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Auranofin-Based Analogues Are Effective Against Clear Cell Renal Carcinoma In Vivo and Display No Significant Systemic Toxicity
journal contribution
posted on 2020-04-17, 19:47 authored by Benelita
T. Elie, Karen Hubbard, Buddhadev Layek, Won Seok Yang, Swayam Prabha, Joe W. Ramos, Maria ContelEffective 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.