NE-AUA 2006 Annual Meeting, September 28 - 30, 2006, The Westin Hotel & Rhode Island Convention Center Providence, Rhode Island
Back to Scientific Program
Back to Annual Meeting
Treatment with Zinc Specific Chelator TPEN Reverses Zn Induced Resistance to Cisplatin in Prostate Cancer
Samuel Sterrett, MD1, Tony Mammen1, Cheng Du, PhD2, K.C. Balaji, MD2.
1University of Nebraska Medical Center, Omaha, NE, USA, 2University of Massachusetts Memorial Medical Center, Worcester, MA,

Introduction: Prostate cancer is generally considered resistant to cisplatin chemotherapy. We have previously demonstrated that zinc induced metallothioneins (MT) induction, a family of small molecular weight trace metal and free radical scavenging proteins, is associated with increased resistance to cisplatin chemotherapy in prostate cancer (Smith et al, In press, Urology). MT gene expression is up regulated in response to the presence of heavy metal ions such as zinc, which is present at the highest concentration (150μg/g) in the prostate compared to other human organs (20-50μg/g). Chelation of Zn by non-specific metal chelator EDTA was associated with reversal of resistance to cisplatin in prostate cancer (data not shown). In order to establish that EDTA induced reversal resistance to cisplatin is Zn mediated, we analyzed the effect of zinc specific chelator, N,N,N,N-Tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) on resistance to cisplatin chemotherapy in prostate cancer.
Methods: We used an advanced and relatively androgen insensitive C4-2 prostate cancer cell line for our experiments. Cells were plated at 3000 cells/well in 96 well plates and treated with increasing concentrations of TPEN up to 256 ÁM to test for tolerance. In another set of experiments, equimolar concentrations (150 μM) of zinc and TPEN were added at 24 hours, followed by treatment with 10μM of cisplatin, which we had established as the IC50 concentration in our cell line model. Viability assays were performed at 72 hours using non radioactive cell proliferation assays (Promega, Madison, WI). Experiments were performed in triplicate, and means were compared by 2-way ANOVA models. P values less than 0.05 were considered significant.
Results: Tolerance of C4-2 cells to TPEN was demonstrated and showed no statistically significant difference in cell viability between untreated cells and cells treated with up to 256 ÁM TPEN (p=0.3) Treatment of C4-2 cells with zinc induced increased resistance to cisplatin. Treatment with TPEN significantly reversed zinc induced resistance to cisplatin chemotherapy, in vitro (p=0.007).
Conclusions: Our data confirms that C4-2 prostate cancer cells are tolerant to TPEN alone in high concentrations and that TPEN significantly reverses Zn induced resistance to cisplatin chemotherapy in prostate cancer. Therapeutic targeting of high concentration of zinc in prostate with TPEN may therefore provide a means to overcome resistance to cisplatin chemotherapy in prostate cancer.


Back to Scientific Program
Back to Annual Meeting