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.
Highlights
Prostate cancer is the most commonly diagnosed cancer in males and is the second highest cause of male cancer-related death [1,2]
Recurrent prostate cancer eventually results in the death of the patient due to resistance to chemotherapy and ineffective chemotherapy, almost inevitably within 2 years from the failure of hormone treatment [4]
We have found that the Pd complex had a significant growth-inhibiting activity against both prostate cancer cell lines and cell lines derived from normal and benign prostate
Summary
Prostate cancer is the most commonly diagnosed cancer in males and is the second highest cause of male cancer-related death [1,2]. Different Pd complexes with promising activity against varying kinds of tumor cell lines from both solid tumors and hematological malignancies have been synthesized and tested over the years [9,10,11,12,13,14,15]. Their lipophilicity or solubility seems to provide satisfactory cytostatic activity [16]. The increased solubility of Pd complexes, compared to platinum, makes Pd complexes more attractive. Pd complexes of glyoxylic oxime were found to have higher aqueous solubility than platinum(II) (Pt) complexes of glyoxylic oxime [17]
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