Abstract
Cancer patients with diabetes have an increasing risk of Dox-induced cardiotoxicity. Despite previous studies reporting benefits of dapagliflozin on the cardiovascular system, it remains unknown whether dapagliflozin has a cardioprotective effect in cancer patients with diabetes. We aimed to investigate the potential of dapagliflozin for preventing doxorubicin (Dox)-induced cardiotoxicity. Using Taiwan National Health Insurance Database, the incidence of heart failure of cancer patients with or without diabetes was investigated. Streptozotocin (STZ)-induced diabetic rats were pretreated with oral dapagliflozin for 6 weeks followed by Dox for 4 weeks via intraperitoneal injection. Sequential echocardiography was applied to assess cardiac function. For in vitro analysis, cardiomyocytes cultured in high glucose were treated with dapagliflozin at 10 μM and subsequently exposed to Dox at 1 μM. Apoptosis and endoplasmic reticulum (ER) stress-related protein expression were measured. Among the studied patients, those with diabetes had a higher risk of major adverse cardiovascular events including the development of heart failure. In diabetic rats, dapagliflozin reduced cardiac fibrosis and significantly improved cardiac function. Dapagliflozin effectively inhibited Dox-induced apoptosis and reactive oxygen species in cardiomyocytes under high glucose. Mechanistically, we showed that dapagliflozin decreased the cardiac expression of Bax and cleaved caspase 3 but increased Bcl-2. Dapagliflozin also significantly reduced ER stress-associated proteins including GRP78, PERK, eIF-2α, ATF-4, and CHOP. Our study revealed for the first time that dapagliflozin mitigated Dox-induced cardiomyocyte apoptosis in diabetes. These results indicate that dapagliflozin could be useful for preventing cardiotoxicity in diabetic cancer patients receiving Dox treatment.
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Data availability
The data are available upon the reasonable request to the corresponding author.
Abbreviations
- Dox:
-
Doxorubicin
- Dapa:
-
Dapagliflozin
- STZ:
-
Streptozotocin
- ER:
-
Endoplasmic reticulum
- ROS:
-
Reactive oxygen species
- SGLT2:
-
Sodium glucose cotransporter
- NHI:
-
National Health Insurance
- NHIRD:
-
National Health Insurance Research Database
- MACCEs:
-
Major adverse cardio- and cerebrovascular events
- CKD:
-
Chronic kidney disease
- ESRD:
-
End-stage renal disease
- COPD:
-
Chronic obstructive pulmonary disease
- IVSd:
-
Interventricular septum thickness in diastole
- LVIDd:
-
Left ventricular internal diameter in diastole
- EF:
-
Ejection fraction
- FS:
-
Fractional shortening
- P–V:
-
Pressure–volume
- HE:
-
Hematoxylin–eosin
- Ves:
-
End-systolic
- Ved:
-
Diastolic volumes
- Pes:
-
End-systolic
- Ped:
-
Diastolic pressures
- + dP/dt and -dP/dt:
-
Maximal velocity of pressure rise and fall
- Ea:
-
Arterial elastance
- tau:
-
Time constant of isovolumic pressure decay
- ESPVR:
-
End-systolic pressure–volume relationship
- EDPVR:
-
End-diastolic pressure–volume relationship
- IVC:
-
Inferior vena cava
- MTT:
-
3-(4,5-Dimethyl-2-thiazolyl)-2,5-dimethyl-2H-tetrazolium bromide
- H2DCF‑DA:
-
Fluorescent 2′,7′‑dichlorofluorescindiacetate
- PI:
-
Propidium iodide
- TUNEL:
-
Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
References
Bastos MB, Burkhoff D, Maly J et al (2020) Invasive left ventricle pressure-volume analysis: overview and practical clinical implications. Eur Heart J 41(12):1286–1297. https://doi.org/10.1093/eurheartj/ehz552
Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev 34(1):106–135. https://doi.org/10.1002/med.21280
Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH (2014) Validation of acute myocardial infarction cases in the national health insurance research database in Taiwan. J Epidemiol 24(6):500–507. https://doi.org/10.2188/jea.je20140076
Fu HY, Sanada S, Matsuzaki T et al (2016) Chemical endoplasmic reticulum chaperone alleviates doxorubicin-induced cardiac dysfunction. Circ Res 118(5):798–809. https://doi.org/10.1161/CIRCRESAHA.115.307604
Hershey DS, Hession S (2017) Chemotherapy and glycemic control in patients with type 2 diabetes and cancer: a comparative case analysis. Asia Pac J Oncol Nurs 4(3):224–232. https://doi.org/10.4103/apjon.apjon_22_17
Hsieh CY, Su CC, Shao SC et al (2019) Taiwan’s national health insurance research database: past and future. Clin Epidemiol 11:349–358. https://doi.org/10.2147/CLEP.S196293
Koleini N, Kardami E (2017) Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget 8(28):46663–46680. https://doi.org/10.18632/oncotarget.16944
Lahnwong S, Chattipakorn SC, Chattipakorn N (2018) Potential mechanisms responsible for cardioprotective effects of sodium-glucose co-transporter 2 inhibitors. Cardiovasc Diabetol 17(1):101. https://doi.org/10.1186/s12933-018-0745-5
