Mohammadi A, Yaghoobi M M, GholamhoseynianNajar A, Kalantari-Khandani B, Sharifi H, Saravani M
Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
Research Department of Biotechnology, Institute of Sciences and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran.
Cell Mol Biol (Noisy-le-grand). 2016 Oct 31;62(12):62-67. doi: 10.14715/cmb/2016.62.12.11.
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.
由于结直肠癌（CRC）的高发病率和死亡率，联合治疗等新的治疗方法似乎很有必要。慢性炎症与结直肠癌发生和发展之间的关系已被证明很重要。塞来昔布是一种选择性COX-2抑制剂，是唯一已被批准用于癌症治疗和预防的非甾体抗炎药（NSAID）。由于COX-2抑制剂的心血管副作用，联合治疗可能会改善治疗效果。17-去甲氧基-17-烯丙基氨基格尔德霉素（17-AAG）是一种热休克蛋白90（HSP90）抑制剂，通过下调炎症关键介质如核因子κB（NF-κB）、JAK/信号转导子和转录激活子（JAK/STAT）发挥抗炎作用。因此，我们研究了17-AAG与塞来昔布联合使用对HT-29细胞活力和凋亡诱导的影响。基于MTT结果，我们发现塞来昔布与17-AAG联合使用时，其抑制作用增强，尤其是在低浓度塞来昔布时。流式细胞术分析表明，凋亡诱导可能是17-AAG与塞来昔布联合使用产生相加抑制作用的机制。为了探究17-AAG与塞来昔布联合诱导凋亡的可能机制，通过蛋白质印迹法测定BAX和BCL-2蛋白水平。联合治疗组的BAX/BCL-2比值相较于单独使用17-AAG或塞来昔布时升高，主要是通过降低BCL-2水平实现的。总之，17-AAG可能通过诱导凋亡增强了塞来昔布对HT-29细胞的抑制作用。
