RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells.
Abstract | INTRODUCTION: METHODS: We generated a gene set from overlay of the druggable genome and a collection of genomically deregulated gene transcripts in breast cancer. We used loss-of-function RNA interference (RNAi) to identify gene products in this set that, when targeted, increase paclitaxel sensitivity. Pharmacological agents that targeted the top scoring hits/genes from our RNAi screens were used in combination with paclitaxel, and the effects on the growth of various breast cancer cell lines were determined. RESULTS: RNAi screens performed herein were validated by identification of genes in pathways that, when previously targeted, enhanced paclitaxel sensitivity in the pre-clinical and clinical settings. When chemical inhibitors, CCT007093 and mithramycin, against two top hits in our screen, PPMID and SP1, respectively, were used in combination with paclitaxel, we observed synergistic growth inhibition in both 2D and 3D breast cancer cell cultures. The transforming growth factor beta ( TGFbeta) receptor inhibitor, LY2109761, that targets the signaling pathway of another top scoring hit, TGFbeta1, was synergistic with paclitaxel when used in combination on select breast cancer cell lines grown in 3D culture. We also determined the relative paclitaxel sensitivity of 22 TNBC cell lines and identified 18 drug-sensitive and four drug-resistant cell lines. Of significance, we found that both CCT007093 and mithramycin, when used in combination with paclitaxel, resulted in synergistic inhibition of the four paclitaxel-resistant TNBC cell lines. CONCLUSIONS:
|
Authors | Joshua A Bauer, Fei Ye, Clayton B Marshall, Brian D Lehmann, Christopher S Pendleton, Yu Shyr, Carlos L Arteaga, Jennifer A Pietenpol |
Journal | Breast cancer research : BCR
(Breast Cancer Res)
Vol. 12
Issue 3
Pg. R41
( 2010)
ISSN: 1465-542X [Electronic] England |
PMID | 20576088
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
Chemical References |
- Antineoplastic Agents, Phytogenic
- Biomarkers, Tumor
- RNA, Small Interfering
- Paclitaxel
|
Topics |
- Antineoplastic Agents, Phytogenic
(pharmacology)
- Biomarkers, Tumor
(antagonists & inhibitors, genetics, metabolism)
- Breast Neoplasms
(drug therapy, genetics, pathology)
- Cell Line, Tumor
- Drug Resistance, Neoplasm
(genetics)
- Drug Synergism
- Female
- Humans
- Neoplasms, Basal Cell
(drug therapy, genetics, pathology)
- Paclitaxel
(pharmacology)
- RNA Interference
- RNA, Small Interfering
(pharmacology)
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|