Cardiotoxicity associated with targeting kinase pathways in cancer

Toxicological Sciences

Volumn 120, Issue 1, 2011, Pages 14-32

  Mellor, Howard R ^a   Bell, Alex R ^a   Valentin, Jean Pierre ^a   Roberts, Ruth R A ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Cancer; Cardiotoxicity; Kinase; Oncology; Toxicology

Indexed keywords

ADENOSINE RECEPTOR; DASATINIB; EPIDERMAL GROWTH FACTOR RECEPTOR 2; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; IMATINIB; ION CHANNEL; LAPATINIB; MITOGEN ACTIVATED PROTEIN KINASE 14; NILOTINIB; PHOSPHATASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PHOSPHOTRANSFERASE; PLACEBO; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN KINASE PIM 1; PROTEIN TYROSINE KINASE INHIBITOR; PROTEIN TYROSINE PHOSPHATASE SHP 2; RAF PROTEIN; SORAFENIB; SUNITINIB; TRASTUZUMAB;

ACTION POTENTIAL; ACUTE LYMPHOCYTIC LEUKEMIA; AGGRESSIVE SYSTEMIC MASTOCYTOSIS; APOPTOSIS; BREAST CANCER; CARDIOTOXICITY; CELL CYCLE PROGRESSION; CELL METABOLISM; CELL PROLIFERATION; CELL SURVIVAL; CHRONIC EOSINOPHILIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; DERMATOFIBROSARCOMA PROTUBERANS; DOSE RESPONSE; DRUG MECHANISM; ENZYME ACTIVITY; ENZYME INHIBITION; GASTROINTESTINAL STROMAL TUMOR; GENETIC TRANSCRIPTION; HEART FUNCTION; HUMAN; HYPEREOSINOPHILIC SYNDROME; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; MYELODYSPLASTIC SYNDROME; MYELOPROLIFERATIVE DISORDER; NONHUMAN; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; SYSTEMIC MASTOCYTOSIS; VASCULARIZATION;

EID: 79952095377     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfq378     Document Type: Review

References (131)

1. Atallah, E., Durand, J. B., Kantarjian, H., and Cortes, J. (2007). Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 110, 1233-1237.
2. Backs, J., Backs, T., Neef, S., Kreusser, M. M., Lehmann, L. H., Patrick, D. M., Grueter, C. E., Qi, X., Richardson, J. A., Hill, J. A., et al. (2009). The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc. Natl. Acad. Sci. U.S.A. 106, 2342-2347.
3. Barrett-Lee, P. J., Dixon, J. M., Farrell, C, Jones, A., Leonard, R., Murray, N., Palmieri, C, Plummer, C. J., Stanley, A., and Verrill, M. W. (2009). Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Ann. Oncol. 20, 816-827.
4. Bello, C. L., Mulay, M., Huang, X., Patyna, S., Dinolfo, M., Levine, S., Van Vugt, A., Toh, M., Baum, C, and Rosen, L. (2009). Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic-pharmacodynamic evaluation of sunitinib. Clin. Cancer Res. 15, 7045-7052.
5. Bhargava, P. (2009). VEGF kinase inhibitors: how do they cause hypertension? Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1-R5.
6. Blanchet, B., Billemont, B., Cramard, J., Benichou, A. S., Chhun, S., Harcouet, L., Ropert, S., Dauphin, A., Goldwasser, F., and Tod, M. (2009). Validation of an HPLC-UV method for sorafenib determination in human plasma and application to cancer patients in routine clinical practice. J. Pharm. Biomed. Anal. 49, 1109-1114.
7. Brave, M., Goodman, V., Kaminskas, E., Farrell, A., Timmer, W., Pope, S., Harapanhalli, R., Saber, H, Morse, D., Bullock, J., et al. (2008). Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin. Cancer Res. 14, 352-359.
