Oestrogen enhances cardiotoxicity induced by Sunitinib by regulation of drug transport and metabolism

Harvey, Pamela A.; Leinwand, Leslie A.

doi:10.1093/cvr/cvv152

Cited by 19 publications

(17 citation statements)

References 56 publications

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“…Similarly, Harvey et al . showed an increased expression of MRP1 by SUN in male rat cardiomyocyte. On the other hand, SUN induced hepatic and renal BCRP mRNA levels dose dependently reaching approximately 4‐fold (fig.…”

Section: Resultsmentioning

confidence: 88%

Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic‐Metabolizing Enzymes and Transporters in Rat Liver and Kidneys

Korashy

Ansari

Maayah

et al. 2016

Basic Clin Pharma Tox

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Sunitinib (SUN) is a multi-targeted tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal tract and renal cancers. To date, very little is known about the effects of SUN on the expression of hepatic and renal xenobiotic-metabolizing enzymes (XMEs) and transporters. The present study was designed to investigate the capacity of chronic SUN treatment to modulate the mRNA and protein expression levels of phase I cytochrome P450 (CYP), phase II conjugating enzymes, and phase III transporters in rat liver and kidneys. For this purpose, SUN (25, 50 and 100 mg/kg) was injected IP into Wistar albino rats for 4 weeks; thereafter, the mRNA and protein expression levels of several XMEs and transporters were determined by RT-PCR and Western blot analysis, respectively. Real-time PCR analysis showed that SUN significantly induced the hepatic and renal CYP1A1, 1A2, 1B1, 2E1 and 4F4, whereas it inhibited CYP2C11 and 4A2. Furthermore, SUN specifically induced renal, but not hepatic, CYP2J3 and 3A2, while it induced only hepatic CYP4A1. With regard to phase II, SUN induced hepatic GSTA1 and UGT1A and renal NQO1 and UGT1A mRNA levels, whereas it inhibited renal GST1A expression. On the other hand, both renal and hepatic P-gp, MRP2 and BCRP transporters were significantly induced by SUN at the mRNA and protein expression levels. Importantly, these differential effects were associated with changes in oxidative stress genes and lipid peroxidation levels. In conclusion, SUN can serve as XME and transporters modulator, which potentially may counteract the efficacy of the treatment, adverse reactions and drug interactions in SUN treatment.Xenobiotic-metabolizing systems include phase I cytochrome P450 (CYP) oxidative enzymes, phase II conjugative enzyme systems and phase III transporters [1]. The mammalian CYP1, 2 and 3 families are single polypeptide membrane-bound haem proteins that play an essential role in the oxidative metabolism of a great variety of xenobiotic and endogenous compounds resulting in the formation of more water-soluble and less toxic metabolites [2]. On the other hand, phase II conjugative enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione transferase (GST) and uridine diphosphate glucuronosyltransferase (UGT) catalyse conjugation reactions necessary for xenobiotic metabolism and/or further metabolism of phase I enzyme products [1]. Thus, these enzymes play an essential role in the detoxification and elimination of xenobiotics and carcinogenic metabolites [1]. In 1992, Ishikawa first proposed a new concept of the phase III xenobiotic-metabolizing system known as transporters that play important roles in drug disposition, therapeutic efficacy and adverse drug reactions [3]. Many of these transporters, such as P-glycoprotein (P-gp), multi-drug resistance-associated protein (MRP) and breast cancer resistant protein (BCRP), have been characterized and are expressed in epithelia of the intestine, liver and kidney [4,5]. Thus, induction or inhibition of thes...

