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Vorinostat and Simvastatin have synergistic effects on triple-negative breast cancer cells via abrogating Rab7 prenylation
- Source :
- European journal of pharmacology. 813
- Publication Year :
- 2017
-
Abstract
- Since the lack of targeted treatment, triple-negative breast cancer (TNBC) has poor outcomes. Histone deacetylase inhibitors (HDACi) blocking the activity of specific HDACs have emerged as cancer therapeutic agents. However, the therapeutic efficiency is still not satisfactory for patients with solid tumor. We thus performed screening for the synergistic agents of Vorinostat (SAHA). The resulting candidate Simvastatin was obtained. The efficacy and mechanism of combination have been studied in TNBC cells. The synergism of SAHA and Simvastatin was evaluated by IC50 of proliferation and combination index (CI). The antitumor activities of combination were further evaluated in TNBC cells. The pro-apoptotic effects were determined by flow cytometry and Western blot. Autophagosome-lysosome fusion was monitored using confocal microscope. The underlying mechanism was further studied by over-expressing of wild-type or inactive (C205S/C207S) Rab7 in compounds treated cells. The in vivo efficacy was also evaluated in mice. The combination of SAHA and Simvastatin had potent synergism in apoptosis of TNBC cells. It exerted pro-apoptosis effect by compromising the fusion between autophagosome and lysosome. Over-expressing of wild-type, but not inactive Rab7 rescued cells from apoptosis induced by the combinatory treatments. Mevalonate supplementation also decreased the combinatory treatment-induced apoptosis. These results indicate that the combinatory treatment enhances the apoptosis of TNBC cells by interrupting Rab7 prenylation and obstructing autophagosome-lysosome fusion. Combination between SAHA and Simvastatin could also significantly decrease the tumor growth in xenografted mice by inducing apoptosis and inhibiting Rab7 prenylation. Rab7 is a potential target for the combined effects of Simvastatin and SAHA.
- Subjects :
- 0301 basic medicine
Simvastatin
Protein Prenylation
Apoptosis
Triple Negative Breast Neoplasms
Biology
Pharmacology
Hydroxamic Acids
Flow cytometry
03 medical and health sciences
Mice
0302 clinical medicine
Prenylation
In vivo
Cell Line, Tumor
medicine
Autophagy
Animals
Humans
Vorinostat
Triple-negative breast cancer
Cell Proliferation
medicine.diagnostic_test
Autophagosomes
Cancer
rab7 GTP-Binding Proteins
medicine.disease
Xenograft Model Antitumor Assays
Histone Deacetylase Inhibitors
030104 developmental biology
rab GTP-Binding Proteins
030220 oncology & carcinogenesis
Female
Lysosomes
medicine.drug
Subjects
Details
- ISSN :
- 18790712
- Volume :
- 813
- Database :
- OpenAIRE
- Journal :
- European journal of pharmacology
- Accession number :
- edsair.doi.dedup.....56214166b2701b6c142979d9956f2176