8. Braz, J. C., Bueno, O. F., Liang, Q., Wilkins, B. J., Dai, Y. S., Parsons, S., Braunwart, J., Glascock, B. J., Klevitsky, R., Kimball, T. F., et al. (2003). Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J. Clin. Invest, ill, 1475-1486.
9. Büssemaker, E., Pistrosch, F., Förster, S., Herbrig, K., Gross, P., Passauer, J., and Brandes, R. P. (2007). Rho kinase contributes to basal vascular tone in humans: role of endothelium-derived nitric oxide. Am J. Physiol. Heart Circ. Physiol. 293, H541-H547.
10. Carroll, M., Ohno-Jones, S., Tamura, S., Buchdunger, E., Zimmermann, J., Lydon, N. B., Gilliland, D. G., and Druker, B. J. (1997). CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 90, 4947-4952.
11. Cheng, H., and Force, T. (2010). Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ. Res. 106, 21-34.
12. Chintalgattu, V., Ai, D., Langley, R. R., Zhang, J., Bankson, J. A., Shih, T. L., Reddy, A. K., Coombes, K. R., Daher, I. N., Pati, S., et al. (2010). Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J. Clin. Invest. 120, 472-484.
13. Choi, J. H., Yang, Y. R., Lee, S. K., Kim, S. H., Kim, Y. H., Cha, J. Y., Oh, S. W., Ha, J. R., Ryu, S. H., and Suh, P. G. (2008). Potential inhibition of PDKl/Akt signaling by phenothiazines suppresses cancer cell proliferation and survival. Ann. N. Y. Acad. Sci. 1138, 393-403.
14. Chow, L. Q., and Eckhardt, S. G. (2007). Sunitinib: from rational design to clinical efficacy. J. Clin. Oncol. 25, 884-896.
15. Chu, T. F., Rupnick, M. A., Kerkela, R., Dallabrida, S. M., Zurakowski, D., Nguyen, L., Woulfe, K., Pravda, E., Cassiola, F., Desai, J., et al. (2007). Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370,2011-2019.
16. Cohen, B. D., Kiener, P. A., Green, J. M., Foy, L., Fell, H. P., and Zhang, K. (1996). The relationship between human epidermal growth-like factor receptor expression and cellular transformation in NIH3T3 cells. J. Biol. Chem. 271, 30897-30903.
17. Crackower, M. A., Oudit, G. Y., Kozieradzki, I., Sarao, R., Sun, H., Sasaki, T., Hirsch, E., Suzuki, A., Shioi, T., Irie-Sasaki, J., et al. (2002). Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737-749.
18. Crone, S. A., Zhao, Y. Y., Fan, L., Gu, Y., Minamisawa, S., Liu, Y., Peterson, K. L., Chen, J., Kahn, R., Condorelli, G., et al. (2002). ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat. Med. 8, 459-465.
19. De Keulenaer, G. W., Doggen, K., and Lemmens, K. (2010). The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ. Res. 106, 35-46.
20. DeBosch, B., Sambandam, N., Weinheimer, C, Courtois, M., and Muslin, A. J. (2006a). Akt2 regulates cardiac metabolism and cardiomyocyte survival. J. Biol. Chem. 281, 32841-32851.
21. DeBosch, B., Treskov, I., Lupu, T. S., Weinheimer, C, Kovacs, A., Courtois, M., and Muslin, A. J. (2006b). Aktl is required for physiological cardiac growth. Circulation 113, 2097-2104.
22. Deininger, M. W., Goldman, J. M., Lydon, N., and Melo, J. V. (1997). The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90, 3691-3698.
23. Dixit, R., and Boelsterli, U. A. (2007). Healthy animals and animal models of human disease(s) in safety assessment of human pharmaceuticals, including therapeutic antibodies. Drug Discov. Today 12, 336-342.
24. Du, X. L., Gao, Z., Lau, C. P., Chiu, S. W., Tse, H. F., Baumgarten, C. M., and Li, G. R. (2004). Differential effects of tyrosine kinase inhibitors on volume-sensitive chloride current in human atrial myocytes: evidence for dual regulation by Src and EGFR kinases. J. Gen. Physiol. 123, 427-439.
