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Simultaneous NF-κB inhibition and E-cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo.
- Source :
-
International journal of cancer [Int J Cancer] 2014 Oct 01; Vol. 135 (7), pp. 1721-32. Date of Electronic Publication: 2014 Mar 07. - Publication Year :
- 2014
-
Abstract
- Suberoylanilide hydroxamic acid (SAHA) is a promising histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA) and whose clinical application for solid tumours is partially limited by decreased susceptibility in cancer cells due to nuclear factor (NF)-κB activation. As an NF-κB inhibitor, celastrol exhibits potent anticancer effects but has failed to enter clinical trials due to its toxicity. In this report, we demonstrated that the combination of celastrol and SAHA exerted substantial synergistic efficacy against human cancer cells in vitro and in vivo accompanied by enhanced caspase-mediated apoptosis. This drug combination inhibited the activation of NF-κB caused by SAHA monotherapy and consequently led to increased apoptosis in cancer cells. Interestingly, E-cadherin was dramatically downregulated in celastrol-resistant cancer cells, and E-cadherin expression was closely related to decreased sensitivity to celastrol. However, our combination treatment significantly augmented the expression of E-cadherin, suggesting that mutual mechanisms contributed to the synergistic anticancer activity. Furthermore, the enhanced anticancer efficacy of celastrol combined with SAHA was validated in a human lung cancer 95-D xenograft model without increased toxicity. Taken together, our data demonstrated the synergistic anticancer effects of celastrol and SAHA due to their reciprocal sensitisation, which was simultaneously regulated by NF-κB and E-cadherin; thus, the combination of celastrol and SAHA was superior to other combination regimens that rely on a single mechanism. Our findings not only open new opportunities for the clinical development of SAHA but should also motivate the clinical investigation of celastrol, which has been hampered by its toxicity.<br /> (© 2014 UICC.)
- Subjects :
- Animals
Apoptosis drug effects
Blotting, Western
Cadherins genetics
Cell Proliferation drug effects
Drug Synergism
Female
Flow Cytometry
Humans
Immunoenzyme Techniques
In Vitro Techniques
Lung Neoplasms metabolism
Lung Neoplasms pathology
Mice
Mice, Nude
NF-kappa B genetics
NF-kappa B metabolism
Pentacyclic Triterpenes
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tripterygium chemistry
Tumor Cells, Cultured
Vorinostat
Cadherins metabolism
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors pharmacology
Hydroxamic Acids pharmacology
Lung Neoplasms drug therapy
NF-kappa B antagonists & inhibitors
Triterpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 135
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 24615207
- Full Text :
- https://doi.org/10.1002/ijc.28810