Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells

Bin Zhang, Silke Suer, Ferenc Livak, Samusi Adediran, Arvind Vemula, Mohammad Afnan Khan, Yi Ning, Arif Hussain

Research output: Contribution to journalArticle

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 androgensensitive 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.

Original languageEnglish (US)
Pages (from-to)310-321
Number of pages12
JournalMolecular Pharmacology
Volume82
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Telomere
Microtubules
Prostatic Neoplasms
docetaxel
Androgens
Paclitaxel
Population
P-Glycoprotein
Drug Resistance
Taxoids
Telomerase
Drug Combinations
sodium arsenite
Pharmaceutical Preparations
DNA Damage
Glycoproteins
Clinical Trials
Breast Neoplasms
Gene Expression

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Zhang, B., Suer, S., Livak, F., Adediran, S., Vemula, A., Khan, M. A., ... Hussain, A. (2012). Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells. Molecular Pharmacology, 82(2), 310-321. https://doi.org/10.1124/mol.111.076752

Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells. / Zhang, Bin; Suer, Silke; Livak, Ferenc; Adediran, Samusi; Vemula, Arvind; Khan, Mohammad Afnan; Ning, Yi; Hussain, Arif.

In: Molecular Pharmacology, Vol. 82, No. 2, 08.2012, p. 310-321.

Research output: Contribution to journalArticle

Zhang, B, Suer, S, Livak, F, Adediran, S, Vemula, A, Khan, MA, Ning, Y & Hussain, A 2012, 'Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells', Molecular Pharmacology, vol. 82, no. 2, pp. 310-321. https://doi.org/10.1124/mol.111.076752
Zhang, Bin ; Suer, Silke ; Livak, Ferenc ; Adediran, Samusi ; Vemula, Arvind ; Khan, Mohammad Afnan ; Ning, Yi ; Hussain, Arif. / Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells. In: Molecular Pharmacology. 2012 ; Vol. 82, No. 2. pp. 310-321.
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