Modulating telomere dynamics may be a useful strategy for targeting
prostate cancer cells, because they generally have short telomeres. Because a plateau has been reached in the development of
taxane-based treatments for
prostate cancer, this study was undertaken to evaluate the relative efficacy of targeting telomeres and microtubules in
taxane-sensitive,
taxane-resistant,
androgen-sensitive, and
androgen-insensitive
prostate cancer cells.
Paclitaxel- and
docetaxel-resistant DU145 cells were developed and their underlying adaptive responses were evaluated. Telomere dynamics and the effects of targeting telomeres with
sodium meta-arsenite (
KML001) (an agent undergoing early clinical trials), including combinations with
paclitaxel and
docetaxel, were evaluated in parental and
drug-resistant cells. The studies were extended to
androgen-sensitive LNCaP cells and
androgen-insensitive LNCaP/C81 cells. Both
P-glycoprotein (Pgp)-dependent and non-Pgp-dependent mechanisms of resistance were recruited within the same population of DU145 cells with selection for drug resistance. Wild-type DU145 cells have a small side population (SP) (0.4-1.2%). The SP fraction increased with increasing drug resistance, which was correlated with enhanced expression of Pgp but not
breast cancer resistance
protein. Telomere dynamics remained unchanged in
taxane-resistant cells, which retained sensitivity to
KML001. Furthermore,
KML001 targeted SP and non-SP fractions, inducing DNA damage signaling in both fractions.
KML001 induced telomere erosion, decreased
telomerase gene expression, and was highly synergistic with the
taxanes in wild-type and
drug-resistant DU145 cells. This synergism extended to
androgen-sensitive and
androgen-insensitive LNCaP cells under basal and
androgen-deprived conditions. These studies demonstrate that
KML001 plus
docetaxel and
KML001 plus
paclitaxel represent highly synergistic
drug combinations that should be explored further in the different disease states of
prostate cancer.