Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo.
Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo.
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新型口服铁螯合剂Deferasirox在体外和体内表现出针对胰腺癌的抗增殖活性。
DOI：
10.1186/s12885-016-2744-9
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发表时间：
2016-08-31
期刊：
影响因子：
3.8
通讯作者：
Sakaida I
中科院分区：
文献类型：
--
作者：
Harima H;Kaino S;Takami T;Shinoda S;Matsumoto T;Fujisawa K;Yamamoto N;Yamasaki T;Sakaida I
铁是细胞复制、新陈代谢和生长所必需的。由于肿瘤细胞的快速增殖对铁的需求量很大，因此缺铁可能是一种新的癌症治疗策略。一种新型口服铁螯合剂铁asirox （DFX）在铁超载患者的临床试验中取得了成功，有望成为一种抗癌药物。然而，没有研究调查DFX对胰腺癌的影响。本研究旨在阐明DFX对胰腺癌的作用。在3种人胰腺癌细胞系BxPC-3、hpf - ii和Panc 10.05中检测了DFX对细胞周期、增殖和凋亡的影响。我们还在裸鼠实验中检测了口服DFX对BxPC-3胰腺癌异种移植物生长的影响。此外，使用从异种移植物中切除的肿瘤进行微阵列分析。DFX以剂量依赖的方式抑制胰腺癌细胞增殖。浓度为10 μM的DFX使细胞周期停留在S期，而浓度为50和100 μM的DFX则诱导细胞凋亡。在裸鼠中，口服160和200 mg/kg的DFX抑制了异种移植物肿瘤的生长，没有严重的副作用（n = 5；对照组平均肿瘤体积为674 mm3，而160 mg/kg DFX组为327 mm3， p <0.05；对照组平均肿瘤体积为674 mm3，而200 mg/kg DFX组为274 mm3， p <0.05）。重要的是，血清生化分析表明，口服160或200 mg/kg DFX显著降低血清铁蛋白水平（n = 5；对照组平均血清铁蛋白为18 ng/ml，对照组为9 ng/ml， p <0.05；对照组平均血清铁蛋白为18 ng/ml，对照组为200 mg/kg DFX为10 ng/ml， p <0.05）。基因表达分析显示，DFX下调了胰腺腺癌信号传导的大部分基因，尤其是TGF-ß1。DFX具有作为胰腺癌治疗剂的潜力。在临床前模型中，铁消耗对DFX的抗增殖作用至关重要，DFX通过抑制TGF-ß信号传导起作用。
Iron is essential for cell replication, metabolism and growth. Because neoplastic cells have high iron requirements due to their rapid proliferation, iron depletion may be a novel therapeutic strategy for cancer. Deferasirox (DFX), a novel oral iron chelator, has been successful in clinical trials in iron-overload patients and has been expected to become an anticancer agent. However, no studies have investigated the effects of DFX on pancreatic cancer. This study aimed to elucidate the effects of DFX against pancreatic cancer. The effects of DFX on cell cycle, proliferation, and apoptosis were examined in three human pancreatic cancer cell lines: BxPC-3, HPAF-II, and Panc 10.05. The effect of orally administered DFX on the growth of BxPC-3 pancreatic cancer xenografts was also examined in nude mice. Additionally, microarray analysis was performed using tumors excised from xenografts. DFX inhibited pancreatic cancer cell proliferation in a dose-dependent manner. A concentration of 10 μM DFX arrested the cell cycle in S phase, whereas 50 and 100 μM DFX induced apoptosis. In nude mice, orally administered DFX at 160 and 200 mg/kg suppressed xenograft tumor growth with no serious side effects (n = 5; average tumor volumes of 674 mm3 for controls vs. 327 mm3 for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm3 for controls vs. 274 mm3 for 200 mg/kg DFX, p <0.05). Importantly, serum biochemistry analysis indicated that serum levels of ferritin were significantly decreased by the oral administration of 160 or 200 mg/kg DFX (n = 5; average serum ferritin of 18 ng/ml for controls vs. 9 ng/ml for 160 mg/kg DFX, p <0.05; average serum ferritin of 18 ng/ml for controls vs. 10 ng/ml for 200 mg/kg DFX, p <0.05). Gene expression analysis revealed that most genes in pancreatic adenocarcinoma signaling, especially transforming growth factor-ß1 (TGF-ß1), were downregulated by DFX. DFX has potential as a therapeutic agent for pancreatic cancer. Iron depletion was essential for the antiproliferative effect of DFX in a preclinical model, and DFX acted through the suppression of TGF-ß signaling.
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作者：
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