Sex-related Differential Susceptibility to Ponatinib Cardiotoxicity and Differential Modulation of the Notch1 Signalling Pathway in a Murine Model

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2022 Feb 5

PMID 35122387

Authors

Rosalinda Madonna

Damiana Pieragostino

Maria Concetta Cufaro

Piero Del Boccio

Angela Pucci

Letizia Mattii

Vanessa Doria

Christian Cadeddu Dessalvi

Riccardo Zucchi

Giuseppe Mercuro

Raffaele De Caterina

Affiliations

Soon will be listed here.

Abstract

Ponatinib (PON), a tyrosine kinase inhibitor approved in chronic myeloid leukaemia, has proven cardiovascular toxicity. We assessed mechanisms of sex-related PON-induced cardiotoxicity and identified rescue strategies in a murine model. PON+scrambled siRNA-treated male mice had a higher number of TUNEL-positive cells (%TdT+6.12 ± 0.17), higher percentage of SA-β-gal-positive senescent cardiac area (%SA-β-gal 1.41 ± 0.59) and a lower reactivity degree (RD) for the survival marker Bmi1 [Abs (OD) 5000 ± 703] compared to female (%TdT+3.75 ± 0.35; %SA-β-gal 0.77 ± 0.02; Bmi1 [Abs (OD) 8567 ± 2173]. Proteomics analysis of cardiac tissue showed downstream activation of cell death in PON+siRNA scrambled compared to vehicle or PON+siRNA-Notch1-treated male mice. Upstream analysis showed beta-oestradiol activation, and downstream analysis showed activation of cell survival and inhibition of cell death in PON+scrambled siRNA compared to vehicle or PON+siRNA-Notch1-treated female mice. PON+scrambled siRNA-treated mice also had a downregulation of cardiac actin-more marked in males-and vessel density-more marked in females. Female hearts showed greater cardiac fibrosis than their male counterparts at baseline, with no significant change after PON treatment. PON+siRNA-scrambled mice had less fibrosis than vehicle or PON+siRNA-Notch1-treated mice. The left ventricular systolic dysfunction showed by PON+scrambled siRNA-treated mice (male %EF 28 ± 9; female %EF 36 ± 7) was reversed in both PON+siRNA-Notch1-treated male (%EF 53 ± 9) and female mice (%EF 52 ± 8). We report sex-related differential susceptibility and Notch1 modulation in PON-induced cardiotoxicity. This can help to identify biomarkers and potential mechanisms underlying sex-related differences in PON-induced cardiotoxicity.

Citing Articles

Recent Advances in Serum Biomarkers for Cardiological Risk Stratification and Insight into the Cardiac Management of the Patients With Hematological Malignancies Treated With Targeted Therapy.

Andreescu M Cureus. 2023; 15(11):e49696.

PMID: 38033434 PMC: 10688222. DOI: 10.7759/cureus.49696.

Mitochondrial Dysfunction in Cardiotoxicity Induced by BCR-ABL1 Tyrosine Kinase Inhibitors -Underlying Mechanisms, Detection, Potential Therapies.

Sun S, Qin J, Liao W, Gao X, Shang Z, Luo D Cardiovasc Toxicol. 2023; 23(7-8):233-254.

PMID: 37479951 DOI: 10.1007/s12012-023-09800-x.

Tyrosine kinase inhibitor-associated ventricular arrhythmias: a case series and review of literature.

Fazal M, Wei C, Lee Chuy K, Hussain K, Gomez S, Ba S J Interv Card Electrophysiol. 2022; 66(5):1165-1175.

PMID: 36411365 PMC: 10199959. DOI: 10.1007/s10840-022-01400-z.

Heart failure and cancer: From active exposure to passive adaption.

Du Y, Wu T Front Cardiovasc Med. 2022; 9:992011.

PMID: 36304546 PMC: 9592839. DOI: 10.3389/fcvm.2022.992011.

Madonna R, Pieragostino D, Cufaro M, Del Boccio P, Pucci A, Mattii L J Cell Mol Med. 2022; 26(5):1380-1391.

PMID: 35122387 PMC: 8899159. DOI: 10.1111/jcmm.17008.

