Doxorubicin (DOX), an anthracycline-based anticancer drug, is commonly used to treat various cancers, but its prolonged use may lead to cardiotoxicity. Despite extensive research efforts, effective strategies for managing DOX-induced cardiotoxicity (DICT) remain limited. This study investigated the DICT-inhibitory efficacy of the water extract of Allium victorialis L. (AVE) and its underlying mechanism. AVE protected mouse cardiomyocytes, H9c2 cells, from DOX-induced toxicity while not interfering with DOX’s cytotoxic effect on the MDA-MB-231 cells, human breast cancer cells. DOX-induced abnormal heart rate, RR interval, cQT prolongation, and segmentation were normalized following AVE supplementation. Also, AVE reduced the serum levels of creatine kinase and lactate dehydrogenase and suppressed myocardial fibrosis and cell death by DICT in the AVE-fed mice group. Moreover, AVE was shown to restore DOX-induced impaired electrophysiological changes in human-induced pluripotent stem cell-derived cardiomyocytes, including reduced total activity and decreased conduction velocity, while also normalizing the beat period irregularity and beat period mean. A total of 57 metabolites were tentatively identified in the AVE sample. Furthermore, PCR microarray and western blot analyses confirmed that AVE reversibly increased the expression of antioxidant-related genes and proteins. Altogether, the antioxidant properties of AVE could be utilized as a new strategy for preventing and treating DICT.
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References
1.
PallerlaS, GauthierT, SableR, et al.Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells. Eur J Med Chem, 2017; 125:914–924; doi: 10.1016/j.ejmech.2016.10.015
2.
KciukM, GielecińskaA, MujwarS, et al.Doxorubicin—An agent with multiple mechanisms of anticancer activity. Cells, 2023; 12(4):659; doi: 10.3390/cells12040659
3.
van der ZandenSY, QiaoX, NeefjesJ. New insights into the activities and toxicities of the old anticancer drug doxorubicin. Febs J, 2021; 288(21):6095–6111; doi: 10.1111/febs.15583
4.
MarinelloJ, DelcuratoloM, CapranicoG. Anthracyclines as topoisomerase II Poisons: From early studies to new perspectives. Int J Mol Sci, 2018; 19(11):3480; doi: 10.3390/ijms19113480
5.
AlAsmariAF, AlharbiM, AlqahtaniF, et al.Diosmin alleviates doxorubicin-induced liver injury via modulation of oxidative stress-mediated hepatic inflammation and apoptosis via NfkB and MAPK Pathway: A preclinical study. Antioxidants (Basel), 2021; 10(12):1998; doi: 10.3390/antiox10121998
6.
ZhangX, QuX, SunYB, et al.Resolvin D1 protects podocytes in adriamycin-induced nephropathy through modulation of 14-3-3beta acetylation. PLoS One, 2013; 8(6):e67471; doi: 10.1371/journal.pone.0067471
AryalB, RaoVA. Deficiency in cardiolipin reduces doxorubicin-induced oxidative stress and mitochondrial damage in human B-Lymphocytes. PLoS One, 2016; 11(7):e0158376; doi: 10.1371/journal.pone.0158376
9.
KimYA, ChoH, LeeN, et al.Doxorubicin-induced heart failure in cancer patients: A cohort study based on the Korean national health insurance database. Cancer Med, 2018; 7(12):6084–6092; doi: 10.1002/cam4.1886
10.
RawatPS, JaiswalA, KhuranaA, et al.Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother, 2021; 139:111708; doi: 10.1016/j.biopha.2021.111708
11.
WenningmannN, KnappM, AndeA, et al.Insights into doxorubicin-induced cardiotoxicity: Molecular mechanisms, preventive strategies, and early monitoring. Mol Pharmacol, 2019; 96(2):219–232; doi: 10.1124/mol.119.115725
KonorevEA, VanamalaS, KalyanaramanB. Differences in doxorubicin-induced apoptotic signaling in adult and immature cardiomyocytes. Free Radic Biol Med, 2008; 45(12):1723–1728; doi: 10.1016/j.freeradbiomed.2008.09.006
15.
LiJ, WangPY, LongNA, et al.p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities. Proc Natl Acad Sci U S A, 2019; 116(39):19626–19634; doi: 10.1073/pnas.1904979116
16.
SinghM, KadhimMM, Turki JalilA, et al.A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity. Cancer Cell Int, 2023; 23(1):88; doi: 10.1186/s12935-023-02936-4
17.
EsakkiA, RamadossR, AnanthapadmanabhanL, et al.Quantification of the Anti-diabetic Effect of Allium cepa. Cureus, 2024; 16(4):e59174; doi: 10.7759/cureus.59174
18.
Mohammadi-MotlaghHR, MostafaieA, MansouriK. Anticancer and anti-inflammatory activities of shallot (Allium ascalonicum) extract. Arch Med Sci, 2011; 7(1):38–44; doi: 10.5114/aoms.2011.20602
19.
SongJH, KimMS, LeeSH, et al.Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1alpha-SOD-mediated mitochondrial protection. Phytomedicine, 2024; 129:155633; doi: 10.1016/j.phymed.2024.155633
20.
ZhaoY, WangC, WangM, et al.Berberine ameliorates doxorubicin-induced cardiotoxicity via sirturin 1-mediated pathway. Oxid Med Cell Longev, 2019:1–13; doi: 10.1155/2019/2150394
21.
YuY, WenS, RuanY, et al.Impact of heart rate and rhythm on corrected QT interval during paroxysmal atrial fibrillation. Am J Cardiol, 2022; 168:64–70; doi: 10.1016/j.amjcard.2021.12.016
22.