25. Dykens, J. A., and Will, Y. (2007). The significance of mitochondrial toxicity testing in drug development. Drug Discov. Today 12, 777-785.
26. Dzeja, P. P., Bast, P., Pucar, D., Wieringa, B., and Terzic, A. (2007). Defective metabolic signaling in adenylate kinase AK1 gene knock-out hearts compromises post-ischemic coronary reflow. J. Biol. Chem. 282, 31366-31372.
27. Eiseler, T., Doppler, H., Yan, I. K., Goodison, S., and Storz, P. (2009). Protein kinase Dl regulates matrix metalloproteinase expression and inhibits breast cancer cell invasion. Breast Cancer Res. 11, R13.
28. Elliott, P. (2006). Pathogenesis of cardiotoxicity induced by anthracyclines. Semin. Oncol. 33(Suppl. 8), S2-S7.
29. Elsea, S. H., and Lucas, R. E. (2002). The mousetrap: what we can learn when the mouse model does not mimic the human disease. ILAR J. 43, 66-79.
30. Escudier, B., Eisen, T., Stadler, W. M., Szczylik, C, Oudard, S., Staehler, M., Negrier, S., Chevreau, C, Desai, A. A., Rolland, F., et al. (2009). Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J. Clin. Oncol. 27,3312-3318.
31. Ewer, M. S., and Lippman, S. M. (2005). Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J. Clin. Oncol. 23, 2900-2902.
32. Fabian, M. A., Biggs, W. H., III., Treiber, D. K., Atteridge, C. E., Azimioara, M. D., Benedetti, M. G., Carter, T. A., Ciceri, P., Edeen, P. T., Floyd, M., et al. (2005). A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23, 329-336.
33. Faivre, S., Delbaldo, C, Vera, K., Robert, C, Lozahic, S., Lassau, N., Bello, C, Deprimo, S., Brega, N., Massimini, G., et al. (2006). Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J. Clin. Oncol. 24, 25-35.
34. Fernandez, A., Sanguino, A., Peng, Z., Ozturk, E., Chen, J., Crespo, A., Wulf, S., Shavrin, A., Qin, C, Ma, J., et al. (2007). An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J. Clin. Invest. 117, 4044-4054.
35. Fielitz, J., Kim, M. S., Shelton, J. M., Qi, X., Hill, J. A., Richardson, J. A., Bassel-Duby, R., and Olson, E. N. (2008). Requirement of protein kinase Dl for pathological cardiac remodeling. Proc. Natl. Acad. Sci. U.S.A. 105, 3059-3063.
36. Force, T., Krause, D. S., and Van Etten, R. A. (2007). Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat. Rev. Cancer 7, 332-344.
37. Franklin, R. A., and McCubrey, J. A. (2009). The involvement of CaM-KII in insulin induced cell proliferation. Cell Cycle 8, 1979.
38. Freebern, W. J., Fang, S. H., Slade, M. D., Wells, S., Canale, J., Mehgill, J., Grubor, B., Shi, H., Fletcher, A., Lombardo, L., et al. (2007). In vitro cardiotoxicity potential comparative assessments of chronic myelogenous leukemia tyrosine kinase inhibitor therapies: dasatinib, imatinib and nilotinib. Blood 110, (ASH Annual Meeting Abstracts) (Abstract 4582).
39. Gleevec. Gleevec (Imatinib Mesylate) FDA NDA Pharmacology Review, http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21335_Gleevec.cfm.
40. Gleevec. Gleevec (Imatinib Mesylate) Prescribing Information. http://www.gleevec.com/prescription-information.jsp.
41. Gordon, L. I., Burke, M. A., Singh, A. T., Prachand, S., Lieberman, E. D., Sun, L., Naik, T. J., Prasad, S. V., and Ardehali, H. (2009). Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J. Biol. Chem. 284, 2080-2087.
