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2000
Volume 20, Issue 2
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

Lenvatinib is a tyrosine kinase inhibitor that can improve progression-free survival in patients with thyroid cancer and hepatocellular carcinoma. However, it is limited by adverse cardiovascular events, including hypertension and cardiac dysfunction. Activation of endoplasmic reticulum stress is involved in cardiomyocyte apoptosis.

Objective

This study aimed to confirm whether the cardiotoxicity of lenvatinib is associated with endoplasmic reticulum stress by targeting the activating transcription factor 6 (ATF6), inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like ER kinase (PERK) signaling pathways.

Methods

Male C57/BL6 mice were intragastric administration with 30 mg/kg/day lenvatinib. Electrocardiography (ECG) and echocardiography were used to detect arrhythmias and cardiac function. Neonatal rat cardiomyocytes were treated with lenvatinib for 48h. Cell counting kit (CCK8), 2´,7´-dichlorodihydrofluoresceine diacetate (H2DCFHDA), Hoechst 33258 and dihydrorhodamine 123 were respectively used for evaluating cell viability, the level of reactive oxygen species (ROS), nuclear morphological changes and mitochondrial membrane potential (MMP) level.

Results

Lenvatinib remarkably decreased the posterior wall thickness of left ventricle during diastole and systole but caused little decrease to the left ventricular ejection fraction (LVEF, %). Furthermore, lenvatinib greatly prolonged the corrected QT interval (QTc) and altered the morphology of cardiomyocytes. No significant difference in fibrosis was found in mouse cardiac slices. Lenvatinib upregulates apoptosis-related protein expression. In addition, lenvatinib increased ERS-related proteins expression (GRP78, CHOP, and ATF6) and enhanced PERK phosphorylation. In neonatal rat cardiac myocytes, lenvatinib markedly decreased the viability of cardiomyocytes and induced apoptosis. Furthermore, ROS production increased and MMP decreased. Similar to the mice experiment, lenvatinib caused upregulation of apoptosis-related and ERS-related proteins and increased the phosphorylation levels of PERK and IRE1α.

Conclusion

Lenvatinib-induced cardiotoxicity is associated with ERS-induced apoptosis by targeting the ATF6, IRE1α, and PERK signaling pathways.

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2025-11-02

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References

  1. SchlumbergerM. TaharaM. WirthL.J. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer.N. Engl. J. Med.2015372762163010.1056/NEJMoa1406470 25671254
     [Google Scholar]
  2. PaddaI.S. ParmarM. Lenvatinib.In: StatPearls.Treasure Island, FLStatPearls Publishing LLC2023
     [Google Scholar]
  3. BoehmS. RothermundtC. HessD. JoergerM. Antiangiogenic drugs in oncology: A focus on drug safety and the elderly-a mini-review.Gerontology201056330330910.1159/000262450 19940466
     [Google Scholar]
  4. SuyamaK. IwaseH. Lenvatinib.Cancer Contr.201825110.1177/1073274818789361 30032643
     [Google Scholar]
  5. IsedaN. ItohS. ToshidaK. Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor‐4 inhibition in hepatocellular carcinoma.Cancer Sci.202211372272228710.1111/cas.15378 35466502
     [Google Scholar]
  6. YamauchiM. OnoA. IshikawaA. Tumor fibroblast growth factor receptor 4 level predicts the efficacy of lenvatinib in patients with advanced hepatocellular carcinoma.Clin. Transl. Gastroenterol.2020115e0017910.14309/ctg.0000000000000179 32677805
     [Google Scholar]
  7. YamamotoY. MatsuiJ. MatsushimaT. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage.Vasc. Cell2014611810.1186/2045‑824X‑6‑18 25197551
     [Google Scholar]
  8. ButtellA. QiuW. The action and resistance mechanisms of Lenvatinib in liver cancer.Mol. Carcinog.20232362510.1002/mc.23625 37671815
     [Google Scholar]
  9. ZschäbitzS. GrüllichC. Lenvantinib: A tyrosine kinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, KIT and RET.Recent Results Cancer Res.201821118719810.1007/978‑3‑319‑91442‑8_13 30069768
     [Google Scholar]
  10. ObiS. SatoT. SatoS. The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting.Hepatol. Int.201913219920410.1007/s12072‑019‑09929‑4 30671808
     [Google Scholar]
  11. OkamotoK. KodamaK. TakaseK. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models.Cancer Lett.201334019710310.1016/j.canlet.2013.07.007 23856031
     [Google Scholar]
  12. WangM. YaoX. BoZ. Synergistic effect of lenvatinib and chemotherapy in hepatocellular carcinoma using preclinical models.J. Hepatocell. Carcinoma20231048349510.2147/JHC.S395474 37007211
     [Google Scholar]
  13. TaharaM. KiyotaN. HoffA.O. Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer.Eur. J. Cancer2021147515710.1016/j.ejca.2020.12.032 33611104
     [Google Scholar]
  14. ChenS. XuB. WuZ. Pembrolizumab plus lenvatinib with or without hepatic arterial infusion chemotherapy in selected populations of patients with treatment-naive unresectable hepatocellular carcinoma exhibiting PD-L1 staining: A multicenter retrospective study.BMC Cancer2021211112610.1186/s12885‑021‑08858‑6 34670506
     [Google Scholar]
  15. LiD. LiuS. ChengC. XuL. ZhaoP. Efficacy and safety of transarterial chemoembolization plus lenvatinib in the treatment of advanced hepatocellular carcinoma: A meta-analysis.Medicine202310235e3481110.1097/MD.0000000000034811 37657057
     [Google Scholar]
  16. ZhuC. MaX. HuY. Safety and efficacy profile of lenvatinib in cancer therapy: A systematic review and meta-analysis.Oncotarget2016728445454455710.18632/oncotarget.10019 27329593
     [Google Scholar]
  17. KwokC. NolanM. Cardiotoxicity of anti-cancer drugs: Cellular mechanisms and clinical implications.Front. Cardiovasc. Med.202310115056910.3389/fcvm.2023.1150569 37745115
     [Google Scholar]
  18. ShengC.C. Amiri-KordestaniL. PalmbyT. 21st century cardio-oncology.JACC Basic Transl. Sci.20161538639810.1016/j.jacbts.2016.05.008 28713868
     [Google Scholar]
  19. HouW. DingM. LiX. Comparative evaluation of cardiovascular risks among nine FDA-approved VEGFR-TKIs in patients with solid tumors: A Bayesian network analysis of randomized controlled trials.J. Cancer Res. Clin. Oncol.202114782407242010.1007/s00432‑021‑03521‑w 33725154
     [Google Scholar]
  20. ObaT. ChinoT. SomaA. Comparative efficacy and safety of tyrosine kinase inhibitors for thyroid cancer: A systematic review and meta-analysis.Endocr. J.202067121215122610.1507/endocrj.EJ20‑0171 32814730
     [Google Scholar]
  21. WassermannJ. BagnisC.I. LeenhardtL. EderhyS. BuffetC. Pre-therapeutic evaluation and practical management of cardiovascular and renal toxicities in patients with metastatic radioiodine-refractory thyroid cancer treated with lenvatinib.Expert Opin. Drug Saf.202221111401141010.1080/14740338.2022.2153115 36458701
     [Google Scholar]
  22. Abdel-QadirH. EthierJ.L. LeeD.S. ThavendiranathanP. AmirE. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis.Cancer Treat. Rev.20175312012710.1016/j.ctrv.2016.12.002 28104567
     [Google Scholar]
  23. ColomboC. CerutiD. De LeoS. Management of hypertension during lenvatinib for advanced thyroid cancer: A suggested diagnostic and therapeutic algorithm.Eur. Thyroid J.2023124e23004710.1530/ETJ‑23‑0047 37097040
     [Google Scholar]
  24. PaschkeL. LinckeT. MühlbergK. LindnerT.H. PaschkeR. Myocardial infarction after long-term treatment with a Tyrosine Kinase Inhibitor (TKI) with Anti-VEGF receptor activity.Case Rep. Endocrinol.201920191310.1155/2019/7927450 31281683
     [Google Scholar]
  25. TotzeckM. MincuR.I. MrotzekS. SchadendorfD. RassafT. Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: A meta-analysis of approximately 29,000 cancer patients.Eur. J. Prev. Cardiol.201825548249410.1177/2047487318755193 29376753
     [Google Scholar]
  26. ChungR. TyeballyS. ChenD. Hypertensive cardiotoxicity in cancer treatment—systematic analysis of adjunct, conventional chemotherapy, and novel therapies-epidemiology, incidence, and pathophysiology.J. Clin. Med.2020910334610.3390/jcm9103346 33081013
     [Google Scholar]
  27. ShahR.R. MorganrothJ. Update on cardiovascular safety of tyrosine kinase inhibitors: With a special focus on QT interval, left ventricular dysfunction and overall risk/benefit.Drug Saf.201538869371010.1007/s40264‑015‑0300‑1 26008987
     [Google Scholar]
  28. KrawczykK. ŚladowskaK. HolkoP. KawalecP. Comparative safety of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis.Front. Pharmacol.202314122392910.3389/fphar.2023.1223929 37745049
     [Google Scholar]
  29. UptonJ.P. AustgenK. NishinoM. Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress.Mol. Cell. Biol.200828123943395110.1128/MCB.00013‑08 18426910
     [Google Scholar]
  30. LiJ. LeeB. LeeA.S. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53.J. Biol. Chem.2006281117260727010.1074/jbc.M509868200 16407291
     [Google Scholar]
  31. ZhangS. LvY. LuoX. Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder.Mol. Med.20232917310.1186/s10020‑023‑00656‑z 37308812
     [Google Scholar]
  32. OsiewaczH.D. BernhardtD. Mitochondrial quality control: Impact on aging and life span-a mini-review.Gerontology201359541342010.1159/000348662 23615432
     [Google Scholar]
  33. KimI. XuW. ReedJ.C. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities.Nat. Rev. Drug Discov.20087121013103010.1038/nrd2755 19043451
     [Google Scholar]
  34. BagchiA.K. MalikA. AkolkarG. Study of ER stress and apoptotic proteins in the heart and tumor exposed to doxorubicin.Biochim. Biophys. Acta Mol. Cell Res.20211868711903910.1016/j.bbamcr.2021.119039 33857568
     [Google Scholar]
  35. RonD. WalterP. Signal integration in the endoplasmic reticulum unfolded protein response.Nat. Rev. Mol. Cell Biol.20078751952910.1038/nrm2199 17565364
     [Google Scholar]
  36. SoniK.K. HwangJ. RamalingamM. Endoplasmic reticulum stress causing apoptosis in a mouse model of an ischemic spinal cord injury.Int. J. Mol. Sci.2023242130710.3390/ijms24021307 36674822
     [Google Scholar]
