Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer

Autor: Ji Young Kim, Hyunsook An, Nahyun Lee, Eunhye Oh, Jae Hong Seo, Youngkwan Cho, Tae Min Cho, Daeil Sung
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Time Factors
Receptor
ErbB-2
Acetaldehyde Dehydrogenase Inhibitors
Mice
Nude
Apoptosis
Breast Neoplasms
Pharmacology
Biology
Aldehyde Dehydrogenase 1 Family
03 medical and health sciences
0302 clinical medicine
Cancer stem cell
Antineoplastic Combined Chemotherapy Protocols
Disulfiram
medicine
Animals
Humans
Phosphorylation
skin and connective tissue diseases
Protein kinase B
Mice
Inbred BALB C
Dose-Response Relationship
Drug
Akt/PKB signaling pathway
Retinal Dehydrogenase
Cancer
Aldehyde Dehydrogenase
medicine.disease
Xenograft Model Antitumor Assays
Tumor Burden
ALDH1A1
Phenotype
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer cell
MCF-7 Cells
Neoplastic Stem Cells
biology.protein
Female
Signal transduction
Proto-Oncogene Proteins c-akt
Copper
Cyclin-Dependent Kinase Inhibitor p27
Signal Transduction
Zdroj: Cancer Letters. 379:39-48
ISSN: 0304-3835
Popis: HER2-positive breast tumors are known to harbor cancer stem-like cell populations and are associated with an aggressive tumor phenotype and poor clinical outcomes. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in many cancer cell types in the presence of copper (Cu). The objective of the present study was to investigate the mechanism of action responsible for the induction of apoptosis by DSF/Cu and its effect on cancer stem cell properties in HER2-positive breast cancers in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a marked decrease in HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels, and p27 nuclear accumulation. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere formation. DSF administration resulted in a significant reduction in tumor growth and an enhancement of apoptosis, as well as HER2 intracellular domain (ICD) and ALDH1A1 downregulation. Our results demonstrate that DSF/Cu induces apoptosis and eliminates cancer stem-like cells via the suppression of HER2/Akt signaling, suggesting that DSF may be potentially effective for the treatment of HER2-positive cancers.
Databáze: OpenAIRE
Externí odkaz: