Lethal and Sub-Lethal Effects and Modulation of Gene Expression Induced by T Kinase Inhibitors in Zebrafish (Danio Rerio) Embryos

Overview

Journal Toxics

Date 2022 Jan 20

PMID 35051046

Authors

Tina Elersek

Matjaz Novak

Mateja Mlinar

Igor Virant

Nika Bahor

Karin Leben

Bojana Zegura

Metka Filipic

Affiliations

Soon will be listed here.

Abstract

Tyrosine kinase inhibitors (TKIs) are designed for targeted cancer therapy. The consumption of these drugs during the last 20 years has been constantly rising. In the zebrafish () embryo toxicity test, we assessed the toxicity of six TKIs: imatinib mesylate, erlotinib, nilotinib, dasatinib, sorafenib and regorafenib. Imatinib mesylate and dasatinib induced lethal effects, while regorafenib, sorfenib and dasatinib caused a significant increase of sub-lethal effects, predominantly oedema, no blood circulation and formation of blood aggregates. The analyses of the changes in the expression of selected genes associated with the hormone system after the exposure to imatinib mesylate, dasatinib and regorafenib demonstrated that all three tested TKIs deregulated the expression of oestrogen receptor esr1, cytochrome P450 aromatase (cypa19b) and hydroxysteroid-dehydrogenase (hsd3b), regorafenib, and also thyroglobulin (tg). The expression of genes involved in the DNA damage response (gadd45 and mcm6) and apoptosis (bcl2) was deregulated only by exposure to regorafenib. The data indicate that common mechanisms, namely antiangiogenic activity and interference with steroidogenesis are involved in the TKI induced sub-lethal effects and potential hormone disrupting activity, respectively. The residues of TKIs may represent an environmental hazard; therefore, further ecotoxicological studies focusing also on the effects of their mixtures are warranted.

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References

Kilarski W, Jura N, Gerwins P . Inactivation of Src family kinases inhibits angiogenesis in vivo: implications for a mechanism involving organization of the actin cytoskeleton. Exp Cell Res. 2003; 291(1):70-82. DOI: 10.1016/s0014-4827(03)00374-4. View

Yamaoka T, Kusumoto S, Ando K, Ohba M, Ohmori T . Receptor Tyrosine Kinase-Targeted Cancer Therapy. Int J Mol Sci. 2018; 19(11). PMC: 6274851. DOI: 10.3390/ijms19113491. View

Elmore S . Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007; 35(4):495-516. PMC: 2117903. DOI: 10.1080/01926230701320337. View

Novak M, Zegura B, Nunic J, Gajski G, Geric M, Garaj-Vrhovac V . Assessment of the genotoxicity of the tyrosine kinase inhibitor imatinib mesylate in cultured fish and human cells. Mutat Res Genet Toxicol Environ Mutagen. 2017; 814:14-21. DOI: 10.1016/j.mrgentox.2016.12.002. View

Huang G, Tian X, Fang X, Ji F . Waterborne exposure to bisphenol F causes thyroid endocrine disruption in zebrafish larvae. Chemosphere. 2016; 147:188-94. DOI: 10.1016/j.chemosphere.2015.12.080. View

Booker V, Halsall C, Llewellyn N, Johnson A, Williams R . Prioritising anticancer drugs for environmental monitoring and risk assessment purposes. Sci Total Environ. 2013; 473-474:159-70. DOI: 10.1016/j.scitotenv.2013.11.145. View

Wang X, Zhan Q, Coursen J, Khan M, Kontny H, Yu L . GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A. 1999; 96(7):3706-11. PMC: 22358. DOI: 10.1073/pnas.96.7.3706. View

Parrella A, Lavorgna M, Criscuolo E, Russo C, Fiumano V, Isidori M . Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans. Chemosphere. 2014; 115:59-66. DOI: 10.1016/j.chemosphere.2014.01.013. View

Girardot F, Monnier V, Tricoire H . Genome wide analysis of common and specific stress responses in adult drosophila melanogaster. BMC Genomics. 2004; 5:74. PMC: 526417. DOI: 10.1186/1471-2164-5-74. View

10.

Mouhayar E, Durand J, Cortes J . Cardiovascular toxicity of tyrosine kinase inhibitors. Expert Opin Drug Saf. 2013; 12(5):687-96. DOI: 10.1517/14740338.2013.788642. View

11.

Cohen M, Williams G, Johnson J, Duan J, Gobburu J, Rahman A . Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002; 8(5):935-42. View

12.

Chimote G, Sreenivasan J, Pawar N, Subramanian J, Sivaramakrishnan H, Sharma S . Comparison of effects of anti-angiogenic agents in the zebrafish efficacy-toxicity model for translational anti-angiogenic drug discovery. Drug Des Devel Ther. 2014; 8:1107-23. PMC: 4145829. DOI: 10.2147/DDDT.S55621. View

13.

Manchado M, Infante C, Asensio E, Planas J, Canavate J . Thyroid hormones down-regulate thyrotropin beta subunit and thyroglobulin during metamorphosis in the flatfish Senegalese sole (Solea senegalensis Kaup). Gen Comp Endocrinol. 2007; 155(2):447-55. DOI: 10.1016/j.ygcen.2007.07.011. View

14.

Brezovsek P, Elersek T, Filipic M . Toxicities of four anti-neoplastic drugs and their binary mixtures tested on the green alga Pseudokirchneriella subcapitata and the cyanobacterium Synechococcus leopoliensis. Water Res. 2014; 52:168-77. DOI: 10.1016/j.watres.2014.01.007. View

15.

Novak M, Zegura B, Baebler S, Stern A, Rotter A, Stare K . Influence of selected anti-cancer drugs on the induction of DNA double-strand breaks and changes in gene expression in human hepatoma HepG2 cells. Environ Sci Pollut Res Int. 2015; 23(15):14751-61. DOI: 10.1007/s11356-015-5420-8. View

16.

Lodish M, Stratakis C . Endocrine side effects of broad-acting kinase inhibitors. Endocr Relat Cancer. 2010; 17(3):R233-44. PMC: 3039175. DOI: 10.1677/ERC-10-0082. View

17.

Lin J, Hu S, Ho P, Hsu H, Postlethwait J, Chung B . Two Zebrafish hsd3b Genes Are Distinct in Function, Expression, and Evolution. Endocrinology. 2015; 156(8):2854-62. PMC: 4511139. DOI: 10.1210/en.2014-1584. View

18.

Olalla A, Negreira N, de Alda M, Barcelo D, Valcarcel Y . A case study to identify priority cytostatic contaminants in hospital effluents. Chemosphere. 2017; 190:417-430. DOI: 10.1016/j.chemosphere.2017.09.129. View

19.

Power D, Llewellyn L, Faustino M, Nowell M, Bjornsson B, Einarsdottir I . Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol. 2001; 130(4):447-59. DOI: 10.1016/s1532-0456(01)00271-x. View

20.

Parrella A, Lavorgna M, Criscuolo E, Russo C, Isidori M . Estrogenic activity and cytotoxicity of six anticancer drugs detected in water systems. Sci Total Environ. 2014; 485-486:216-222. DOI: 10.1016/j.scitotenv.2014.03.050. View