  37. NakagawaT. ZhuH. MorishimaN. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β.Nature200040367659810310.1038/47513 10638761
     [Google Scholar]
  38. LiY. GuoY. TangJ. JiangJ. ChenZ. New insights into the roles of CHOP-induced apoptosis in ER stress.Acta Biochim. Biophys. Sin.201547214614710.1093/abbs/gmu128 25634437
     [Google Scholar]
  39. Gunaydin AkyildizA. BoranT. JannuzziA.T. AlpertungaB. Mitochondrial dynamics imbalance and mitochondrial dysfunction contribute to the molecular cardiotoxic effects of lenvatinib.Toxicol. Appl. Pharmacol.202142311557710.1016/j.taap.2021.115577 34019861
     [Google Scholar]
  40. LiJ. GuJ. Cardiovascular toxicities with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A meta-analysis of 77 randomized controlled trials.Clin. Drug Investig.201838121109112310.1007/s40261‑018‑0709‑2 30327999
     [Google Scholar]
  41. GhataliaP. JeY. KaymakcalanM.D. SonpavdeG. ChoueiriT.K. QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors.Br. J. Cancer2015112229630510.1038/bjc.2014.564 25349964
     [Google Scholar]
  42. GhataliaP. MorganC.J. JeY. Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors.Crit. Rev. Oncol. Hematol.2015942228237 25577572
     [Google Scholar]
  43. DaherI.N. DaigleT.R. BhatiaN. DurandJ.B. The prevention of cardiovascular disease in cancer survivors.Tex. Heart Inst. J.2012392190198 22740730
     [Google Scholar]
  44. WangH. WangY. LiJ. Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes.BMC Med.202321114710.1186/s12916‑023‑02838‑2 37069550
     [Google Scholar]
  45. TelermanA. GranotG. LeibovitchC. Neutrophil extracellular traps are increased in chronic myeloid leukemia and are differentially affected by tyrosine kinase inhibitors.Cancers202114111910.3390/cancers14010119 35008283
     [Google Scholar]
  46. XuY. ChenJ.T. HollandI. Analysis of long- and medium-term particulate matter exposures and stroke in the US-based Health Professionals Follow-up Study.Environ. Epidemiol.202156e178 34909558
     [Google Scholar]
  47. BouitbirJ. PanajatovicM.V. KrähenbühlS. Mitochondrial toxicity associated with imatinib and sorafenib in isolated rat heart fibers and the cardiomyoblast H9c2 cell line.Int. J. Mol. Sci.2022234228210.3390/ijms23042282 35216404
     [Google Scholar]
  48. ChenM.H. KerkeläR. ForceT. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics.Circulation20081181849510.1161/CIRCULATIONAHA.108.776831 18591451
     [Google Scholar]
  49. KalkavanH. GreenD.R. MOMP, cell suicide as a BCL-2 family business.Cell Death Differ.2018251465510.1038/cdd.2017.179 29053143
     [Google Scholar]
  50. HetzC. ZhangK. KaufmanR.J. Mechanisms, regulation and functions of the unfolded protein response.Nat. Rev. Mol. Cell Biol.202021842143810.1038/s41580‑020‑0250‑z 32457508
     [Google Scholar]
  51. HetzC. BernasconiP. FisherJ. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha.Science2006312577357257610.1126/science.1123480 16645094
     [Google Scholar]
  52. WeiM.C. ZongW.X. ChengE.H.Y. Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death.Science2001292551772773010.1126/science.1059108 11326099
     [Google Scholar]
  53. GuoM. QuS. LuH. Biochanin A alleviates cerebral ischemia/reperfusion injury by suppressing endoplasmic reticulum stress-induced apoptosis and p38MAPK signaling pathway in vivo and in vitro.Front. Endocrinol.20211264672010.3389/fendo.2021.646720 34322090
     [Google Scholar]
  54. GormanA.M. HealyS.J.M. JägerR. SamaliA. Stress management at the ER: Regulators of ER stress-induced apoptosis.Pharmacol. Ther.2012134330631610.1016/j.pharmthera.2012.02.003 22387231
     [Google Scholar]
  55. SzegezdiE. LogueS.E. GormanA.M. SamaliA. Mediators of endoplasmic reticulum stress‐induced apoptosis.EMBO Rep.20067988088510.1038/sj.embor.7400779 16953201
     [Google Scholar]
