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Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2013 Jul 15; Vol. 19 (14), pp. 3881-93. Date of Electronic Publication: 2013 Jun 05. - Publication Year :
- 2013
-
Abstract
- Purpose: FK506-binding protein like (FKBPL) and its peptide derivative, AD-01, have already shown tumor growth inhibition and CD44-dependent antiangiogenic activity. Here, we explore the ability of AD-01 to target CD44-positive breast cancer stem cells (BCSC).<br />Experimental Design: Mammosphere assays and flow cytometry were used to analyze the effect of FKBPL overexpression/knockdown and AD-01 treatment ± other anticancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples, and xenografts. Delays in tumor initiation were evaluated in vivo. The anti-stem cell mechanisms were determined using clonogenic assays, quantitative PCR (qPCR), and immunofluorescence.<br />Results: AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere-forming efficiency and ESA(+)/CD44(+)/CD24(-) or aldehyde dehydrogenase (ALDH)(+) cell subpopulations in vitro and tumor initiation in vivo. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism seems to be due to AD-01-mediated BCSC differentiation shown by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4, and Sox2, were also significantly reduced. Furthermore, we showed additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo- and radiotherapy-induced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signaling.<br />Conclusions: AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial.
- Subjects :
- Animals
Breast Neoplasms metabolism
Breast Neoplasms mortality
Drug Resistance, Neoplasm
Female
Humans
Immunophilins metabolism
MCF-7 Cells
Mice
Mice, SCID
Radiation Tolerance
Receptors, Notch antagonists & inhibitors
Receptors, Notch metabolism
Signal Transduction
Spheroids, Cellular drug effects
Tacrolimus Binding Proteins
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Breast Neoplasms drug therapy
Hyaluronan Receptors metabolism
Immunophilins pharmacology
Neoplastic Stem Cells drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 19
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 23741069
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-13-0595