42. Gray, R. P. (2005). Cardiology in the ageing heart: models. Drug Discov. Today 7, 233-237.
43. Grazette, L. P., Boecker, W., Matsui, T., Semigran, M., Force, T. L., Hajjar, R. J., and Rosenzweig, A. (2004). Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J. Am. Coll. Cardiol. 44, 2231-2238.
44. Gschwind, A., Fischer, O. M., and Ullrich, A. (2004). The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 4, 361-370.
45. Gysin, S., Lee, S. H., Dean, N. M., and McMahon, M. (2005). Pharmacologie inhibition of RAF->MEK->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kipl. Cancer Res. 65, 4870-4880.
46. Haga, N., Fujita, N., and Tsuruo, T. (2003). Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis. Oncogene 22, 5579-5585.
47. Hasinoff, B. B., Patel, D., and O'Hara, K. A. (2008). Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib. Mol. Pharmacol. 74, 1722-1728.
48. Hatfield, A., Owen, S., and Pilot, P. R. (2007). In reply to 'Cardiotoxicity of the cancer therapeutic agent imatinib mesylate'. Nat. Med. 13, 13; author reply 15-16.
49. Heinrich, M. C, Griffith, D. J., Druker, B. J., Wait, C. L., Ott, K. A., and Zigler, A. J. (2000). Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96, 925-932.
50. Herceptin. Herceptin (trastuzumab) MoH Approved Prescribing Information 2003. Available at: http://www.health.gov.il/units/pharmacy/tmfot/alonim/864.pdf. Revised March 2009. Herceptin. (2009).
51. Herceptin (2009) (Trastuzumab) Prescribing Information. Available at: http://www.herceptin.com/index.jsp?hl=en&;q=herceptin+prescribing+information&meta=.
52. Hsieh, P. C, MacGillivray, C, Gannon, J., Cruz, F. U., and Lee, R. T. (2006). Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation 114, 637-644.
53. Ichijo, H., Nishida, E., Irie, K., ten Dijke, P., Saitoh, M., Moriguchi, T., akagi, M., Matsumoto, K., Miyazono, K., and Gotoh, Y. (1997). Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 90-94.
54. Ito, K., Akazawa, H., Tamagawa, M., Furukawa, K., Ogawa, W., Yasuda, N., udo, Y., Liao, C. H., Yamamoto, R., Sato, T., et al. (2009). PDKl coordinates survival pathways and beta-adrenergic response in the heart. Proc. Natl. Acad. Sci. U.S.A. 106, 8689-8694.
55. Jacobson, K. A., and Gao, Z. G. (2006). Adenosine receptors as therapeutic argets.Proc. Natl. Rev. Drug Discov. 5, 247-264.
56. Kantarjian, H. M., Giles, F., Gattermann, N., Bhalla, K., Alimena, G., alandri, F., Ossenkoppele, G. J., Nicolini, F. E., O'Brien, S. G., Litzow, M., et al. (2007). Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in hronic phase following imatinib resistance and intolerance. Blood 110, 3540-3546.
57. Karbowski, M., and Youle, R. J. (2003). Dynamics of mitochondrial orphology in healthy cells and during apoptosis. Cell Death Differ. 10, 870-880.
58. Kerkela, R., Grazette, L., Yacobi, R., Iliescu, C, Patten, R., Beahm, C, alters, B., Shevtsov, S., Pesant, S., Clubb, F. J., et al. (2006). Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat. Med. 12, 908-916.
59. Knight, Z. A., and Shokat, K. M. (2007). Chemical genetics: where genetics nd pharmacology meet. Cell 128, 425-430.
60. Kontaridis, M. I., Yang, W., Bence, K. K., Cullen, D., Wang, B., Bodyak, N., e, Q., Hinek, A., Kang, P. M., Liao, R., et al. (2008). Deletion of Ptpnll (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways. Circulation 117, 1423-1435.
