The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel

Erin M. Goldblatt, Erin R. Gentry, Melanie J. Fox, Sergei M. Gryaznov, Changyu Shen, Brittney-Shea Herbert

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. Telomerase activity can be detected in 85% to 90% of human tumors, which stabilizes telomeres to prevent apoptosis or cellular senescence. Previous reports showed the efficacy of the novel telomerase template antagonist, GRN163L, as a potential anticancer agent. The objective of the present study was to elucidate the molecular effects of GRN163L in MDA-MB-231 breast cancer cells and to determine whether GRN163L could be used in mechanism-based combination therapy for breast cancer. We observed that GRN163L reduced MDA-MB-231 growth rates without a significant effect on breast cancer cell viability within the first 14 days in vitro. In addition, GRN163L altered cell morphology, actin filament organization, and focal adhesion formation in MDA-MB-231 cells. Importantly, the cellular response to GRN163L significantly augmented the effects of the microtubule stabilizer paclitaxel in MDA-MB-231 breast cancer cell growth in vitro and in vivo compared with paclitaxel alone or a mismatch control oligonucleotide plus paclitaxel. Furthermore, in vitro MDA-MB-231 invasive potential was significantly inhibited with GRN163L and paclitaxel. These data support a rationale for potentially combining GRN163L with paclitaxel for the treatment of breast cancer in the clinical setting.

Original languageEnglish
Pages (from-to)2027-2035
Number of pages9
JournalMolecular Cancer Therapeutics
Volume8
Issue number7
DOIs
StatePublished - Jul 1 2009

Fingerprint

Telomerase
Paclitaxel
Breast Neoplasms
Growth
Telomere
Focal Adhesions
Cell Aging
Actin Cytoskeleton
Oligonucleotides
Microtubules
Antineoplastic Agents
Genetic Recombination
Cell Survival
Chromosomes
Apoptosis
DNA
In Vitro Techniques
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel. / Goldblatt, Erin M.; Gentry, Erin R.; Fox, Melanie J.; Gryaznov, Sergei M.; Shen, Changyu; Herbert, Brittney-Shea.

In: Molecular Cancer Therapeutics, Vol. 8, No. 7, 01.07.2009, p. 2027-2035.

Research output: Contribution to journalArticle

Goldblatt, Erin M. ; Gentry, Erin R. ; Fox, Melanie J. ; Gryaznov, Sergei M. ; Shen, Changyu ; Herbert, Brittney-Shea. / The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel. In: Molecular Cancer Therapeutics. 2009 ; Vol. 8, No. 7. pp. 2027-2035.
@article{9e5de4b3320b4bbca795440a3646e833,
title = "The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel",
abstract = "Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. Telomerase activity can be detected in 85{\%} to 90{\%} of human tumors, which stabilizes telomeres to prevent apoptosis or cellular senescence. Previous reports showed the efficacy of the novel telomerase template antagonist, GRN163L, as a potential anticancer agent. The objective of the present study was to elucidate the molecular effects of GRN163L in MDA-MB-231 breast cancer cells and to determine whether GRN163L could be used in mechanism-based combination therapy for breast cancer. We observed that GRN163L reduced MDA-MB-231 growth rates without a significant effect on breast cancer cell viability within the first 14 days in vitro. In addition, GRN163L altered cell morphology, actin filament organization, and focal adhesion formation in MDA-MB-231 cells. Importantly, the cellular response to GRN163L significantly augmented the effects of the microtubule stabilizer paclitaxel in MDA-MB-231 breast cancer cell growth in vitro and in vivo compared with paclitaxel alone or a mismatch control oligonucleotide plus paclitaxel. Furthermore, in vitro MDA-MB-231 invasive potential was significantly inhibited with GRN163L and paclitaxel. These data support a rationale for potentially combining GRN163L with paclitaxel for the treatment of breast cancer in the clinical setting.",
author = "Goldblatt, {Erin M.} and Gentry, {Erin R.} and Fox, {Melanie J.} and Gryaznov, {Sergei M.} and Changyu Shen and Brittney-Shea Herbert",
year = "2009",
month = "7",
day = "1",
doi = "10.1158/1535-7163.MCT-08-1188",
language = "English",
volume = "8",
pages = "2027--2035",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel

AU - Goldblatt, Erin M.

AU - Gentry, Erin R.

AU - Fox, Melanie J.

AU - Gryaznov, Sergei M.

AU - Shen, Changyu

AU - Herbert, Brittney-Shea

PY - 2009/7/1

Y1 - 2009/7/1

N2 - Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. Telomerase activity can be detected in 85% to 90% of human tumors, which stabilizes telomeres to prevent apoptosis or cellular senescence. Previous reports showed the efficacy of the novel telomerase template antagonist, GRN163L, as a potential anticancer agent. The objective of the present study was to elucidate the molecular effects of GRN163L in MDA-MB-231 breast cancer cells and to determine whether GRN163L could be used in mechanism-based combination therapy for breast cancer. We observed that GRN163L reduced MDA-MB-231 growth rates without a significant effect on breast cancer cell viability within the first 14 days in vitro. In addition, GRN163L altered cell morphology, actin filament organization, and focal adhesion formation in MDA-MB-231 cells. Importantly, the cellular response to GRN163L significantly augmented the effects of the microtubule stabilizer paclitaxel in MDA-MB-231 breast cancer cell growth in vitro and in vivo compared with paclitaxel alone or a mismatch control oligonucleotide plus paclitaxel. Furthermore, in vitro MDA-MB-231 invasive potential was significantly inhibited with GRN163L and paclitaxel. These data support a rationale for potentially combining GRN163L with paclitaxel for the treatment of breast cancer in the clinical setting.

AB - Telomeres are repetitive (TTAGGG)n DNA sequences found at the end of chromosomes that protect the ends from recombination, end to end fusions, and recognition as damaged DNA. Telomerase activity can be detected in 85% to 90% of human tumors, which stabilizes telomeres to prevent apoptosis or cellular senescence. Previous reports showed the efficacy of the novel telomerase template antagonist, GRN163L, as a potential anticancer agent. The objective of the present study was to elucidate the molecular effects of GRN163L in MDA-MB-231 breast cancer cells and to determine whether GRN163L could be used in mechanism-based combination therapy for breast cancer. We observed that GRN163L reduced MDA-MB-231 growth rates without a significant effect on breast cancer cell viability within the first 14 days in vitro. In addition, GRN163L altered cell morphology, actin filament organization, and focal adhesion formation in MDA-MB-231 cells. Importantly, the cellular response to GRN163L significantly augmented the effects of the microtubule stabilizer paclitaxel in MDA-MB-231 breast cancer cell growth in vitro and in vivo compared with paclitaxel alone or a mismatch control oligonucleotide plus paclitaxel. Furthermore, in vitro MDA-MB-231 invasive potential was significantly inhibited with GRN163L and paclitaxel. These data support a rationale for potentially combining GRN163L with paclitaxel for the treatment of breast cancer in the clinical setting.

UR - http://www.scopus.com/inward/record.url?scp=67651176018&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651176018&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-08-1188

DO - 10.1158/1535-7163.MCT-08-1188

M3 - Article

C2 - 19509275

AN - SCOPUS:67651176018

VL - 8

SP - 2027

EP - 2035

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 7

ER -