Enzastaurin cardiotoxicity: QT interval prolongation, negative inotropic responses and negative chronotropic action

被引：3

作者：

Zhang, He-qiang ^{[1
]}

Lin, Jia-le ^{[1
]}

Pan, Lei ^{[1
]}

Mao, Liang ^{[1
,3
]}

Pang, Jing-long ^{[1
]}

Yuan, Qian ^{[1
]}

Li, Gui-yang ^{[2
]}

Yi, Gang-si ^{[1
]}

Lin, Yang-bin ^{[1
]}

Feng, Bao-long ^{[1
]}

Li, Yun-da ^{[1
]}

Wang, Yan ^{[2
]}

Jie, Ling-jun ^{[1
,2
]}

Zhang, Yan-hui ^{[1
]}

机构：

[1] Xiamen Univ, Xiamen Cardiovasc Hosp, Inst Cardiovasc Dis, Sch Med, Xiamen 361104, Fujian, Peoples R China

[2] Xiamen Univ, Xiamen Cardiovasc Hosp, Sch Med, Dept Cardiol, Xiamen, Fujian, Peoples R China

[3] Southwest Med Univ, Key Lab Med Electrophysiol, Luzhou, Sichuan, Peoples R China

来源：

BIOCHEMICAL PHARMACOLOGY | 2023年 / 209卷

基金：

中国国家自然科学基金;

关键词：

Enzastaurin; Cardiotoxicity; QT interval prolongation; Cardiac systolic function; Ryanodine receptor type 2; PROTEIN-KINASE-C; BETA-INHIBITOR ENZASTAURIN; MULTICENTER PHASE-II; MULTIPLE-MYELOMA; BREAST-CANCER; MOLECULAR DETERMINANTS; VENTRICULAR MYOCYTES; SELECTIVE INHIBITORS; POTASSIUM CURRENTS; RADIATION-THERAPY;

D O I：

10.1016/j.bcp.2023.115443

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Several clinical trials observed that enzastaurin prolonged QT interval in cancer patients. However, the mech-anism of enzastaurin-induced QT interval prolongation is unclear. Therefore, this study aimed to assess the effect and mechanism of enzastaurin on QT interval and cardiac function. The Langendorff and Ion-Optix MyoCam systems were used to assess the effects of enzastaurin on QT interval, cardiac systolic function and intracellular Ca2+ transient in guinea pig hearts and ventricular myocytes. The effects of enzastaurin on the rapid delayed rectifier (IKr), the slow delayed rectifier K+ current (IKs), transient outward potassium current (Ito), action po-tentials, Ryanodine Receptor 2 (RyR2) and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) expression and activity in HEK 293 cell system and primary cardiomyocytes were investigated using whole-cell recording technique and western blotting. We found that enzastaurin significantly prolonged QT interval in guinea pig hearts and increased the action potential duration (APD) in guinea pig cardiomyocytes in a dose-dependent manner. Enzastaurin potently inhibited IKr by binding to the human Ether-`a-go-go-Related gene (hERG) channel in both open and closed states, and hERG mutant channels, including S636A, S631A, and F656V attenuated the inhibitory effect of enzastaurin. Enzastaurin also moderately decreased IKs. Additionally, enzas-taurin also induced negative chronotropic action. Moreover, enzastaurin impaired cardiac systolic function and reduced intracellular Ca2+ transient via inhibition of RyR2 phosphorylation. Taken together, we found that enzastaurin prolongs QT, reduces heart rate and impairs cardiac systolic function. Therefore, we recommend that electrocardiogram (ECG) and cardiac function should be continuously monitored when enzastaurin is adminis-tered to cancer patients.

引用

页数：14

共 77 条

[1]

Alig J, 2009, P NATL ACAD SCI USA, V106, P12189, DOI 10.1073/pnas.0810332106

[2]

Anand Vidhu, 2016, JACC Clin Electrophysiol, V2, P777, DOI 10.1016/j.jacep.2016.05.007

[3] Inhibitors of protein kinase C sensitise multiple myeloma cells to common genotoxic drugs [J].

Baumann, Philipp ;

Armann, Jakob ;

Mandl-Weber, Sonja ;

Gruen, Gabriel ;

Oduncu, Fuat ;

Schmidmaier, Ralf .

EUROPEAN JOURNAL OF HAEMATOLOGY, 2008, 80 (01) :37-45

[4] The Adverse Cardiovascular Effects and Cardiotoxicity of Kratom (Mitragyna speciosa Korth.): A Comprehensive Review [J].

Bin Abdullah, Mohammad Farris Iman Leong ;

Singh, Darshan .

FRONTIERS IN PHARMACOLOGY, 2021, 12

[5] Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma [J].

Butowski, Nicholas ;

Chang, Susan M. ;

Lamborn, Kathleen R. ;

Polley, Mei-Yin ;

Pieper, Russell ;

Costello, Joseph F. ;

Vandenberg, Scott ;

Parvataneni, Rupa ;

Nicole, Angelina ;

Sneed, Patricia K. ;

Clarke, Jennifer ;

Hsieh, Emily ;

Costa, Bruno M. ;

Reis, Rui M. ;

Hristova-Kazmierski, Maria ;

Nicol, Steven J. ;

Thornton, Donald E. ;

Prados, Michael D. .

NEURO-ONCOLOGY, 2011, 13 (12) :1331-1338

[6] Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer [J].

Carducci, Michael A. ;

Musib, Luna ;

Kies, Merrill S. ;

Pili, Roberto ;

Truong, Mylene ;

Brahmer, Julie R. ;

Cole, Patricia ;

Sullivan, Rana ;

Riddle, Jeanne ;

Schmidt, Jill ;

Enas, Nathan ;

Sinha, Vikram ;

Thornton, Donald E. ;

Herbst, Roy S. .

JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (25) :4092-4099

[7] In vitro and in vivo models for testing arrhythmogenesis in drugs [J].

Carlsson, L .

JOURNAL OF INTERNAL MEDICINE, 2006, 259 (01) :70-80

[8] Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics [J].

Chen, Ming Hui ;

Kerkelae, Risto ;

Force, Thomas .

CIRCULATION, 2008, 118 (01) :84-95

[9] L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices [J].

Chen, XW ;

Piancentino, V ;

Furukawa, S ;

Goldman, B ;

Margulies, KB ;

Houser, SR .

CIRCULATION RESEARCH, 2002, 91 (06) :517-524

[10]

Cirigliano SM, 2013, PANCREAS, V42, P1060, DOI 10.1097/MPA.0b013e31828fd141

← 1 2 3 4 5 6 7 8 →