Abstract
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.
Footnotes
This work was supported by the Department of Defense [Grant PC081047] and the Department of Veterans Affairs (Medical Research Service Merit Review Award to A.H.). S.S. was supported in part by a grant from Komipharm International Co. (Kyongki-Do, South Korea).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- KML001
- sodium meta-arsenite
- ABC
- ATP-binding cassette
- APL
- acute promyelocytic leukemia
- AR
- androgen receptor
- wt
- wild-type
- ATO
- arsenic trioxide
- BCRP
- breast cancer resistance protein
- CI
- combination index
- DRI
- dose reduction index
- FACS
- fluorescence-activated cell sorting
- FAM
- fluorescein amidite
- FISH
- fluorescence in situ hybridization
- HBSS
- Hanks' balanced salt solution
- PBS
- phosphate-buffered saline
- hTERT
- human telomere reverse transcriptase
- PE
- phycoerythrin
- Pgp
- P-glycoprotein
- PCR
- polymerase chain reaction
- PNA
- peptide nucleic acid
- SP
- side population
- VP
- verapamil
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- Ko143
- (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester
- Hoechst 33342
- 2′-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-2′,5′-bi-1H-benzimidazole.
- Received November 14, 2011.
- Accepted May 14, 2012.
- U.S. Government work not protected by U.S. copyright
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