61. Krause, D. S., and Van Etten, R. A. (2005). Tyrosine kinases as targets for ancer therapy. N. Engl. J. Med. 353, 172-187.
62. Krieg, T., Qin, Q., Mcintosh, E. C, Cohen, M. V., and Downey, J. M. (2002). ACh and adenosine activate PI3-kinase in rabbit hearts through trans-activation of receptor tyrosine kinases. Am. J. Physiol. Heart Circ. Physiol. 283, H2322-H2330.
63. Lage, R., Dieguez, C, Vidal-Puig, A., and Lopez, M. (2008). AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol. Med. 14, 539-549.
64. Lee, H. A., Kim, E. J., Hyun, S. A., Park, S. G., and Kim, K. S. (2010). Electrophysiological effects of the anti-cancer drug lapatinib on cardiac repolarization. Basic Clin. Pharmacol. Toxicol. 107, 614-618.
65. Liu, H., Sun, H. Y., Lau, C. P., and Li, G. R. (2007). Regulation of voltage-gated cardiac sodium current by epidermal growth factor receptor kinase in guinea pig ventricular myocytes. J. Mol. Cell. Cardiol. 42, 760-768.
66. Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F., de Oliveira, A. C, Santoro, A., Raoul, J. L., Forner, A., et al. (2008). Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378-390.
67. Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002). The protein kinase complement of the human genome. Science 298, 1912-1934.
68. Marroquin, L. D., Hynes, J., Dykens, J. A., Jamieson, J. D., and Will, Y. (2007). Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol. Sci. 97, 539-547.
69. McDermott, U., Ames, R. Y., Iafrate, A. J., Maheswaran, S., Stubbs, H., Greninger, P., McCutcheon, K., Milano, R., Tarn, A., Lee, D. Y., et al. (2009). Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors. Cancer Res. 69, 3937-3946.
70. McMullen, J. R., Shioi, T., Zhang, L., Tarnavski, O., Sherwood, M. C, Kang, P. M., and Izumo, S. (2003). Phosphoinositide 3-kinase(pl l0alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc. Natl. Acad. Sci. U.S.A. 100, 12355-12360.
71. Mego, M., Reckova, M., Obertova, J., Sycova-Mila, Z., Brozmanova, K., and Mardiak, J. (2007). Increased cardiotoxicity of sorafenib in sunitinib-pretreated patients with metastatic renal cell carcinoma. Ann. Oncol. 18, 1906-1907.
72. Mora, A., Davies, A. M., Bertrand, L., Sharif, I., Budas, G. R., Jovanovic, S., Mouton, V., Kahn, C. R., Lucocq, J. M., Gray, G. A., et al. (2003). Deficiency of PDKl in cardiac muscle results in heart failure and increased sensitivity to hypoxia. EMBO J. 22, 4666-4676.
73. Morello, F., Perino, A., and Hirsch, E. (2009). Phosphoinositide 3-kinase signalling in the vascular system. Cardiovasc. Res. 82, 261-271.
74. Motzer, R. J., Hutson, T. E., Tomczak, P., Michaelson, M. D., Bukowski, R. M., Rixe, O., Oudard, S., Negrier, S., Szczylik, C, Kim, S. T., et al. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115-124.
75. Muraski, J. A., Fischer, K. M., Wu, W., Cottage, C. T., Quijada, P., Mason, M., Din, S., Gude, N., Alvarez, R., Jr., Rota, M., et al. (2008). Pim-1 kinase antagonizes aspects of myocardial hypertrophy and compensation to pathological pressure overload. Proc. Natl. Acad. Sci. U.S.A. 105, 13889-13894.
76. Nexavar. Nexavar (Sorafenib) FDA NDA Pharmacology Review. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021923_sOOO_Nexavar_PharmR.pdf. Revised February 2009.
