The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells
<b>Background:</b> Breast and ovarian cancer stem cells (CSC) can contribute to the invasive and chemoresistance phenotype of tumors. TH1902, a newly developed sortilin (SORT1)-targeted peptide-docetaxel conjugate is currently in phase-1 clinical trial. Whether TH1902 impacts the chemore...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2022-09-01
|
Series: | Pharmaceutics |
Subjects: | |
Online Access: | https://www.mdpi.com/1999-4923/14/9/1910 |
_version_ | 1797483577378603008 |
---|---|
author | Michel Demeule Cyndia Charfi Jean-Christophe Currie Alain Zgheib Bogdan Alexandru Danalache Richard Béliveau Christian Marsolais Borhane Annabi |
author_facet | Michel Demeule Cyndia Charfi Jean-Christophe Currie Alain Zgheib Bogdan Alexandru Danalache Richard Béliveau Christian Marsolais Borhane Annabi |
author_sort | Michel Demeule |
collection | DOAJ |
description | <b>Background:</b> Breast and ovarian cancer stem cells (CSC) can contribute to the invasive and chemoresistance phenotype of tumors. TH1902, a newly developed sortilin (SORT1)-targeted peptide-docetaxel conjugate is currently in phase-1 clinical trial. Whether TH1902 impacts the chemoresistance phenotype of human triple-negative breast CSC (hTNBCSC) and ovarian CSC (hOvCSC) is unknown. <b>Methods and Results:</b> Immunophenotyping of hTNBCSC and hOvCSC was performed by flow cytometry and confirmed the expression of SORT1, and of CSC markers CD133, NANOG, and SOX2. Western blotting demonstrated the expression of the drug efflux pumps from the P-gp family members, ABCB1 and ABCB5. The cellular uptake of the fluorescent Alexa<sup>488</sup>-peptide from TH1902 was inhibited upon siRNA-mediated repression of <i>SORT1</i> or upon competition with SORT1 ligands. In contrast to docetaxel, TH1902 inhibited in vitro migration, induced cell apoptosis and lead to G2/M cell cycle arrest of the hTNBCSC. These events were unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. In vivo, using immunosuppressed nude mice xenografts, TH1902 significantly inhibited the growth of hTNBCSC and hOvCSC xenografts (~80% vs. ~35% for docetaxel) when administered weekly as intravenous bolus for three cycles at 15 mg/kg, a dose equivalent to the maximal tolerated dose of docetaxel. Therapeutic efficacy was further observed when carboplatin was combined to TH1902. <b>Conclusions:</b> Overall, TH1902 exerts a superior anticancer activity than the unconjugated docetaxel, in part, by circumventing the CSC drug resistance phenotype that could potentially reduce cancer recurrence attributable to CSC. |
first_indexed | 2024-03-09T22:49:01Z |
format | Article |
id | doaj.art-0b8a08e7364d4c5baf46b5c7fe2801e9 |
institution | Directory Open Access Journal |
issn | 1999-4923 |
language | English |
last_indexed | 2024-03-09T22:49:01Z |
publishDate | 2022-09-01 |
publisher | MDPI AG |
record_format | Article |
series | Pharmaceutics |
spelling | doaj.art-0b8a08e7364d4c5baf46b5c7fe2801e92023-11-23T18:22:49ZengMDPI AGPharmaceutics1999-49232022-09-01149191010.3390/pharmaceutics14091910The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like CellsMichel Demeule0Cyndia Charfi1Jean-Christophe Currie2Alain Zgheib3Bogdan Alexandru Danalache4Richard Béliveau5Christian Marsolais6Borhane Annabi7Theratechnologies Inc., Montréal, QC H3A 1T8, CanadaTheratechnologies Inc., Montréal, QC H3A 1T8, CanadaTheratechnologies Inc., Montréal, QC H3A 1T8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montréal, QC H3C 3P8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montréal, QC H3C 3P8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montréal, QC H3C 3P8, CanadaTheratechnologies Inc., Montréal, QC H3A 1T8, CanadaLaboratoire d’Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montréal, QC H3C 3P8, Canada<b>Background:</b> Breast and ovarian cancer stem cells (CSC) can contribute to the invasive and chemoresistance phenotype of tumors. TH1902, a newly developed sortilin (SORT1)-targeted peptide-docetaxel conjugate is currently in phase-1 clinical trial. Whether TH1902 impacts the chemoresistance phenotype of human triple-negative breast CSC (hTNBCSC) and ovarian CSC (hOvCSC) is unknown. <b>Methods and Results:</b> Immunophenotyping of hTNBCSC and hOvCSC was performed by flow cytometry and confirmed the expression of SORT1, and of CSC markers CD133, NANOG, and SOX2. Western blotting demonstrated the expression of the drug efflux pumps from the P-gp family members, ABCB1 and ABCB5. The cellular uptake of the fluorescent Alexa<sup>488</sup>-peptide from TH1902 was inhibited upon siRNA-mediated repression of <i>SORT1</i> or upon competition with SORT1 ligands. In contrast to docetaxel, TH1902 inhibited in vitro migration, induced cell apoptosis and lead to G2/M cell cycle arrest of the hTNBCSC. These events were unaffected by the presence of the P-gp inhibitors cyclosporine A or PSC-833. In vivo, using immunosuppressed nude mice xenografts, TH1902 significantly inhibited the growth of hTNBCSC and hOvCSC xenografts (~80% vs. ~35% for docetaxel) when administered weekly as intravenous bolus for three cycles at 15 mg/kg, a dose equivalent to the maximal tolerated dose of docetaxel. Therapeutic efficacy was further observed when carboplatin was combined to TH1902. <b>Conclusions:</b> Overall, TH1902 exerts a superior anticancer activity than the unconjugated docetaxel, in part, by circumventing the CSC drug resistance phenotype that could potentially reduce cancer recurrence attributable to CSC.https://www.mdpi.com/1999-4923/14/9/1910breast cancercancer stem cellsdocetaxelmultidrug resistanceovarian cancerpeptide-drug conjugate |
spellingShingle | Michel Demeule Cyndia Charfi Jean-Christophe Currie Alain Zgheib Bogdan Alexandru Danalache Richard Béliveau Christian Marsolais Borhane Annabi The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells Pharmaceutics breast cancer cancer stem cells docetaxel multidrug resistance ovarian cancer peptide-drug conjugate |
title | The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells |
title_full | The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells |
title_fullStr | The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells |
title_full_unstemmed | The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells |
title_short | The TH1902 Docetaxel Peptide-Drug Conjugate Inhibits Xenografts Growth of Human SORT1-Positive Ovarian and Triple-Negative Breast Cancer Stem-like Cells |
title_sort | th1902 docetaxel peptide drug conjugate inhibits xenografts growth of human sort1 positive ovarian and triple negative breast cancer stem like cells |
topic | breast cancer cancer stem cells docetaxel multidrug resistance ovarian cancer peptide-drug conjugate |
url | https://www.mdpi.com/1999-4923/14/9/1910 |
work_keys_str_mv | AT micheldemeule theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT cyndiacharfi theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT jeanchristophecurrie theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT alainzgheib theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT bogdanalexandrudanalache theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT richardbeliveau theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT christianmarsolais theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT borhaneannabi theth1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT micheldemeule th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT cyndiacharfi th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT jeanchristophecurrie th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT alainzgheib th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT bogdanalexandrudanalache th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT richardbeliveau th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT christianmarsolais th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells AT borhaneannabi th1902docetaxelpeptidedrugconjugateinhibitsxenograftsgrowthofhumansort1positiveovarianandtriplenegativebreastcancerstemlikecells |