PMID- 31025080 OWN - NLM STAT- MEDLINE DCOM- 20200721 LR - 20210422 IS - 1432-0738 (Electronic) IS - 0340-5761 (Linking) VI - 93 IP - 6 DP - 2019 Jun TI - Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo. PG - 1697-1712 LID - 10.1007/s00204-019-02448-z [doi] AB - Sunitinib (SNT) is a multi-targeted receptor tyrosine kinase inhibitor that has been approved by the FDA for cancer therapy. However, its cardiotoxicity has limited the clinical applicability with no effective therapeutic approach available. As a broadband kinase inhibitor, the function of several kinases that are essential to cardiac function might also be affected by SNT, such as calmodulin-dependent protein kinase (CaMKII), cyclic-AMP-dependent protein kinases (PKA), AMP-activated protein kinase (AMPK), and phosphoinositide 3 kinase (PI3K). In this study, we investigated whether SNT-induced cardiotoxicity could be prevented by blocking SNT-induced alteration in the corresponding signaling pathways. In human induced pluripotent stem cell-derived cardiomyocytes, SNT (0.5-20 micromol/L) inhibited contractility of cardiomyocytes in a concentration-dependent manner, and the inhibitory effect was prevented either by PIP3 (1 micromol/L) application or PI3K overexpression. On the contrary, the CaMKII inhibitor KN-93 (50 nmol/L), PKA inhibitor H89 (1 micromol/L), and AMPK activators metformin (2 mmol/L) and 5-aminoimidazole-4-carboxamide 1-b-D-ribofuranoside (2 mmol/L) presented negligible effects. Oral SNT administration (40 mg/kg/day) in mice progressively decreased the PI3K activity and cardiac function in 2 weeks with a significant decrease in the expression and activity of Cav1.2 and SERCA. Cardiac-specific PI3K overexpression through adeno-associated virus 9-mediated gene delivery in mice prevented SNT-induced reduction in cardiac function, calcium transient, calcium current, and Cav1.2 expression. In summary, our data indicate that increased PI3K activity is protective against SNT-induced calcium mishandling and contractile dysfunction. Cardiac-specific PI3K activation could be an effective therapeutic approach to treat SNT cardiotoxicity in patients with cancer. FAU - Li, Congxin AU - Li C AD - Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China. FAU - Zou, Ruya AU - Zou R AD - Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China. FAU - Zhang, Hua AU - Zhang H AD - Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China. FAU - Wang, Yuhong AU - Wang Y AD - Institute of Masteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. FAU - Qiu, Bo AU - Qiu B AD - Hebei General Hospital, Shijiazhuang, 050017, China. FAU - Qiu, Suhua AU - Qiu S AD - Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, 050017, Hebei, China. AD - The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China. FAU - Wang, Wei AU - Wang W AD - Department of Physiology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. FAU - Xu, Yanfang AU - Xu Y AUID- ORCID: 0000-0001-9332-5418 AD - Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China. yanfangxu@hebmu.edu.cn. AD - The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, 050017, Hebei, China. yanfangxu@hebmu.edu.cn. AD - The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China. yanfangxu@hebmu.edu.cn. LA - eng GR - 31771259/National Natural Science Foundation of China/International GR - 81670370/National Natural Science Foundation of China/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190425 PL - Germany TA - Arch Toxicol JT - Archives of toxicology JID - 0417615 RN - 0 (Antineoplastic Agents) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - V99T50803M (Sunitinib) SB - IM MH - Antineoplastic Agents/*toxicity MH - Calcium Signaling/drug effects MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors/genetics MH - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors MH - Dose-Response Relationship, Drug MH - Gene Transfer Techniques MH - Genetic Therapy MH - Heart Diseases/*chemically induced/*genetics/prevention & control MH - Humans MH - Induced Pluripotent Stem Cells MH - Myocytes, Cardiac/drug effects MH - Phosphatidylinositol 3-Kinases/*biosynthesis/*genetics MH - Signal Transduction/*drug effects/*genetics MH - Sunitinib/*toxicity OTO - NOTNLM OT - Cardiac contractile dysfunction OT - Excitation-contraction coupling OT - Human induced pluripotent stem cell-derived cardiomyocyte OT - Phosphoinositide 3-kinase OT - Sunitinib OT - Tyrosine kinase inhibitor EDAT- 2019/04/27 06:00 MHDA- 2020/07/22 06:00 CRDT- 2019/04/27 06:00 PHST- 2019/02/22 00:00 [received] PHST- 2019/04/09 00:00 [accepted] PHST- 2019/04/27 06:00 [pubmed] PHST- 2020/07/22 06:00 [medline] PHST- 2019/04/27 06:00 [entrez] AID - 10.1007/s00204-019-02448-z [pii] AID - 10.1007/s00204-019-02448-z [doi] PST - ppublish SO - Arch Toxicol. 2019 Jun;93(6):1697-1712. doi: 10.1007/s00204-019-02448-z. Epub 2019 Apr 25.