title: Differential cytotoxic activity of a novel palladium-based compound on prostate cell lines, primary prostate epithelial cells and prostate stem cells.
abstract: The outcome for patients with advanced metastatic and recurrent prostate cancer is still poor. Therefore, new chemotherapeutics are required, especially for killing cancer stem cells that are thought to be responsible for disease recurrence. In this study, we screened the effect of a novel palladium-based anticancer agent (Pd complex) against six different prostate cancer cell lines, and primary cultures from seven Gleason 6/7 prostate cancer, three Gleason 8/9 prostate cancer and four benign prostate hyperplasia patient samples, as well as cancer stem cells selected from primary cultures. MTT and ATP viability assays were used to assess cell growth and flow cytometry to assess cell cycle status. In addition, immunofluorescence was used to detect γH2AX nuclear foci, indicative of DNA damage, and Western blotting to assess the induction of apoptosis and autophagy. The Pd complex showed a powerful growth-inhibitory effect against both cell lines and primary cultures. More importantly, it successfully reduced the viability of cancer stem cells as first reported in this study. The Pd complex induced DNA damage and differentially induced evidence of cell death, as well as autophagy. In conclusion, this novel agent may be promising for use against the bulk of the tumour cell population as well as the prostate cancer stem cells, which are thought to be responsible for the resistance of metastatic prostate cancer to chemotherapy. This study also indicates that the combined use of the Pd complex with an autophagy modulator may be a more promising approach to treat prostate cancer. In addition, the differential effects observed between cell lines and primary cells emphasise the importance of the model used to test novel drugs including its genetic background, and indeed the necessity of using cells cultured from patient samples.
authors.affiliation: Department of Medical Biochemistry, Medical School, Uludag University, Bursa, Turkey. eulukaya@uludag.edu.tr
authors.forename: Engin
authors.initials: E
authors.lastname: Ulukaya
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Frame
authors.forename: Buse
authors.initials: B
authors.lastname: Cevatemre
authors.forename: Davide
authors.initials: D
authors.lastname: Pellacani
authors.forename: Hannah
authors.initials: H
authors.lastname: Walker
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Mann
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Simms
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stower
authors.forename: Veysel T
authors.initials: VT
authors.lastname: Yilmaz
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010165:Palladium / Q000737:chemistry / Q000633:toxicity*; D011467:Prostate / Q000166:cytology* / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D010165:Palladium