Abstract
Triple-negative breast cancer is a subtype of breast cancer with poor clinical outcome, and currently, no effective targeted therapies are available. Since cancer develops owing to deregulation of apoptosis, employing therapeutic strategies with the ability to target the molecules involved in apoptosis induction would provide a valid approach to hinder tumor progression. Hydrazide-hydrazones and oxamide molecules are the subject of intense studies due to their anticancer effects via apoptosis induction. In the present study, we attempted to elucidate the mechanism of action of a synthesized compound (compound A) in inducing cell death. Annexin/PI and Western blotting analyses, DAPI staining, mitochondrial membrane potential probe, and flow cytometry were applied for the in vitro evaluations. 4T1 syngeneic mouse model and immunohistochemistry were used for the in vivo assessments. Compound A caused cell death by inducing apoptosis in MDA-MB-231 cells in a mitochondrial-dependent manner at high concentrations after 72 h of incubation. Compound A also impeded tumor growth in a 4T1 syngeneic mouse model as evidenced by hematoxylin and eosin staining of the tumors. Furthermore, it significantly diminished the expression of pro-caspase-3, Ki67, and CD31 markers in the tumor sections. Conclusively, this study for the first time reports the anti-cancer efficacy of compound A in both in vitro and in vivo models and its potential in the treatment of triple-negative breast cancer.
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Abbreviations
- ANOVA:
-
Analysis of variance
- CCCP:
-
Carbonyl cyanide 3-chlorophenylhydrazone
- DAPI:
-
4′,6-Diamidino-2-phenylindole
- DMEM:
-
Dulbecco’s Modified Eagle’s Medium
- DMSO:
-
Dimethyl sulfoxide
- EDTA:
-
Ethylenediaminetetraacetic acid
- FBS:
-
Fetal bovine serum
- H&E:
-
Hematoxylin and eosin
- HER2:
-
Human epidermal growth factor receptor 2
- IC50 :
-
Inhibitory concentration
- IHC:
-
Immunohistochemistry
- MMP:
-
Mitochondrial membrane potential
- NBF:
-
Neutral buffered formalin
- NCBI:
-
National Cell Bank of Pasture Institute of Iran
- PBS:
-
Phosphate-buffered saline
- PI:
-
Propidium iodide
- PVDF:
-
Polyvinylidene fluoride
- SDS-PAGE:
-
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
- SEM:
-
Standard error of mean
- TNBC:
-
Triple-negative breast cancer
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Acknowledgements
We would like to thank the Physiology and Pharmacology Department of Pasteur Institute of Iran for kindly supplying the experimental instruments.
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This work was financially supported by Pasteur Institute of Iran.
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RT made contributions to the biological experiments and collective data. SD and ZK contributed to the in vivo experiments. SAEN synthesized the compound. AA designed the structures. MS wrote the manuscript, provided the technical support, and supervised the whole project. The authors declare that all data were generated in-house and that no paper mill was used.
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Tahmasvand, R., Dehghani, S., Kooshafar, Z. et al. In vitro and in vivo activity of a novel oxamide-hydrazone hybrid derivative against triple-negative breast cancer. Naunyn-Schmiedeberg's Arch Pharmacol 397, 5119–5129 (2024). https://doi.org/10.1007/s00210-023-02931-6
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DOI: https://doi.org/10.1007/s00210-023-02931-6