Protective effect of 23‐hydroxybetulinic acid on doxorubicin‐induced cardiotoxicity: a correlation with the inhibition of carbonyl reductase‐mediated metabolism

Abstract

Background and Purpose The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. 23‐Hydroxybetulinic acid (23‐HBA), isolated from Pulsatilla chinensis, enhances the anticancer effect of doxorubicin while simultaneously reducing its cardiac toxicity, but does not affect the concentration of doxorubicin in the plasma and heart. As the metabolite doxorubicinol is more potent than doxorubicin at inducing cardiac toxicity, in the present study we aimed to clarify the role of doxorubicinol in the protective effect of 23‐HBA. Experimental Approach Doxorubicin was administered to mice for two weeks in the presence or absence of 23‐HBA. The heart pathology, function, myocardial enzymes and accumulation of doxorubicin and doxorubicinol were then analysed. A cellular pharmacokinetic study of doxorubicin and doxorubicinol, carbonyl reductase 1 (CBR1) interference and molecular docking was performed in vitro. Key Results 23‐HBA alleviated the doxorubicin‐induced cardiotoxicity in mice, and this was accompanied by inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts. In H9c2 cells, the protective effect of 23‐HBA was shown to be closely associated with a decreased rate and extent of accumulation of doxorubicinol in mitochondria and nuclei. siRNA and docking analysis demonstrated that CBR1 has a crucial role in doxorubicin‐mediated cardiotoxicity and 23‐HBA inhibits this metabolic pathway. Conclusions and Implications Inhibition of CBR‐mediated doxorubicin metabolism might be one of the protective mechanisms of 23‐HBA against doxorubicin‐induced cardiotoxicity. The present study provides a new research strategy guided by pharmacokinetic theory to elucidate the mechanism of drugs with unknown targets. Linked Articles This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Drug target identification using network analysis: Taking active components in Sini decoction as an example

“…DOX mediated H9C2 cytotoxicity was also copied as described previously 73 . Cells were incubated with aconitine, hypaconitine, mesaconitine, higenamine, hypaconine, mesaconine, glycyrrhizic acid, quercetin and 6-gingerol (6.25–100 μM) in DMEM supplemented with 0.5% fetal bovine serum at 37 °C for 2 h followed by incubation with or without DOX (2 μM) for another 24 h. Cell viability then was tested by CCK-8 (Beyotime Biotechnology, Jiangsu, China).…”

Mitochondrial Dysfunction Associated with Doxorubicin

“…Another study, however, stated that the peak plasma concentration of patients treated with DOX is between 2 and 6 μM after bolus injection, but typically 1-2 μM [24]. DOX is reported to be very low when bound to plasma proteins [25]. The plasma clearance of DOX is measured between 324 and 809 mL/min/m 2 , dominantly by biliary excretion; the maximum volume is around 809-1214 L/m 2 .…”

“…However, elimination velocity is slow within the range 20-48 h [26]. After injection, DOX is disseminated to the heart, liver, kidneys, and intestine [25].…”

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines –

“…Despite this discrepancy as to the role of CBR polymorphisms in the cardiotoxicity of anthracyclines, the link between carbonyl reductases and cardiotoxicity resulting from anthracycline treatment is supported by a number of additional recent studies [63][64][65]. A convincing line of evidence supporting this link is a very recent study showing that the compound 23-hydroxybetulinic acid inhibits carbonyl reductase activity and was able to reduce both the accumulation of DOXOL in mice hearts and DOX-induced cardiotoxicity [66]. There is less support for the role of AKRs in promoting the cardiotoxicity of anthracyclines.…”