77. Nexavar. (2009). Nexavar (Sorafenib) Prescribing Information. Available at: http://www.nexavar.com/scripts/pages/en/index.php.
78. Nicolson, T. J., Mellor, H. R., and Roberts, R. R. (2010). Gender differences in drug toxicity. Trends Pharmacol. Sci. 31, 108-114.
79. Oudit, G. Y., Kassiri, Z., Zhou, J., Liu, Q. C, Liu, P. P., Backx, P. H., Dawood, F., Crackower, M. A., Scholey, J. W., and Penninger, J. M. (2008). Loss of PTEN attenuates the development of pathological hypertrophy and heart failure in response to biomechanical stress. Cardiovasc. Res. 78, 505-514.
80. Ozcelik, C, Erdmann, B., Pilz, B., Wettschureck, N., Britsch, S., Hubner, N., Chien, K. R., Birchmeier, C, and Garratt, A. N. (2002). Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc. Natl. Acad. Sci. U.S.A. 99, 8880-8885.
81. Parsons, M., Young, L., Lee, J. E., Jacobson, K. A., and Liang, B. T. (2000). Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D. FASEB J. 14, 1423-1431.
82. Patrucco, E., Notte, A., Barberis, L., Selvetella, G., Maffei, A., Brancaccio, M., Marengo, S., Russo, G., Azzohno, O., Rybalkin, S. D., et al. (2004). P13Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118, 375-387.
83. Peng, X., Pentassuglia, L., and Sawyer, D. B. (2010). Emerging anticancer therapeutic targets and the cardiovascular system: is there cause for concern? Circ. Res. 106, 1022-1034.
84. Perez, E. A., Koehler, M., Byrne, J., Preston, A. J., Rappold, E., and Ewer, M. S. (2008). Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin. Proc. 83, 679-686.
85. Petrelli, A., and Valabrega, G. (2009). Multitarget drugs: the present and the future of cancer therapy. Expert Opin. Pharmacother. 10, 589-600.
86. Pollard, C. E., Valentin, J. P., and Hammond, T. G. (2008). Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective. Br. J. Pharmacol. 154, 1538-1543.
87. Princen, F., Bard, E., Sheikh, F., Zhang, S. S., Wang, J., Zago, W. M., Wu, D., Trelles, R. D., Bailly-Maitre, B., Kahn, C. R., et al. (2009). Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death. Mol. Cell Biol. 29, 378-388.
88. Purcell, N. H., Wilkins, B. J., York, A., Saba-El-Leil, M. K., Meloche, S., Robbins, J., and Molkentin, J. D. (2007). Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc. Natl. Acad. Sci. U.S.A. 104, 14074-14079.
89. Ravdin, P. M., and Chamness, G. C. (1995). The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers-a review. Gene 159, 19-27.
90. Ryberg, M., Nielsen, D., Cortese, G., Nielsen, G., Skovsgaard, T., and Andersen, P. K. (2008). New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J. Natl. Cancer Inst. 100, 1058-1067.
91. Sawyers, C. L. (2002). Imatinib GIST keeps finding new indications: successful treatment of dermatofibrosarcoma protuberans by targeted inhibition of the platelet-derived growth factor receptor. J. Clin. Oncol. 20, 3568-3569.
92. Schimmel, K. J., Richel, D. J., van den Brink, R. B., and Guchelaar, H. J. (2004). Cardiotoxicity of cytotoxic drugs. Cancer Treat. Rev. 30, 181-191.
93. Schmidinger, M., Zielinski, C. C, Vogl, U. M., Bojic, A., Bojic, M., Schukro, C, Ruhsam, M., Hejna, M., and Schmidinger, H. (2008). Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 26, 5204-5212.
94. Seidman, A., Hudis, C, Pierri, M. K., Shak, S., Paton, V., Ashby, M., Murphy, M., Stewart, S. J., and Keefe, D. (2002). Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 20, 1215-1221.
