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.
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.
Authors: T Dan; S M Hewitt; N Ohri; D Ly; B P Soule; S L Smith; K Matsuda; C Council; U Shankavaram; M E Lippman; J B Mitchell; K Camphausen; N L Simone Journal: Breast Cancer Res Treat Date: 2013-11-26 Impact factor: 4.872
Authors: Laura Nelson; Hayley D McKeen; Andrea Marshall; Laoighse Mulrane; Jane Starczynski; Sarah J Storr; Fiona Lanigan; Christopher Byrne; Ken Arthur; Shauna Hegarty; Ahlam Abdunnabi Ali; Fiona Furlong; Helen O McCarthy; Ian O Ellis; Andrew R Green; Emad Rakha; Leonie Young; Ian Kunkler; Jeremy Thomas; Wilma Jack; David Cameron; Karin Jirström; Anita Yakkundi; Lana McClements; Stewart G Martin; William M Gallagher; Janet Dunn; John Bartlett; Darran O'Connor; Tracy Robson Journal: Oncotarget Date: 2015-05-20
Authors: Abdelrahim Alqudah; Kelly-Ann Eastwood; Djurdja Jerotic; Naomi Todd; Denise Hoch; Ross McNally; Danilo Obradovic; Stefan Dugalic; Alyson J Hunter; Valerie A Holmes; David R McCance; Ian S Young; Chris J Watson; Tracy Robson; Gernot Desoye; David J Grieve; Lana McClements Journal: Front Endocrinol (Lausanne) Date: 2021-06-02 Impact factor: 5.555
Authors: Linda Smit; Katrien Berns; Katherine Spence; W David Ryder; Nik Zeps; Mandy Madiredjo; Roderick Beijersbergen; René Bernards; Robert B Clarke Journal: Oncotarget Date: 2016-01-19