Acute Doxorubicin Cardiotoxicity Is Associated With p53-Induced Inhibition of the Mammalian Target of Rapamycin Pathway

Abstract

Background-Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity. Methods and Results-Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose Key Words: heart failure Ⅲ apoptosis Ⅲ myocytes A nthracyclines such as doxorubicin, daunomycin, epirubicin, and idarubicin are widely used and highly successful anticancer chemotherapeutic drugs. Unfortunately, these drugs also induce acute cardiotoxicity, which is characterized by hypotension, tachycardia, arrhythmia, and transient depression of left ventricular function. [1][2][3][4] In addition, high cumulative doses are associated with late-onset cardiomyopathy that is refractory to standard treatment. It is widely thought that free radical-induced mitochondrial damage contributes to doxorubicin-induced cardiotoxicity. 5 In addition, doxorubicin can induce DNA damage, inhibit DNA and protein synthesis, promote myofiber degeneration, inhibit transcription of specific gene programs, and induce cardiomyocyte apoptosis via a caspase-3-dependent mechanism. Because doxorubicin can interfere with many different intracellular processes, it has proven difficult to determine the molecular mechanism of its acute and chronic cardiotoxicity. Clinical Perspective p 106Numerous studies have shown that doxorubicin-induced cardiomyocyte apoptosis is associated with increased expression of the p53 tumor suppressor protein. Moreover, reduction of p53 activity via genetic deletion 6 or chemical inhibition 7 is cardioprotective during short-term doxorubicin treatment. To further characterize the role of p53 in acute doxorubicin-induced cardiotoxicity, MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) 8 were studied 7 days after the initiation of treatment. Cardiac function was improved, with a concomitant reduction in cardiomyocyte apoptosis, in the MHC-CB7 mice compared with their doxorubicin-treated nontransgenic siblings. Surprisingly, expression of the MHC-CB7 transgene also markedly blunted the doxorubicin-induced reduction of cardiac mass observed in nontransgenic mice. Western blot analyses indicated that doxorubicin treatment reduced the level of activated mammalian target of rapamycin (mTOR) in nontransgenic mice. mTOR is a serine/threonine protein kinase that regulates protein translation and cell growth. 9 Expression of the MHC-CB7 transgene blocked doxorubicin-induced reduction of mTOR activity. To establish the role of mTOR signaling in doxorubicin-induced cardiotoxicity, mice expressing constitutively active mTOR in the myocardium (MHC-mTORca mice) 10 were subjected to doxorubicin treatment. Expression of the MHC-mTORca transgene was suffi...

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

“…The mechanism of this type of cellular injury is likely multifactorial including the formation of reactive oxygen species, elevation of cytoplasmic Ca 2? concentration and activation of intracellular proteases as well as inhibition of the mTOR signaling pathway and the cardiac transcription factor GATA4 (Lim et al 2004;Pentassuglia et al 2009;Timolati et al 2006;Zhu et al 2009). We have used myofibrillar changes as a marker for cancer therapy-associated cardiotoxicity with different classes of drugs such as paclitaxel, anti-ErbB2 antibodies, MEK-inhibitors and small tyrosine kinase inhibitors for ErbB1/ErbB2 (Pentassuglia et al 2007(Pentassuglia et al , 2009Sawyer et al 2002).…”

Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity

“…Two-dimensional short-axis images were obtained with a high-resolution micro-ultrasound system (Vevo 770, VisualSonics) equipped with a 40 MHz mechanical scan probe. Fractional shortening (FS), ejection fraction, left ventricular internal diameter (LVID) during systole, LVID during diastole, end-systolic volume, and end-diastolic volume were calculated with Vevo Analysis software (version 2.2.3) as described previously (Zhu et al, 2009). LVID during systole and diastole were measured from M-mode recording at the level of the mid-papillary muscle, whereas end-systolic and end-diastolic volumes were measured with B-mode recording in a plane containing the aortic and mitral valves.…”

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

“…apoptosis and interstitial fibrosis at later stages of LV dilated cardiomyopathy (8,9). There is growing evidence that the DOX-induced cardiac apoptosis and fibrosis are mainly caused by excess production of ROS (10)(11)(12)(13), which is initiated by NADPH oxidase (Nox) activation (13,14).…”