95. Shneyvays, V., Mamedova, L., Zinman, T., Jacobson, K., and Shainberg, A. (2001). Activation of A(3)adenosine receptor protects against doxorubicin-induced cardiotoxicity. J. Mol. Cell. Cardiol. 33, 1249-1261.
96. Sica, D. A. (2006). Angiogenesis inhibitors and hypertension: an emerging issue. J. Clin. Oncol. 24, 1329-1331.
97. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., and McGuire, W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177-182.
98. Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J. A., Wong, S. G., eith, D. E., Levin, W. J., Stuart, S. G., Udove, J., Ullrich, A., et al. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707-712.
99. Spector, N. L., Yarden, Y., Smith, B., Lyass, L., Trusk, P., Pry, K., Hill, J. E., ia, W., Seger, R., and Bacus, S. S. (2007). Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells. Proc. Natl. Acad. Sci. U.S.A. 104, 10607-10612.
100. Speyer, J. (2002). Cardiac dysfunction in the trastuzumab clinical experience. J, Clin. Oncol. 20, 1156-1157.
101. Sprycel. (2009). Sprycel (Dasatinib) Prescribing Information. Available at:http://www.sprycel.com/. Revised June 2009.
102. Sridhar, S. S., Hedley, D., and Siu, L. L. (2005). Raf kinase as a target for anticancer therapeutics. Mol. Cancer Ther. 4, 677-685.
103. Steelman, L. S., Stadelman, K. M., Chappell, W. H., Horn, S., Basecke, J., ervello, M., Nicoletti, F., Libra, M., Stivala, F., Martelli, A. M., et al. (2008). Akt as a therapeutic target in cancer. Expert Opin. Ther. Targets 12 1139-1165.
104. Sukel, M. P., Breekveldt-Postma, N. S., Erkens, J. A., van der Linden, P. D. Beiderbeck, A. B., Coebergh, J. W., and Herings, R. M. (2008). Incidence of cardiovascular events in breast cancer patients receiving chemotherapy in clinical practice. Pharmacoepidemiol. Drug Saf. 17, 125-134.
105. Sutent. Sutent (Sunitinib) FDA NDA Pharmacology Review. Available t: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021938_S000_ Sutent PharmR.pdf. Accessed January 24, 2011.
106. Sutent. Sutent (Sunitinib) Prescribing Information. Available at: http://www.sutent.com/GIST/gist_prescribing_information.aspx. Accessed January 24, 2011.
107. Takahara, A., Sugiyama, A., Satoh, Y., Yoneyama, M., and Hashimoto, K. (2003) Cardiovascular effects of Y-27632, a selective Rho-associated kinase nhibitor, assessed in the halothane-anesthetised canine model. Eur. J. Pharmacol. 460, 51-57.
108. Takai, N., Ueda, T., Nasu, K., Yamashita, S., Toyofuku, M., and Narahara, H. 2009). Targeting calcium/calmodulin-dependence kinase I and II as a potential anti-proliferation remedy for endometrial carcinomas. Cancer Lett. 277, 235-243.
109. Tasigna. (2009). Tasigna (Nilotinib) Prescribing Information. Available at:http://www.pharma.us.novartis.com/products/name/tasigna.jsp. Revised August 2009.
110. Telli, M. L., Witteles, R. M., Fisher, G. A., and Srinivas, S. (2008). Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann. Oncol. 19, 1613-1618.
111. Thomson, M. (2002). Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria. Cell. Mol. Life Sci. 59, 13-219.
112. Tokarska-Schlattner, M., Zaugg, M., Zuppinger, C, Wallimann, T., and chlattner, U. (2006). New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics. J. Mol. Cell. Cardiol. 41, 389-405.
113. Tykerb. (2008). Tykerb (Lapatinib) FDA NDA Pharmacology Review. vailable at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022059s000TOC.cfm. Revised July 2008.
114. Tykerb. (2008). Tykerb (Lapatinib) Prescribing Information. Available at:http://www.tykerb.com/hcp/prescribing-tykerb.html. Revised July 2008.