  56. ChenS. MelchiorW.B.Jr GuoL. Endoplasmic reticulum stress in drug- and environmental toxicant-induced liver toxicity.J. Environ. Sci. Health Part C Environ. Carcinog. Ecotoxicol. Rev.20143218310410.1080/10590501.2014.881648 24598041
     [Google Scholar]
  57. KarnaK.K. ShinY.S. ChoiB.R. KimH.K. ParkJ.K. The role of endoplasmic reticulum stress response in male reproductive physiology and pathology: A review.World J. Mens Health202038448449410.5534/wjmh.190038 31385474
     [Google Scholar]
  58. HetzC. The unfolded protein response: controlling cell fate decisions under ER stress and beyond.Nat. Rev. Mol. Cell Biol.20121328910210.1038/nrm3270 22251901
     [Google Scholar]
  59. IurlaroR. Muñoz-PinedoC. Cell death induced by endoplasmic reticulum stress.FEBS J.2016283142640265210.1111/febs.13598 26587781
     [Google Scholar]
  60. OakesS.A. PapaF.R. The role of endoplasmic reticulum stress in human pathology.Annu. Rev. Pathol.201510117319410.1146/annurev‑pathol‑012513‑104649 25387057
     [Google Scholar]
  61. JuaidN. AminA. AbdallaA. Anti-hepatocellular carcinoma biomolecules: Molecular targets insights.Int. J. Mol. Sci.202122191077410.3390/ijms221910774 34639131
     [Google Scholar]
  62. BouabdallahS. Al-MaktoumA. AminA. Steroidal Saponins: Naturally occurring compounds as inhibitors of the hallmarks of cancer.Cancers20231515390010.3390/cancers15153900 37568716
     [Google Scholar]
  63. AwadB. HamzaA.A. Al-MaktoumA. Al-SalamS. AminA. Combining crocin and sorafenib improves their tumor-inhibiting effects in a rat model of diethylnitrosamine-induced cirrhotic-hepatocellular carcinoma.Cancers20231516406310.3390/cancers15164063 37627094
     [Google Scholar]
  64. NelsonD.R. HroutA.A. AlzahmiA.S. ChaiboonchoeA. AminA. Salehi-AshtianiK. Molecular mechanisms behind Safranal’s toxicity to HepG2 cells from dual omics.Antioxidants2022116112510.3390/antiox11061125 35740022
     [Google Scholar]
  65. YangS. ChenY. WangL. WangT. YangC. Antioxidant characteristics and hepatoprotective effects of a formula derived from Maydis stigma, Nelumbo nucifera and Taraxacum officinale against carbon tetrachloride-induced hepatic damage in rats.Pak. J. Pharm. Sci.202033521312142 33824122
     [Google Scholar]
  66. LiS. ZhouH. ZhangX. The efficacy and safety of anlotinib alone and in combination with other drugs in previously treated advanced thymic epithelia tumors: A retrospective analysis.Recent Patents Anticancer Drug Discov.202318452853710.2174/1574892818666221122114753 36415100
     [Google Scholar]
  67. HamzaA.A. HeebaG.H. HassaninS.O. ElwyH.M. BekhitA.A. AminA. Hibiscus-cisplatin combination treatment decreases liver toxicity in rats while increasing toxicity in lung cancer cells via oxidative stress-apoptosis pathway.Biomed. Pharmacother.202316511514810.1016/j.biopha.2023.115148 37450997
     [Google Scholar]
  68. LouY. WangZ. XuY. 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.201536387388010.3892/ijmm.2015.2291 26202177
     [Google Scholar]
  69. GuoJ.J. MaL.L. ShiH.T. Alginate oligosaccharide prevents acute doxorubicin cardiotoxicity by suppressing oxidative stress and endoplasmic reticulum-mediated apoptosis.Mar. Drugs2016141223110.3390/md14120231 27999379
     [Google Scholar]
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Tyrosine Kinase Inhibitor Lenvatinib Causes Cardiotoxicity by Inducing Endoplasmic Reticulum Stress and Apoptosis through Activating ATF6, IRE1α and PERK Signaling Pathways
Recent Patents on Anti-Cancer Drug Discovery 20, 168 (2025); https://doi.org/10.2174/0115748928265981231204044653
/content/journals/pra/10.2174/0115748928265981231204044653
/content/journals/pra/10.2174/0115748928265981231204044653
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  • Article Type:     Research Article
Keyword(s): apoptosis; ATF6; cardiotoxicity; endoplasmic reticulum stress; IRE1α; lenvatinib; PERK; Tyrosine kinase inhibitor

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