21th EORTC-NCI-AACR Boston, MA
The telomere targeting agent sodium metaarsenite (KML001) exhibits activity in taxane-resistant prostate cancer (PC) cells
Angelika M. Burger, Bin Zhang, Patrick Nolan, Bradley Brucz and Arif Hussain
Abstract
Background: Tumor growth is sustained by cancer stem cells (CSC),a rare fraction of cells expressing high levels of drug effluxpumps
responsible for therapy failure and tumor recurrence.The enzyme telomerase is critical to maintaining the self-renewalproperties of CSC.
We have recently found that sodium metaarsenite(KML001), a drug in phase I/II clinical trials in Europe andthe US, can target both the catalytic
subunit of telomeraseand telomeres. PC cell lines appear to be among the most sensitivetumor cell types to KML001. In this study, we examined
chemotherapy-naïveand taxane (paclitaxcel/Pac and docetaxel/Doc)-resistant DU145PC cell lines for stem cell content, and the potential for
KML001to inhibit their mature and stem cell subpopulations.
Methods: Methyltetrazolium (MTT)-based assays were used to determinethe IC50 and IC100 values, and the relative resistance of DU145,
DU145/Doc50 and DU145/Pac200 cells to KML001, docetaxel andpaclitaxel. Fluorescence activated cell sorting (FACS) was employedto
determine the prostate stem cell surface marker CD44, theside population and Pgp content in these cells. Telomerase activitywas evaluated
by a PCR ELISA assay and telomere length was assessedby Southern blots. Cells were treated with IC50 and IC100 concentrationsof KML001
for 72 hrs to investigate its effects on the sidepopulation.
Results: We found that while DU145/Doc50 and DU145/Pac200 cellswere 2,000- and 400-fold resistant to docetaxel and paclitaxel, respectively,
they retained sensitivity to KML001 (IC50 = 4µM).Resistance to taxanes was associated with expression of Pgp;parental DU145 cells expressed
Pgp in 0.24% of the cell population,DU145/Doc50 in 47% and DU145/Pac200 in 79% of the cells. Moreover, Pgp expression correlated with the
detection of a side population(SP), a cell fraction known to be enriched for CSC. The SP was3.7% in DU145 cells and 56%–67% in the taxane-resistantcells. In contrast, telomerase activity and telomere lengthsremained unchanged in all three cell lines. Exposure of thevarious DU145 cell
lines to KML001 for 72 hrs resulted in adramatic reduction in the SP. Similar to the Pgp inhibitor verapamil,KML001 reduced SP cells to ~93% of
controls in both parentaland taxane-resistant cell lines. However, unlike verapamil,KML001 was able to reduce the mature cell population to
thesame extent as the SP.
Conclusion: Overall, our data in the DU145 model demonstratethat KML001 can eradicate both mature drug-resistant and prostatecancer stem
cells, which may offer a new treatment approachin this disease.
