Telomere and Microtubule Targeting in Treatment-Sensitive and Treatment-Resistant Human Prostate Cancer Cells
Zhang B, Suer S, Livak F, Adediran S, Vemula A, Khan MA, Ning Y, Hussain A.
Abstract
Modulating telomere dynamics may be a useful strategy for targeting prostate cancer (PC) cells as they generally have short telomeres.
As a plateau has been reached with taxane-based therapies in PC, this study was undertaken to evaluate the relative efficacy of
targeting telomeres and microtubules in taxane-sensitive, taxane-resistant, androgen-sensitive and androgen-insensitive PC cells.
Paclitaxel- and docetaxel-resistant DU145 cells were developed and their underlying adaptive responses evaluated. Telomere dynamics,
and the effects of targeting telomeres with KML001 (sodium metaarsenite), an agent undergoing early clinical trials, were evaluated in
parental and drug-resistant cells, including in combinations with paclitaxel and docetaxel. The studies were extended to androgen-
sensitive LNCaP and androgen-insensitive LNCaP/C81 cells. Both P-glycoprotein (Pgp) and non-Pgp mechanisms of resistance were
recruited within the same population of DU145 cells upon selection for drug resistance. Wt DU145 cells have a small side population
(SP; 0.4-1.2%). The SP fraction increased with increasing drug resistance and correlated with enhanced Pgp but not Breast Cancer
Resistance Protein (BCRP) expression. Telomere dynamics remained unchanged in taxane-resistant cells, which retained sensitivity to
KML001. Further, KML001 targeted SP and non-SP fractions, inducing DNA damage signaling in both. KML001 induced telomere
erosion and decreased telomerase gene expression, and was also highly synergistic with the taxanes in wt 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 with docetaxel or paclitaxel are highly synergistic drug combinations and should
be explored further in the different disease states of PC.