Lipshultz SE, Scully RE, Lipsitz SR et al (2010) Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11(10):950–961. https://doi.org/10.1016/S1470-2045(10)70204-7
Lou Y, Wang Z, Xu Y et al (2015) Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int J Mol Med 36(3):873–880. https://doi.org/10.3892/ijmm.2015.2291
McMurray JJV, Solomon SD, Inzucchi SE et al (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303
Menna P, Paz OG, Chello M, Covino E, Salvatorelli E, Minotti G (2012) Anthracycline cardiotoxicity. Expert Opin Drug Saf 11(Suppl 1):S21-36. https://doi.org/10.1517/14740338.2011.589834
Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL (2012) Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 52(6):1213–1225. https://doi.org/10.1016/j.yjmcc.2012.03.006
Shakir DK, Rasul KI (2009) Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. J Clin Med Res 1(1):8–12. https://doi.org/10.4021/jocmr2009.02.1225
Supriya R, Tam BT, Pei XM et al (2016) Doxorubicin induces inflammatory modulation and metabolic dysregulation in diabetic skeletal muscle. Front Physiol 7:323. https://doi.org/10.3389/fphys.2016.00323
Volkova M, Russell R 3rd (2011) Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev 7(4):214–220. https://doi.org/10.2174/157340311799960645
Wang XY, Yang CT, Zheng DD et al (2012) Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress. Mol Cell Biochem 363(1–2):419–426. https://doi.org/10.1007/s11010-011-1194-6
Wexler LH, Andrich MP, Venzon D et al (1996) Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol 14(2):362–372. https://doi.org/10.1200/JCO.1996.14.2.362
Wilson AJ, Gill EK, Abudalo RA, Edgar KS, Watson CJ, Grieve DJ (2018) Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting. Heart 104(4):293–299. https://doi.org/10.1136/heartjnl-2017-311448
Xu F, Li X, Liu L et al (2017) Attenuation of doxorubicin-induced cardiotoxicity by esculetin through modulation of Bmi-1 expression. Exp Ther Med 14(3):2216–2220. https://doi.org/10.3892/etm.2017.4763
Yao Y, Lu Q, Hu Z, Yu Y, Chen Q, Wang QK (2017) A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure. Nat Commun 8(1):133. https://doi.org/10.1038/s41467-017-00171-w
Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128. https://doi.org/10.1056/NEJMoa1504720
Acknowledgements
We especially thank the support from Professor Wei-Jan Chen in Linkou Chang Gung Memorial Hospital/Chang Gung University, Taiwan
Funding
This study was supported by Chi-Mei Medical Center, Ministry of Science and Technology (MOST105-2628-B-384 -001 -MY3; 108-2628-B-384), National Health Research Institute (NHRI-EX106-10618SC).
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All authors were involved in the conception and design of the study and data interpretation. WC and YL drafted the paper and performed data analysis. WC and YL were involved in the data analysis and interpretation. All authors critically revised the paper and approved it for submission.
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This study was approved by the Institutional Review Board of Chi-Mei Medical Center (CV code: 10406-E01). Given that the data are derived from the NHIRD databank, the consent to participate is not applicable.
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204_2020_2951_MOESM2_ESM.tif
Supplementary file2 (TIF 575 KB) Supplement Figure 2. The study design investigating the effects of dapagliflozin on the cardiac function in Dox-treated STZ rats. The STZ rats were pretreated with dapagliflozin for 6 weeks followed by treatment for 4 weeks.
204_2020_2951_MOESM3_ESM.tif
Supplementary file3 (TIF 915 KB) Supplement Figures 3. Effects of dapagliflozin on (a) body weight, (b) blood sugar, and (c) heart rate in the control, STZ, STZ+Dox, and STZ+Dox+Dapa rats. Data presented are the means ± standard deviations (S.D.). ***P < 0.001 compared with the indicated groups (N = 3-6).
204_2020_2951_MOESM4_ESM.tif
Supplementary file4 (TIF 379 KB) Supplement Figures 4. The cytotoxicity test of dapagliflozin (Dapa) and doxorubicin (Dox) in the cardiomyocytes (H9C2). The cells were treated with increasing concentrations of (a) Dox (0.01 to 100 M) or (b) dapagliflozin (0.1 to 20 M). The MTT assay was conducted to measure cell viability. Data presented are the means ± standard deviations (S.D.). *P < 0.05 compared with the control (N = 3-5).
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Chang, WT., Lin, YW., Ho, CH. et al. Dapagliflozin suppresses ER stress and protects doxorubicin-induced cardiotoxicity in breast cancer patients. Arch Toxicol 95, 659–671 (2021). https://doi.org/10.1007/s00204-020-02951-8
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DOI: https://doi.org/10.1007/s00204-020-02951-8