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Homoharringtonine, an approved anti-leukemia drug, suppresses triple negative breast cancer growth through a rapid reduction of anti-apoptotic protein abundance

Authors :
Radosevic-Robin, Nina
Penault-Llorca, Frederique
Cachin, Florent
Miot-Noirault, Elisabeth
Kwiatkowski, Fabrice
Furtado, Ludivine
El Guerrab, Abderrahim
Arnaud BRIAT
Yakhni, Mohamad
Chezal, Jean-Michel
Imagerie Moléculaire et Stratégies Théranostiques (IMoST)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP)
UNICANCER
service de recherche clinique
UNICANCER-UNICANCER
Source :
American Journal of Cancer Research, American Journal of Cancer Research, e-Century Publishing, 2019, 9 (5), pp.1043-1060, Publons
Publication Year :
2019
Publisher :
HAL CCSD, 2019.

Abstract

International audience; Triple negative breast cancers (TNBC) without BRCA1/2 gene mutation or BRCAness are nowadays the breast malignancies most difficult to treat. Improvement of their treatment, for all phases of the disease, is an important unmet medical need. We analyzed the effect of homoharringtonine (HHT), a natural protein synthesis inhibitor approved for treatment of chronic myeloid leukemia, on four cell lines representing aggressive, BRCA1/2 non-mutated, TNBC genomic categories. We show that HHT inhibits in vitro growth of all cell lines for more than 80%, after 48-72 h exposure to 20-100 ng/mL, the concentrations achievable in human plasma after subcutaneous administration of the drug. HHT, at 100 ng/mL, strongly reduced levels of a major TNBC survival factor, anti-apoptotic protein Mcl-1, after only 2 h of exposure, in all cell lines except MDA-MB-231. Other anti-apoptotic proteins, Bcl-2, survivin and XIAP, were also strongly downregulated. Moreover, in vivo growth of the least sensitive cell line to HHT in vitro, MDA-MB-231, was inhibited for 36.5% in mice, by 1 mg/kg of the drug, given subcutaneously, bi-daily, over 7 days. These results demonstrate marked antineoplastic activity of homoharringtonine in TNBC, making further development of the drug in this disease highly warranted.

Details

Language :
English
ISSN :
21566976
Database :
OpenAIRE
Journal :
American Journal of Cancer Research, American Journal of Cancer Research, e-Century Publishing, 2019, 9 (5), pp.1043-1060, Publons
Accession number :
edsair.pmid.dedup....d77e4451866ec105e598f579903dff45