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Auranofin-Based Analogues Are Effective Against Clear Cell Renal Carcinoma In Vivo and Display No Significant Systemic Toxicity.
ACS Pharmacology & Translational Science Pub Date : 2020-04-09 , DOI: 10.1021/acsptsci.9b00107
Benelita T Elie 1, 2 , Karen Hubbard 2, 3 , Buddhadev Layek 4 , Won Seok Yang 5 , Swayam Prabha 4 , Joe W Ramos 5 , Maria Contel 1, 2, 2, 2, 5
Affiliation  

Effective pharmacological treatments for patients with advanced clear cell renal carcinoma (ccRCC) are limited. Bimetallic titanium–gold containing compounds exhibit significant cytotoxicity against ccRCC in vitro and in vivo and inhibit invasion and angiogenisis in vitro and markers driving these phenomena. However, in vivo preclinical evaluations of such compounds have not examined their pharmacokinetics, pathology, and hematology. Here we use NOD.CB17-Prkdc SCID/J mice bearing xenograft ccRCC Caki-1 tumors to evaluate the in vivo efficacies of two titanium–gold compounds Titanocref and Titanofin (based on auranofin analogue scaffolds) accompanied by pharmacokinetic and pathology studies. A therapeutic trial was performed over 21 days at 5 mg/kg/72h of Titanocref and 10 mg/kg/72h of Titanofin tracking changes in tumor size. We observed a significant reduction of 51% and 60%, respectively (p < 0.01) in tumor size in the Titanocref- and Titanofin-treated mice compared to the starting size, while the vehicle-treated mice exhibited a tumor size increase of 138% (p < 0.01). Importantly, no signs of pathological complication as a result of treatment were found. In addition, Titanocref and Titanofin treatment reduced angiogenesis by 38% and 54%, respectively. Microarray and qRT-PCR analysis of ccRCC Caki-1 cells treated with Titanocref revealed that the compound alters apoptosis, JNK MAP kinase, and ROS pathways within 3 h of treatment. We further show activation of apoptosis by Titanocref and Titanofin in vivo by caspase 3 assay. Titanocref is active against additional kidney cancer cells. Titanocref and Titanofin are therefore promising candidates for further evaluation toward clinical application in the treatment of ccRCC.

中文翻译:

基于金诺芬的类似物对体内透明细胞肾癌有效,并且没有明显的全身毒性。

晚期透明细胞肾癌(ccRCC)患者的有效药物治疗是有限的。含氮化合物的双金属钛-金表现出对肾透明细胞癌的细胞毒性显著在体外在体内,抑制侵袭和血管生成的体外和标记驱动这些现象。然而,此类化合物的体内临床前评估尚未检查其药代动力学,病理学和血液学。在这里,我们使用带有异种移植ccRCC Caki-1肿瘤的NOD.CB17-Prkdc SCID / J小鼠来评估体内两种钛金化合物Titanocref和Titanofin(基于金诺芬类似物支架)的功效以及药代动力学和病理学研究。在21天内以5 mg / kg / 72h的Titanocref和10 mg / kg / 72h的Titanofin进行治疗试验,追踪肿瘤大小的变化。我们观察到,与起始大小相比,用Titanocref和Titanofin治疗的小鼠的肿瘤大小分别显着减少了51%和60%(p <0.01),而用载体治疗的小鼠的肿瘤大小却增加了138% (p<0.01)。重要的是,没有发现因治疗而引起的病理并发症的迹象。此外,Titanocref和Titanofin治疗分别使血管生成减少了38%和54%。用Titanocref处理的ccRCC Caki-1细胞的芯片和qRT-PCR分析表明,该化合物在处理3小时内改变了细胞凋亡,JNK MAP激酶和ROS途径。我们进一步显示通过胱天蛋白酶3测定体内通过Titanocref和Titanofin激活凋亡。Titanocref对其他肾癌细胞具有活性。因此,Titanocref和Titanofin是有希望的候选物,可用于进一步评估ccRCC的临床应用。
更新日期:2020-04-09
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