin A3). Thioredoxin containing protein 5 was up-regulated in resistant xenografts only upon in vivo CPA therapy. A truncated version of cathepsin B translocated into mitochondria in the resistant clones whereas it stays cytoplasmic in corresponding parental PC3 cells. Annexin A3 (ANXA3) presents a very interesting candidate which was found to be up-regulated both in vitro and in xenografts, with protein levels further increased by metronomic CPA treatment in vivo. It is noteworthy that independent studies in other epithelial cancers recently identified ANXA3 as cancer progression and resistance marker.
authors.affiliation: Pharmaceutical Biology-Biotechnology, Department of Pharmacy, Center for Drug Research, Butenandtstr. 5-13, Building D, 81377 Munich, Germany.
authors.forename: Lilja
authors.initials: L
authors.lastname: Thoenes
authors.forename: Miriam
authors.initials: M
authors.lastname: Hoehn
authors.forename: Roman
authors.initials: R
authors.lastname: Kashirin
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.forename: Georg J
authors.initials: GJ
authors.lastname: Arnold
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Michael
authors.initials: M
authors.lastname: Guenther
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D020543:Proteome; D003520:Cyclophosphamide