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Section: Resultsmentioning

confidence: 88%

Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic‐Metabolizing Enzymes and Transporters in Rat Liver and Kidneys

Korashy

Ansari

Maayah

et al. 2016

Basic Clin Pharma Tox

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“…We also studied female mice from a single strain and acknowledge that there may be strain‐related differences in drug response. Interestingly, in contrast to most types of cardiac insult, female mice are more prone to sunitinib‐induced cardiotoxicity than male mice . It is possible that the inclusion of 4 mice that were euthanized early because of excessive weight loss could have affected our data analysis; however, none of those mice showed evidence of heart failure (mean fractional shortening 56% at Day 7).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in contrast to most types of cardiac insult, female mice are more prone to sunitinibinduced cardiotoxicity than male mice. 11 It is possible that the inclusion of 4 mice that were euthanized early because of excessive weight loss could have affected our data analysis; however, none of those mice showed evidence of heart failure (mean fractional shortening 56% at Day 7). Lastly, we did not pursue the possibility that upregulation of cardioprotective NFjB signaling, 59 in addition to STAT3 activation, might buffer the cardiac effects of EGFR inhibition with erlotinib.…”

Section: Discussionmentioning

confidence: 99%

“…Female FVB mice, 14 to 16 weeks old, from Jackson Laboratory were used for all experiments, because female mice are more susceptible to sunitinib‐induced cardiotoxicity . Female Sprague‐Dawley rats with newborn litters were from Charles River.…”

Section: Methodsmentioning

confidence: 99%

“…Female FVB mice, 14 to 16 weeks old, from Jackson Laboratory were used for all experiments, because female mice are more susceptible to sunitinib-induced cardiotoxicity. 11 Female Sprague-Dawley rats with newborn litters were from Charles River. Animal care and experimental protocols were approved by the UNC IACUC and complied with Guide for the Care and the Use of Laboratory Animals (National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory Animals, 2011).…”

Section: Animalsmentioning

confidence: 99%

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Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition

Stuhlmiller

Zawistowski

Chen

et al. 2017

JAHA

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BackgroundMost novel cancer therapeutics target kinases that are essential to tumor survival. Some of these kinase inhibitors are associated with cardiotoxicity, whereas others appear to be cardiosafe. The basis for this distinction is unclear, as are the molecular effects of kinase inhibitors in the heart.Methods and ResultsWe administered clinically relevant doses of sorafenib, sunitinib (cardiotoxic multitargeted kinase inhibitors), or erlotinib (a cardiosafe epidermal growth factor receptor inhibitor) to mice daily for 2 weeks. We then compared the effects of these 3 kinase inhibitors on the cardiac transcriptome using RNAseq and the cardiac kinome using multiplexed inhibitor beads coupled with mass spectrometry. We found unexpectedly broad molecular effects of all 3 kinase inhibitors, suggesting that target kinase selectivity does not define either the molecular response or the potential for cardiotoxicity. Using in vivo drug administration and primary cardiomyocyte culture, we also show that the cardiosafety of erlotinib treatment may result from upregulation of the cardioprotective signal transducer and activator of transcription 3 pathway, as co‐treatment with erlotinib and a signal transducer and activator of transcription inhibitor decreases cardiac contractile function and cardiomyocyte fatty acid oxidation.ConclusionsCollectively our findings indicate that preclinical kinome and transcriptome profiling may predict the cardiotoxicity of novel kinase inhibitors, and suggest caution for the proposed therapeutic strategy of combined signal transducer and activator of transcription/epidermal growth factor receptor inhibition for cancer treatment.

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Sex‐Specific Classification of Drug‐Induced Torsade de Pointes Susceptibility Using Cardiac Simulations and Machine Learning

Iseppe

Zhu

et al. 2021

Clin Pharma and Therapeutics

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Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. While this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (1) TdP classifiers require different features in females vs. males; (2) malebased classifiers perform more poorly when applied to female data; (3) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially lifethreatening consequences for the female population..

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Oestrogen enhances cardiotoxicity induced by Sunitinib by regulation of drug transport and metabolism

Cited by 19 publications

References 56 publications

Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic‐Metabolizing Enzymes and Transporters in Rat Liver and Kidneys

Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic‐Metabolizing Enzymes and Transporters in Rat Liver and Kidneys

Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition

Sex‐Specific Classification of Drug‐Induced Torsade de Pointes Susceptibility Using Cardiac Simulations and Machine Learning

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