Elie Benelita T, Hubbard Karen, Layek Buddhadev, Yang Won Seok, Prabha Swayam, Ramos Joe W, Contel Maria
Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States.
Biology, Chemistry and Biochemistry PhD Programs, The Graduate Center, The City University of New York, New York, New York 10016, United States.
ACS Pharmacol Transl Sci. 2020 Apr 9;3(4):644-654. doi: 10.1021/acsptsci.9b00107. eCollection 2020 Aug 14.
Effective pharmacological treatments for patients with advanced clear cell renal carcinoma (ccRCC) are limited. Bimetallic titanium-gold containing compounds exhibit significant cytotoxicity against ccRCC and and inhibit invasion and angiogenisis and markers driving these phenomena. However, 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 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 ( < 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% ( < 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 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.
对于晚期肾透明细胞癌（ccRCC）患者，有效的药物治疗方法有限。含双金属钛 - 金的化合物对ccRCC表现出显著的细胞毒性，并抑制侵袭和血管生成以及驱动这些现象的标志物。然而，此类化合物的临床前评估尚未考察其药代动力学、病理学和血液学。在此，我们使用携带异种移植ccRCC Caki - 1肿瘤的NOD.CB17 - Prkdc SCID/J小鼠，来评估两种钛 - 金化合物Titanocref和Titanofin（基于金诺芬类似物支架）的疗效，并同时进行药代动力学和病理学研究。以5 mg/kg/72h的Titanocref和10 mg/kg/72h的Titanofin进行了为期21天的治疗试验，跟踪肿瘤大小的变化。我们观察到，与起始大小相比，接受Titanocref和Titanofin治疗的小鼠肿瘤大小分别显著减少了51%和60%（<0.01），而接受赋形剂治疗的小鼠肿瘤大小增加了138%（<0.01）。重要的是，未发现治疗导致的病理并发症迹象。此外，Titanocref和Titanofin治疗分别使血管生成减少了38%和54%。对用Titanocref处理的ccRCC Caki - 1细胞进行的微阵列和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丝裂原活化蛋白激酶和ROS途径。我们通过caspase 3检测进一步显示了Titanocref和Titanofin对细胞凋亡的激活作用。Titanocref对其他肾癌细胞也有活性。因此，Titanocref和Titanofin有望成为进一步评估用于ccRCC治疗临床应用的候选药物。
