Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway.
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). EXPERIMENTAL DESIGN: Mammosphere assays...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2013
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| _version_ | 1797065496510595072 |
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| author | McClements, L Yakkundi, A Papaspyropoulos, A Harrison, H Ablett, M Jithesh, P McKeen, H Bennett, R Donley, C Kissenpfennig, A McIntosh, S McCarthy, H O'Neill, E Clarke, R Robson, T |
| author_facet | McClements, L Yakkundi, A Papaspyropoulos, A Harrison, H Ablett, M Jithesh, P McKeen, H Bennett, R Donley, C Kissenpfennig, A McIntosh, S McCarthy, H O'Neill, E Clarke, R Robson, T |
| author_sort | McClements, L |
| collection | OXFORD |
| description | 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). 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. 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. CONCLUSIONS: AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial. |
| first_indexed | 2024-03-06T21:29:26Z |
| format | Journal article |
| id | oxford-uuid:442b87b0-a581-4914-93ad-7ee274e2ff81 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:29:26Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:442b87b0-a581-4914-93ad-7ee274e2ff812022-03-26T15:00:00ZTargeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:442b87b0-a581-4914-93ad-7ee274e2ff81EnglishSymplectic Elements at Oxford2013McClements, LYakkundi, APapaspyropoulos, AHarrison, HAblett, MJithesh, PMcKeen, HBennett, RDonley, CKissenpfennig, AMcIntosh, SMcCarthy, HO'Neill, EClarke, RRobson, TPURPOSE: 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). 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. 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. CONCLUSIONS: AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial. |
| spellingShingle | McClements, L Yakkundi, A Papaspyropoulos, A Harrison, H Ablett, M Jithesh, P McKeen, H Bennett, R Donley, C Kissenpfennig, A McIntosh, S McCarthy, H O'Neill, E Clarke, R Robson, T Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. |
| title | Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. |
| title_full | Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. |
| title_fullStr | Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. |
| title_full_unstemmed | Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. |
| title_short | Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. |
| title_sort | targeting treatment resistant breast cancer stem cells with fkbpl and its peptide derivative ad 01 via the cd44 pathway |
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