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Simvastatin-romidepsin combination kills bladder cancer cells synergistically
- Source :
- Translational Oncology, Translational Oncology, Vol 14, Iss 9, Pp 101154-(2021)
- Publication Year :
- 2021
- Publisher :
- Neoplasia Press, 2021.
-
Abstract
- Highlights • Simvastatin-romidepsin combination kills bladder cancer cells synergistically. • The combination induces histone acetylation by activating AMPK. • AMPK activation and histone acetylation are associated with ER stress induction. • Positive feedback cycle between ER stress induction and PPARγ expression.<br />The HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. We postulated that combining simvastatin with the histone deacetylase (HDAC) inhibitor romidepsin would kill bladder cancer cells by inducing histone acetylation cooperatively. The combination of romidepsin and simvastatin induced robust apoptosis and killed bladder cancer cells synergistically. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment with 0.5 mg/kg romidepsin and 15 mg/kg simvastatin was well tolerated and inhibited tumor growth significantly. Mechanistically, the combination induced histone acetylation by activating AMPK. The combination also decreased the expression of HDACs, thus further promoting histone acetylation. This AMPK activation was essential for the combination's action because compound C, an AMPK inhibitor, suppressed the combination-induced histone acetylation and the combination's ability to induce apoptosis. We also found that the combination increased the expression of peroxisome proliferator-activated receptor (PPAR) γ, leading to reactive oxygen species production. Furthermore, the combination induced endoplasmic reticulum (ER) stress and this ER stress was shown to be associated with increased AMPK expression and histone acetylation, thus playing an important role in the combination's action. Our study also suggests there is a positive feedback cycle between ER stress induction and PPARγ expression.
- Subjects :
- 0301 basic medicine
Cancer Research
Simvastatin
p-H2AX, phosphorylated histone H2AX
Peroxisome proliferator-activated receptor
HDAC, histone deacetylase
PPAR, peroxisome proliferator-activated receptor
DMSO, dimethyl sulfoxide
Romidepsin
ER, endoplasmic reticulum
03 medical and health sciences
0302 clinical medicine
ROS, reactive oxygen species
CHX, cycloheximide
GRP, glucose-regulated protein
HE, hematoxylin-eosin
AMP-activated protein kinase (AMPK)
medicine
Peroxisome proliferator-activated receptor (PPAR) γ
RC254-282
Original Research
CDK, cyclin-dependent kinase
chemistry.chemical_classification
p-AMPK, phosphorylated AMP-activated protein kinase
biology
7-AAD, 7-amino-actinomycin D
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
AMPK
CI, combination index
Endoplasmic reticulum (ER) stress
AMPK, AMP-activated protein kinase
030104 developmental biology
Histone
Oncology
chemistry
Histone acetylation
ERp, endoplasmic reticulum resident protein
Acetylation
030220 oncology & carcinogenesis
Unfolded protein response
biology.protein
Cancer research
Histone deacetylase
FITC, fluorescein isothiocyanate
DHE, dihydroethidium
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19365233
- Volume :
- 14
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Translational Oncology
- Accession number :
- edsair.doi.dedup.....e307f591ff280827973e9d9fbb9adae0