title: HSP90 inhibitor enhances anti-proliferative and apoptotic effects of celecoxib on HT-29 colorectal cancer cells via increasing BAX/BCL-2 ratio.
abstract: Due to the high prevalence and mortality rate of colorectal cancer (CRC), new treatment approaches like combination therapy seem to be necessary. The relationship between chronic inflammation and colorectal cancer development and progression has been shown to be important. Celecoxib, a selective COX-2 inhibitor, is the only non-steroidal anti-inflammatory drug (NSAID) that has been approved for cancer therapy and prevention. Because of cardiovascular side effects of COX-2 inhibitors, combination therapy may improve the therapeutic profile. 17-Demethoxy-17-allylamino geldanamycin (17-AAG), a heat shock protein 90 (HSP90) inhibitor, shows anti-inflammatory effects via down-regulation of the key mediators of inflammation such as Nuclear Factor κB (NF-kB), JAK/Signal Transducer and Activator of Transcription (JAK/STAT). Thus, we studied the effect(s) of combination of 17-AAG and celecoxib on HT-29 cells viability and apoptosis induction. Based on MTT results, we showed an increase in the inhibitory effect of celecoxib when combined with 17-AAG, especially at low a concentration of celecoxib.  Flow cytometry analysis demonstrated that apoptosis induction is probably the mechanism of additive inhibitory effects of 17-AAG and celecoxib combination. To explore the possible mechanism of apoptosis induction by 17-AAG and celecoxib combination, levels of BAX and BCL-2 proteins were determined by western blotting. The BAX/BCL-2 ratio in the combination group was increased compared to 17-AAG or celecoxib alone, mainly via decreasing BCL-2 levels. In conclusion, 17-AAG, increased inhibitory effects of celecoxib on HT-29 cells, probably by induction of apoptosis.
authors.affiliation: Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Mohammadi
authors.affiliation: Research Department of Biotechnology, Institute of Sciences and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran.
authors.forename: M M
authors.initials: MM
authors.lastname: Yaghoobi
authors.affiliation: Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: A
authors.initials: A
authors.lastname: GholamhoseynianNajar
authors.affiliation: Department of Oncology and Hematology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: B
authors.initials: B
authors.lastname: Kalantari-Khandani
authors.affiliation: Modeling in Health Research Center, Institute of Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran.
authors.forename: H
authors.initials: H
authors.lastname: Sharifi
authors.affiliation: Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran. moh.saravani@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Saravani
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D000068579:Celecoxib / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D052246:Cyclooxygenase 2 Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C112765:tanespimycin; D000068579:Celecoxib