Prodrug of ICRF-193 provides promising protective effects against chronic anthracycline cardiotoxicity in a rabbit modelin vivo

Abstract

The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer survivors. A bisdioxopiperazine agent dexrazoxane has been developed as a cardioprotective drug to prevent these adverse events, but it is uncertain whether it is the best representative of the class. This study used a rabbit model of chronic ANT cardiotoxicity to examine another bisdioxopiperazine compound called GK-667, a water-soluble prodrug of ICRF-193, as a potential cardioprotectant. The cardiotoxicity was induced by DAU (3 mg/kg, i.v. weekly, 10 weeks), and GK-667 (1 or 5 mg/kg, i.v.) was administered before each DAU dose. The treatment with GK-667 was well tolerated and provided full protection against DAU-induced mortality and left ventricular (LV) dysfunction (determined by echocardiography and LV catheterization). Markers of cardiac damage/dysfunction revealed minor cardiac damage in the group co-treated with GK-667 in the lower dose, whereas almost full protection was achieved with the higher dose. This was associated with similar prevention of DAU-induced dysregulation of redox and calcium homeostasis proteins. GK-667 dose-dependently prevented p53-mediated DNA damage response in the LV myocardium not only in the chronic experiment but also after single DAU administration. These effects appear essential for cardioprotection, presumably because of the topoisomerase IIβ inhibition provided by its active metabolite ICRF-193. In addition, GK-667 administration did not alter the plasma pharmacokinetics of DAU and its main metabolite daunorubicinol in rabbits in vivo. Hence, GK-667 merits further investigation as a promising drug candidate for cardioprotection against chronic ANT cardiotoxicity.

Current Status and Trends of Research on Anthracycline-Induced Cardiotoxicity from 2002 to 2021: A Twenty-Year Bibliometric and Visualization Analysis

“…They clarified the cardioprotective mechanism of dexrazoxane, the only clinically approved drug against ACT, is the interaction with topoisomerase-II β (Top2 β ) but not metal chelation and protection against direct oxidative damage [ 33 ]. They also found a water-soluble prodrug of dexrazoxane analogs (ICRF-193), named GK-667 for short, which is a promising agent against ACT [ 34 ]. Lipshultz Steven E. paid more attention to the clinical observation and management of ACT in children.…”

Inhibition of Topoisomerase 2 catalytic activity impacts the integrity of heterochromatin and repetitive DNA and leads to interlinks between clustered repeats

“…The clinical relevance is highlighted by the fact that ICRF-193 can efficiently induce DNA damage in replicating human cells (Figure 1H-1J). Furthermore, since we observed that cells commence the G2 phase without first completing DNA replication (Figure S1N), it is highly probable that they will move into mitosis with defects and therefore carry genomic instability into has yet to be used in the clinical setting for cancer treatment due to its extremely low aqueous solubility, however recent studies have shown that pre-drugs can be used to overcome this obstacle 49,50 . Thus, our findings can be used to analyze and predict the responses of human cells to treatment with ICRF-193.…”

Exploring the effects of topoisomerase II inhibitor XK469 on anthracycline cardiotoxicity and DNA damage

“…The animals received the same treatments as above, but the experiment was terminated 6 h after administration of the single dose. This time was used based on previously published data ( Kollarova-Brazdova et al , 2021 ). The heart was excised, washed, and briefly perfused with ice-cold saline to remove blood, and the left ventricle was harvested for analysis of p53 by Western blot and p53 target genes by reverse transcription quantitative real-time PCR (RT-qPCR).…”

“…Acquired chemiluminescent signal was normalized to total protein content. Western blot analysis of p53 levels in left ventricular myocardial samples was performed as described previously ( Kollarova-Brazdova et al , 2021 ). Proteins from left ventricular myocardial samples were separated by SDS-PAGE on TGX Stain-Free precast gels (Bio-Rad).…”