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Genistein sensitizes bladder cancer cells to HCPT treatment in vitro and in vivo via ATM/NF-κB/IKK pathway-induced apoptosis.
- Source :
-
PloS one [PLoS One] 2013; Vol. 8 (1), pp. e50175. Date of Electronic Publication: 2013 Jan 24. - Publication Year :
- 2013
-
Abstract
- Bladder cancer is the most common malignant urological disease in China. Hydroxycamptothecin (HCPT) is a DNA topoisomerase I inhibitor, which has been utilized in chemotherapy for bladder cancer for nearly 40 years. Previous research has demonstrated that the isoflavone, genistein, can sensitize multiple cancer cell lines to HCPT treatment, such as prostate and cervical cancer. In this study, we investigated whether genistein could sensitize bladder cancer cell lines and bladder epithelial cell BDEC cells to HCPT treatment, and investigated the possible underlying molecular mechanisms. Genistein could significantly and dose-dependently sensitize multiple bladder cancer cell lines and BDEC cells to HCPT-induced apoptosis both in vitro and in vivo. Genistein and HCPT synergistically inhibited bladder cell growth and proliferation, and induced G2/M phase cell cycle arrest and apoptosis in TCCSUP bladder cancer cell and BDEC cell. Pretreatment with genistein sensitized BDEC and bladder cancer cell lines to HCPT-induced DNA damage by the synergistic activation of ataxia telangiectasia mutated (ATM) kinase. Genistein significantly attenuated the ability of HCPT to induce activation of the anti-apoptotic NF-κB pathway both in vitro and in vivo in a bladder cancer xenograft model, and thus counteracted the anti-apoptotic effect of the NF-κB pathway. This study indicates that genistein could act as a promising non-toxic agent to improve efficacy of HCPT bladder cancer chemotherapy.
- Subjects :
- Animals
Apoptosis drug effects
Ataxia Telangiectasia Mutated Proteins
Camptothecin pharmacology
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Line, Tumor
DNA Fragmentation drug effects
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm drug effects
Drug Synergism
G2 Phase Cell Cycle Checkpoints drug effects
Humans
I-kappa B Kinase genetics
I-kappa B Kinase metabolism
Mice
Mice, Nude
NF-kappa B genetics
NF-kappa B metabolism
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Urinary Bladder Neoplasms genetics
Urinary Bladder Neoplasms metabolism
Urinary Bladder Neoplasms pathology
Xenograft Model Antitumor Assays
Antineoplastic Agents, Phytogenic pharmacology
Camptothecin analogs & derivatives
Gene Expression Regulation, Neoplastic drug effects
Genistein pharmacology
Signal Transduction drug effects
Topoisomerase I Inhibitors pharmacology
Urinary Bladder Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23365634
- Full Text :
- https://doi.org/10.1371/journal.pone.0050175