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Caffeine citrate enhanced cisplatin antitumor effects in osteosarcoma and fibrosarcoma in vitro and in vivo.
BMC Cancer ( IF 3.4 ) Pub Date : 2019-07-15 , DOI: 10.1186/s12885-019-5891-y Kensaku Abe 1 , Norio Yamamoto 1 , Katsuhiro Hayashi 1 , Akihiko Takeuchi 1 , Hiroyuki Tsuchiya 1
BMC Cancer ( IF 3.4 ) Pub Date : 2019-07-15 , DOI: 10.1186/s12885-019-5891-y Kensaku Abe 1 , Norio Yamamoto 1 , Katsuhiro Hayashi 1 , Akihiko Takeuchi 1 , Hiroyuki Tsuchiya 1
Affiliation
BACKGROUND
While multiagent chemotherapy has dramatically improved the prognosis of sarcoma, the novel chemotherapeutics have hardly developed over the past 30 years. Caffeine can induce apoptosis, delays in cell cycle progression and can enhance the cytocidal effects of anti-cancer agents. Citrate has been reported to enhance the cytocidal effect of cisplatin in gastric cancer in vitro. However its effect in sarcoma cells had not been reported.
METHODS
This study was designed to evaluate whether the addition of caffeine, citrate, or caffeine citrate to cisplatin improved its cytocidal effect (cell survival, proliferation, and apoptosis) on human osteosarcoma (HOS), human fibrosarcoma (HT1080) and murine osteosarcoma (LM8) cell lines. We also tested the various combinations in a mouse heterotopic transplantation model in vivo. In cell survival assay, combination index (CI) of caffeine citrate was calculated as a combination of anhydrous caffeine and citric acid, and the synergy was evaluated (CI < 1.0).
RESULTS
In all cell lines, cisplatin combined with caffeine citrate significantly reinforced the anticancer effect compared with cisplatin alone, combination of cisplatin and anhydrous caffeine, and combination of cisplatin and citric acid. Moreover, CI was < 1.0 in all conditions. The anticancer agent reinforcement effect of caffeine citrate was synergy of anhydrous caffeine and citric acid. In cell proliferation and cell cycle assay revealed that caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in inducing G0/G1 cell-cycle arrest with subsequent suppressed cell proliferation. In mitochondrial depolarization and caspase 3/7 activity assay revealed that caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in apoptosis associated with decreased mitochondrial membrane potential. In vivo, three different drug concentrations were tested, and cisplatin combined with caffeine citrate was found to have the strongest antitumor effect.
CONCLUSIONS
This is the first report demonstrating that caffeine citrate has a significantly greater potentiating effect on cisplatin than adding either caffeine or citric acid. The combination of cisplatin with caffeine citrate is a novel treatment that might hold promise for improving the outcome of osteosarcoma and fibrosarcoma, which up till now has generally not responded well to chemotherapy.
中文翻译:
柠檬酸咖啡因在体外和体内均可增强顺铂在骨肉瘤和纤维肉瘤中的抗肿瘤作用。
背景技术尽管多剂化学疗法显着改善了肉瘤的预后,但在过去的30年中几乎没有新的化学疗法。咖啡因可以诱导细胞凋亡,延缓细胞周期进程,并可以增强抗癌药的杀细胞作用。据报道,柠檬酸盐可增强顺铂在体外对胃癌的杀细胞作用。然而,尚未报道其在肉瘤细胞中的作用。方法本研究旨在评估在顺铂中添加咖啡因,柠檬酸盐或柠檬酸咖啡因是否能改善其对人骨肉瘤(HOS),人纤维肉瘤(HT1080)和鼠类骨肉瘤(LM8)的杀细胞作用(细胞存活,增殖和凋亡) ) 细胞系。我们还在小鼠异位移植模型中测试了各种组合。在细胞存活测定中,将咖啡因柠檬酸盐的组合指数(CI)计算为无水咖啡因和柠檬酸的组合,并评价了协同作用(CI <1.0)。结果在所有细胞系中,与单独的顺铂,顺铂和无水咖啡因的组合以及顺铂和柠檬酸的组合相比,顺铂联合柠檬酸咖啡因显着增强了抗癌作用。此外,在所有条件下,CI均<1.0。柠檬酸咖啡因的抗癌剂增强作用是无水咖啡因和柠檬酸的协同作用。在细胞增殖和细胞周期分析中,发现咖啡因柠檬酸盐作为组合药物比咖啡因和柠檬酸具有更强的诱导G0 / G1细胞周期停滞并随后抑制细胞增殖的作用。在线粒体去极化和caspase 3/7活性检测中,与咖啡因和柠檬酸组合使用的柠檬酸咖啡因作为联合药物,在与线粒体膜电位降低相关的凋亡中作用最强。在体内,测试了三种不同的药物浓度,发现顺铂与柠檬酸咖啡因的结合具有最强的抗肿瘤作用。结论这是第一个报道,证明柠檬酸咖啡因对顺铂的增强作用明显大于添加咖啡因或柠檬酸。顺铂与柠檬酸咖啡因的联合使用是一种新颖的治疗方法,可能有望改善骨肉瘤和纤维肉瘤的预后,到目前为止,它们对化学疗法的反应还不太好。
更新日期:2019-07-15
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
柠檬酸咖啡因在体外和体内均可增强顺铂在骨肉瘤和纤维肉瘤中的抗肿瘤作用。
背景技术尽管多剂化学疗法显着改善了肉瘤的预后,但在过去的30年中几乎没有新的化学疗法。咖啡因可以诱导细胞凋亡,延缓细胞周期进程,并可以增强抗癌药的杀细胞作用。据报道,柠檬酸盐可增强顺铂在体外对胃癌的杀细胞作用。然而,尚未报道其在肉瘤细胞中的作用。方法本研究旨在评估在顺铂中添加咖啡因,柠檬酸盐或柠檬酸咖啡因是否能改善其对人骨肉瘤(HOS),人纤维肉瘤(HT1080)和鼠类骨肉瘤(LM8)的杀细胞作用(细胞存活,增殖和凋亡) ) 细胞系。我们还在小鼠异位移植模型中测试了各种组合。在细胞存活测定中,将咖啡因柠檬酸盐的组合指数(CI)计算为无水咖啡因和柠檬酸的组合,并评价了协同作用(CI <1.0)。结果在所有细胞系中,与单独的顺铂,顺铂和无水咖啡因的组合以及顺铂和柠檬酸的组合相比,顺铂联合柠檬酸咖啡因显着增强了抗癌作用。此外,在所有条件下,CI均<1.0。柠檬酸咖啡因的抗癌剂增强作用是无水咖啡因和柠檬酸的协同作用。在细胞增殖和细胞周期分析中,发现咖啡因柠檬酸盐作为组合药物比咖啡因和柠檬酸具有更强的诱导G0 / G1细胞周期停滞并随后抑制细胞增殖的作用。在线粒体去极化和caspase 3/7活性检测中,与咖啡因和柠檬酸组合使用的柠檬酸咖啡因作为联合药物,在与线粒体膜电位降低相关的凋亡中作用最强。在体内,测试了三种不同的药物浓度,发现顺铂与柠檬酸咖啡因的结合具有最强的抗肿瘤作用。结论这是第一个报道,证明柠檬酸咖啡因对顺铂的增强作用明显大于添加咖啡因或柠檬酸。顺铂与柠檬酸咖啡因的联合使用是一种新颖的治疗方法,可能有望改善骨肉瘤和纤维肉瘤的预后,到目前为止,它们对化学疗法的反应还不太好。