Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Circ Res. 2010 Jan 8;106(1):21-34. doi: 10.1161/CIRCRESAHA.109.206920.
In 2002, Hoshijima and Chien drew largely theoretical parallels between the dysregulation of the signaling pathways driving cancer and those driving cardiac hypertrophy (Hoshijima M, Chien KR. J Clin Invest. 2002;109:849-855). On the surface, this statement appeared to stretch the limits of reason, given the fact that cancer cells are known for their proliferative capacity, and adult cardiomyocytes are, except under unusual circumstances, terminally differentiated and incapable of re-entering the cell cycle. However, on closer examination, there are numerous parallels between signaling pathways that drive tumorigenesis and signaling pathways that regulate hypertrophic responses and survival in cardiomyocytes. Indeed, this issue appears to be at the core of the cardiotoxicity (often manifest as a dilated cardiomyopathy) that can result from treatment with agents typically referred to as "targeted therapeutics," which target specific protein kinases that are dysregulated in cancer. Herein, we examine the cardiotoxicity of targeted therapeutics, focusing on the underlying molecular mechanisms, thereby allowing an understanding of the problem but also allowing the identification of novel, and sometimes surprising, roles played by protein kinases in the heart.
2002 年，Hoshijima 和 Chien 主要从理论上比较了驱动癌症的信号通路失调与驱动心肌肥厚的信号通路（Hoshijima M, Chien KR. J Clin Invest. 2002;109:849-855）。从表面上看，这一说法似乎超出了常理，因为众所周知，癌细胞具有增殖能力，而成年心肌细胞除了在特殊情况下，已经终末分化，无法重新进入细胞周期。然而，进一步研究表明，驱动肿瘤发生的信号通路与调节心肌肥厚反应和生存的信号通路之间存在许多相似之处。事实上，这一问题似乎是导致通常被称为“靶向治疗”的药物治疗所引起的心脏毒性（常表现为扩张型心肌病）的核心问题，这些药物靶向在癌症中失调的特定蛋白激酶。在此，我们研究了靶向治疗的心脏毒性，重点关注潜在的分子机制，从而不仅可以理解这一问题，还可以发现蛋白激酶在心脏中发挥的新的、有时令人惊讶的作用。
