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Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo

  • Organ Toxicity and Mechanisms
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Abstract

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 µmol/L) inhibited contractility of cardiomyocytes in a concentration-dependent manner, and the inhibitory effect was prevented either by PIP3 (1 µmol/L) application or PI3K overexpression. On the contrary, the CaMKII inhibitor KN-93 (50 nmol/L), PKA inhibitor H89 (1 µmol/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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31771259 to Y. X., 81670370 to W. W.), the Science and Technology Foundation of Hebei Province (17274803D to Y. X.), the Outstanding Youth Foundations of Natural Science Foundation of Hebei Province (H2017206381 to W. W.), the Office of Education Foundation of Hebei Province of China (SLRC2017046 to W. W., CY201618 to W. W.), and the Hebei Province Graduate Student Innovation Project (CXZZBS2018063 to C. L.).

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Authors and Affiliations

  1. Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

    Congxin Li, Ruya Zou, Hua Zhang, Suhua Qiu & Yanfang Xu

  2. The Key Laboratory of New Drug Pharmacology and Toxicology, Shijiazhuang, 050017, Hebei, China

    Congxin Li, Ruya Zou, Hua Zhang, Suhua Qiu & Yanfang Xu

  3. The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, 050017, China

    Congxin Li, Ruya Zou, Hua Zhang, Suhua Qiu & Yanfang Xu

  4. Institute of Masteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Yuhong Wang

  5. Hebei General Hospital, Shijiazhuang, 050017, China

    Bo Qiu

  6. Department of Physiology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

    Wei Wang

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  1. Congxin Li
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Contributions

CL, RZ, HZ, YW, and SQ performed the research, YX and WW designed the research study, CL, WW, and BQ analyzed the data. CL, WW, and YX wrote the paper.Compliance with ethical standards

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Correspondence to Yanfang Xu.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Li, C., Zou, R., Zhang, H. et al. Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo. Arch Toxicol 93, 1697–1712 (2019). https://doi.org/10.1007/s00204-019-02448-z

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