References

Trivedi P, Kushwaha S, Tripathi D, Jena G . Cardioprotective effects of hesperetin against doxorubicin-induced oxidative stress and DNA damage in rat. Cardiovasc Toxicol. 2011; 11(3):215-25. DOI: 10.1007/s12012-011-9114-2. View

Falk R, Falk A, Dyson M, Melidoni A, Parthiban K, Young J . Generation of anti-Notch antibodies and their application in blocking Notch signalling in neural stem cells. Methods. 2012; 58(1):69-78. PMC: 3502869. DOI: 10.1016/j.ymeth.2012.07.008. View

Harvey P, Leinwand L . Oestrogen enhances cardiotoxicity induced by Sunitinib by regulation of drug transport and metabolism. Cardiovasc Res. 2015; 107(1):66-77. PMC: 4560048. DOI: 10.1093/cvr/cvv152. View

Blume-Jensen P, Hunter T . Oncogenic kinase signalling. Nature. 2001; 411(6835):355-65. DOI: 10.1038/35077225. View

Pelzer T, Schumann M, Neumann M, deJager T, Stimpel M, Serfling E . 17beta-estradiol prevents programmed cell death in cardiac myocytes. Biochem Biophys Res Commun. 2000; 268(1):192-200. DOI: 10.1006/bbrc.2000.2073. View

Ismail I, Andrin C, McDonald D, Hendzel M . BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J Cell Biol. 2010; 191(1):45-60. PMC: 2953429. DOI: 10.1083/jcb.201003034. View

Lionetti V, Matteucci M, Ribezzo M, Silvestre D, Brambilla F, Agostini S . Regional mapping of myocardial hibernation phenotype in idiopathic end-stage dilated cardiomyopathy. J Cell Mol Med. 2014; 18(3):396-414. PMC: 3955147. DOI: 10.1111/jcmm.12198. View

Park I, Morrison S, Clarke M . Bmi1, stem cells, and senescence regulation. J Clin Invest. 2004; 113(2):175-9. PMC: 311443. DOI: 10.1172/JCI20800. View

Kato R, Yamazoe Y . Sex-specific cytochrome P450 as a cause of sex- and species-related differences in drug toxicity. Toxicol Lett. 1992; 64-65 Spec No:661-7. DOI: 10.1016/0378-4274(92)90245-f. View

10.

Pentassuglia L, Graf M, Lane H, Kuramochi Y, Cote G, Timolati F . Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. Exp Cell Res. 2009; 315(7):1302-12. PMC: 4991362. DOI: 10.1016/j.yexcr.2009.02.001. View

11.

Singh A, Umbarkar P, Tousif S, Lal H . Cardiotoxicity of the BCR-ABL1 tyrosine kinase inhibitors: Emphasis on ponatinib. Int J Cardiol. 2020; 316:214-221. PMC: 8095092. DOI: 10.1016/j.ijcard.2020.05.077. View

12.

Chatoo W, Abdouh M, David J, Champagne M, Ferreira J, Rodier F . The polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity. J Neurosci. 2009; 29(2):529-42. PMC: 2744209. DOI: 10.1523/JNEUROSCI.5303-08.2009. View

13.

Madonna R, Pieragostino D, Cufaro M, Doria V, Del Boccio P, Deidda M . Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway. J Clin Med. 2020; 9(3). PMC: 7141219. DOI: 10.3390/jcm9030820. View

14.

Saussele S, Haverkamp W, Lang F, Koschmieder S, Kiani A, Jentsch-Ullrich K . Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management. Acta Haematol. 2019; 143(3):217-231. PMC: 7384349. DOI: 10.1159/000501927. View

15.

Garate-Carrillo A, Gonzalez J, Ceballos G, Ramirez-Sanchez I, Villarreal F . Sex related differences in the pathogenesis of organ fibrosis. Transl Res. 2020; 222:41-55. PMC: 7721117. DOI: 10.1016/j.trsl.2020.03.008. View

16.

Liu N, Zhang J, Ji C . The emerging roles of Notch signaling in leukemia and stem cells. Biomark Res. 2013; 1(1):23. PMC: 4177577. DOI: 10.1186/2050-7771-1-23. View

17.

Wu S, Ko Y, Teng M, Ko Y, Hsu L, Hsueh C . Adriamycin-induced cardiomyocyte and endothelial cell apoptosis: in vitro and in vivo studies. J Mol Cell Cardiol. 2002; 34(12):1595-607. DOI: 10.1006/jmcc.2002.2110. View

18.

Ren M, Cowell J . Constitutive Notch pathway activation in murine ZMYM2-FGFR1-induced T-cell lymphomas associated with atypical myeloproliferative disease. Blood. 2011; 117(25):6837-47. PMC: 3128478. DOI: 10.1182/blood-2010-07-295725. View

19.

Guentchev M, McKay R . Notch controls proliferation and differentiation of stem cells in a dose-dependent manner. Eur J Neurosci. 2006; 23(9):2289-96. DOI: 10.1111/j.1460-9568.2006.04766.x. View

20.

Balistreri C, Madonna R, Melino G, Caruso C . The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases. Ageing Res Rev. 2016; 29:50-65. DOI: 10.1016/j.arr.2016.06.004. View