115. Van den Akker, N. M., Winkel, L. C, Nisancioglu, M. H., Maas, S., isse, L. J., Armulik, A., Poelmann, R. E., Lie-Venema, H., Betsholtz, C, and Gittenberger-de Groot, A. C. (2008). PDGF-B signaling is important for murine cardiac development: its role in developing atrioventricular valves, coronarles, and cardiac innervation. Dev. Dyn. 237, 494-503.
116. Verheul, H. M., and Pinedo, H. M. (2007). Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat. Rev. Cancer 7, 475485.
117. Veronese, M. L., Mosenkis, A., Flaherty, K. T., Gallagher, M., Stevenson, J. P., Townsend, R. R., and O'Dwyer, P. J. (2006). Mechanisms of hypertension associated with BAY 43-9006. J. Clin. Oncol. 24, 1363-1369.
118. Viani, G. A., Afonso, S. L., Stefano, E. J., De Fendi, L. I., and Soares, F. V. (2007). Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 7, 153.
119. Wallace, D. C. (1999). Mitochondrial diseases in man and mouse. Science 283, 1482-1488.
120. Wallace, K. B. (2008). Mitochondrial off targets of drug therapy. Trends Pharmacol. Sci. 29, 361-366.
121. Wang, H., Lindsey, S., Konieczna, I., Bei, L., Horvath, E., Huang, W., Saberwal, G., and Eklund, E. A. (2009). Constitutively active SHP2 cooperates with HoxAl0 overexpression to induce acute myeloid leukemia. J. Biol. Chem. 284, 2549-2567.
122. Weisberg, E., Manley, P. W., Breitenstein, W., Bruggen, J., Cowan-Jacob, S. W., Ray, A., Huntly, B., Fabbro, D., Fendrich, G., Hall-Meyers, E., et al. (2005). Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7, 129-141.
123. White, D. E., Coutu, P., Shi, Y. F., Tardif, J. C, Nattel, S., St Arnaud, R., Dedhar, S., and Muller, W. J. (2006). Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure. Genes Dev. 20, 2355-2360.
124. Will, Y., Dykens, J. A., Nadanaciva, S., Hirakawa, B., Jamieson, J., Marroquin, L. D., Hynes, J., Patyna, S., and Jessen, B. A. (2008). Effect of the multitargeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicol. Sci. 106, 153-161.
125. Yamaguchi, O., Watanabe, T., Nishida, K., Kashiwase, K., Higuchi, Y., Takeda, T., Hikoso, S., Hirotani, S., Asahi, M., Taniike, M., et al. (2004). Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J. Clin. Invest. 114, 937-943.
126. Yang, J. C, Haworth, L., Sherry, R. M., Hwu, P., Schwartzentruber, D. J., Topalian, S. L., Steinberg, S. M., Chen, H. X., and Rosenberg, S. A. (2003). A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427434.
127. Zhang, D. Y., Wang, Y., Lau, C. P., Tse, H. F., and Li, G. R. (2008a). Both EGFR kinase and Src-related tyrosine kinases regulate human ether-a-go-go-related gene potassium channels. Cell. Signal. 20, 1815-1821.
128. Zhang, J., Yang, P. L., and Gray, N. S. (2009). Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 9, 28-39.
129. Zhang, P., Hu, X., Xu, X., Fassett, J., Zhu, G., Viollet, B., Xu, W., Wiczer, B., Bernlohr, D. A., Bache, R. J., et al. (2008b). AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension 52, 918-924.
130. Zhou, X., and Agazie, Y. M. (2009). Molecular mechanism for SHP2 in promoting HER2-induced signaling and transformation. J. Biol. Chem. 284, 12226-12234.
131. Zuppinger, C, and Suter, T. M. (2010). Cancer therapy-associated cardiotox-icity and signaling in the myocardium. J. Cardiovasc. Pharmacol. 56, 141-146.