LiRA, LeppoM, MikiT, et al.Molecular basis of electrocardiographic ST-segment elevation. Circ Res, 2000; 87(10):837–839; doi: 10.1161/01.res.87.10.837
23.
BenjanuwattraJ, Siri-AngkulN, ChattipakornSC, et al.Doxorubicin and its proarrhythmic effects: A comprehensive review of the evidence from experimental and clinical studies. Pharmacol Res, 2020; 151:104542; doi: 10.1016/j.phrs.2019.104542
24.
SandamaliJAN, HewawasamRP, FernandoM, et al.Electrocardiographic and biochemical analysis of anthracycline induced cardiotoxicity in breast cancer patients from Southern Sri Lanka. BMC Cancer, 2023; 23(1):210; doi: 10.1186/s12885-023-10673-0
25.
MaG, WangY, LiY, et al.MiR-206, a key modulator of skeletal muscle development and disease. Int J Biol Sci, 2015; 11(3):345–352; doi: 10.7150/ijbs.10921
26.
CuiZY, HanX, JiangYC, et al.Allium victorialis L. extracts promote activity of FXR to ameliorate alcoholic liver disease: Targeting Liver Lipid Deposition and Inflammation. Front Pharmacol, 2021; 12:738689; doi: 10.3389/fphar.2021.738689
27.
KimDH, ParkJS, ChoiHI, et al.The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD. Cell Death Dis, 2021; 12(4):320; doi: 10.1038/s41419-021-03620-z
28.
FengHZ, JinJP. A protocol to study ex vivo mouse working heart at human-like heart rate. J Mol Cell Cardiol, 2018; 114:175–184; doi: 10.1016/j.yjmcc.2017.11.011
29.
BourqueK, Jones-TabahJ, PetrinD, et al.Comparing the signaling and transcriptome profiling landscapes of human iPSC-derived and primary rat neonatal cardiomyocytes. Sci Rep, 2023; 13(1):12248; doi: 10.1038/s41598-023-39525-4
30.
DouW, ZhaoQ, MalhiM, et al.Label-free conduction velocity mapping and gap junction assessment of functional iPSC-Cardiomyocyte monolayers. Biosens Bioelectron, 2020; 167:112468; doi: 10.1016/j.bios.2020.112468
31.
Jamil-CopleyS, VergaraP, CarbucicchioC, et al.Application of ripple mapping to visualize slow conduction channels within the infarct-related left ventricular scar. Circ Arrhythm Electrophysiol, 2015; 8(1):76–86; doi: 10.1161/CIRCEP.114.001827
32.
KingJH, HuangCLH, FraserJA. Determinants of myocardial conduction velocity: Implications for arrhythmogenesis. Front Physiol, 2013; 4:154; doi: 10.3389/fphys.2013.00154
33.
HauserKF, FoldesJK, TurbekCS. Dynorphin A (1-13) neurotoxicity in vitro: Opioid and non-opioid mechanisms in mouse spinal cord neurons. Exp Neurol, 1999; 160(2):361–375; doi: 10.1006/exnr.1999.7235
34.
HanX, LeiQ, LiuH, et al.SerpinA3N regulates the secretory phenotype of mouse senescent astrocytes contributing to neurodegeneration. J Gerontol A Biol Sci Med Sci, 2024; 79(4):glad278; doi: 10.1093/gerona/glad278
35.
HenleyJR, HuangKH, WangD, et al.Calcium mediates bidirectional growth cone turning induced by myelin-associated glycoprotein. Neuron, 2004; 44(6):909–916; doi: 10.1016/j.neuron2004.11.030
36.
ErmakG, DaviesKJ. Calcium and oxidative stress: From cell signaling to cell death. Mol Immunol, 2002; 38(10):713–721; doi: 10.1016/s0161-5890(01)00108-0
37.
LuD, MaY, ZhangW, et al.Knockdown of cytochrome P450 2E1 inhibits oxidative stress and apoptosis in the cTnT(R141W) dilated cardiomyopathy transgenic mice. Hypertension, 2012; 60(1):81–89; doi: 10.1161/HYPERTENSIONAHA.112.191478
38.
TolosaL, JimenezN, PerezG, et al.Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury. Arch Toxicol, 2018; 92(1):383–399; doi: 10.1007/s00204-017-2036-4
39.
ShiratakiY, MotohashiN, TaniS, et al.Antioxidative activity of Allium victorialis L. extracts. Anticancer Res, 2001; 21(5):3331–3339.
40.
KimYS, JungDH, LeeIS, et al.Effects of Allium victorialis leaf extracts and its single compounds on aldose reductase, advanced glycation end products and TGF-beta1 expression in mesangial cells. BMC Complement Altern Med, 2013; 13:251; doi: 10.1186/1472-6882-13-251
41.
GaoY, WangB, QinG, et al.Therapeutic potentials of allicin in cardiovascular disease: Advances and future directions. Chin Med, 2024; 19(1):93; doi: 10.1186/s13020-024-00936-8
42.
ValkoM, LeibfritzD, MoncolJ, et al.Free radicals and antioxidants in normal physiologicalfunctions and human disease. Int J Biochem Cell Biol, 2007; 39(1):44–84; doi: 10.1016/j.biocel.2006.07.001
43.
D’ArchivoM, FilesiC, Di BenedettoR, et al.Polyphenols, dietary sources and bioavailability. Ann Ist Super Sanita, 2007; 43(4):348–361.
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