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Commentary
Apoptosis and anthracycline cardiotoxicity
1 Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado and 2 Scott & White Cancer Research Institute, Temple, Texas
Requests for reprints: Andrew Thorburn, Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Fitzsimons Campus, P.O. Box 6511, Mail Stop 8303, Aurora, CO 80045. Phone: 303-724-3649; Fax: 303-724-3663. E-mail: Andrew.Thorburn{at}uchsc.edu
Anthracyclines were originally isolated from Streptomyces and consist of aglyconic and sugar moieties (1). The molecules are among the most effective anticancer drugs available with antitumor activity against both hematopoietic and solid tumors (2); however, important side effects of these compounds include dilative cardiomyopathy and congestive heart failure (3). This cardiac toxicity is commonly a late effect occurring months posttreatment and is linked to total anthracycline dose, dose schedule, patient age, prior mediastinal irradiation, and prior chemotherapy (3). A better understanding of the molecular mechanisms for anthracycline-induced tumor cell and cardiomyocyte dysfunction and/or death may permit the development of strategies to widen the therapeutic index of this class of agents. Lien et al. (4) provide experiments that support a role for the extrinsic pathway of apoptosis in this toxicity and suggest that signaling by tumor necrosis factor-
(TNF) plays an important role in modulating the cardiac toxicity caused by these drugs.
The critical events underlying both tumor cell killing and cardiomyocyte injury from anthracyclines are unknown. Previous research has led to four dominant hypotheses (5). Anthracyclines may stabilize a reaction intermediate with topoisomerase II and DNA leading to DNA strand breaks and p53-mediated genotoxic programmed cell death. Anthracyclines may bind to allosteric sites on the 20S proteosome leading to the accumulation of undegraded proteins and apoptosis. Third, one-electron redox cycling of anthracycline generates free radicals which may directly cause lipid and DNA damage or indirectly trigger apoptosis by modification of the mitochondrial membranes, kinase signaling molecules (p38MAPK), acidic sphingomyelinases, apoptotic regulatory proteins (Fas, Fax, BclXL) or transcription factors (GATA-4, IRP-1, and nuclear factor-
B). Fourth, alcohol derivatives of anthracyclines may release iron from aconitase, facilitating iron-mediated free radical generation and cell injury. If we are to rationally design strategies to alleviate the cardiac toxicity that is caused by anthracyclines, we must first work out how the damage is caused. There are data supporting each of the molecular mechanisms listed above and no clear evidence that any one set of events is the principal cause of either tumor cell killing or cardiomyocyte injury. This confusion makes it valuable to search for common themes, one of which is that many of the proposed mechanisms of cardiac damage could lead to cardiomyocyte apoptosis.
A complication is that although anthracycline-induced apoptosis of cardiomyocytes is commonly found in vitro, we do not know if apoptosis is a necessary step for anthracycline-induced chronic cardiomyopathy in vivo (5). Most reports of anthracyclines (in particular doxorubicin) systemically given to rats showed cardiac muscle apoptosis measured by terminal nucleotidyl transferase–mediated nick end labeling positivity, DNA fragmentation, increased caspase-3 activity, annexin V binding, and electron microscopic evidence of nuclear fragmentation with intact plasma membranes (6–12). However, there is conflicting data on the specific apoptotic pathway involved. Two studies showed doxorubicin-induced in vivo mitochondrial injury with reduced state 3 oxygen consumption, reduced aconitase, increased malondialdehyde, increased carbonyl groups, and increased free thiols (6, 8). These findings are consistent with anthracycline-mediated electron leakage from the electron transport complexes. Childs et al. found increased cytosolic cytochrome c supportive of an intrinsic mitochondrial apoptosis pathway (8). Other investigators showed rapid protective changes in the mitochondria to anthracyclines with increased Cu/Zn superoxide dismutase, increased Bcl2/Bax, and no changes in mitochondrial hydrogen peroxide (6, 10). Cytosolic cytochrome c release was not seen nor was caspase-9 activated. Interestingly, hydrogen peroxide released from the protected mitochondria damaged key proteins and enzymes of the sarcoplasmic reticulum. This triggered the sarcoplasmic reticulum–mediated apoptotic pathway with caspase-12 and calpain activation (10). Finally, the studies of Lien et al. (4), Nakamura et al. (12), and Yamaoka et al. (13) showed increased cardiac Fas levels and protection in at least one study by anti-Fas ligand (12). In these three studies, the extrinsic (i.e., death receptor) apoptotic pathway was therefore important. It is not clear why different cell death machineries were triggered in these different in vivo experiments with the same anthracycline and the same time course.
In the article by Lien et al., a new twist is presented (4). The authors examine the role of TNF signaling and its effects on cardiomyocyte apoptosis after treatment with anthracyclines. TNF signals through two cell surface receptors, TNFR1 and TNFR2, to activate a variety of signaling pathways that activate nuclear factor-B, c-Jun-NH2-kinase, and other mitogen-activated protein kinases and caspase-8 (14). In some cell types, TNF treatment preferentially induces apoptosis via the caspase-8 pathway; however, in most cases, this apoptotic signal is counteracted by pro-survival signals that are simultaneously activated, especially through nuclear factor-B. In the heart, TNF could have both beneficial and detrimental effects, but has been strongly implicated in providing protection during postischemic injury in both the heart (15) and brain (16). Lien et al. show that Adriamycin treatment leads to increased levels of TNF that, therefore, could affect anthracycline-induced toxicity either by increasing or decreasing the damage in the heart (4). In this issue of Molecular Cancer Therapeutics, this question is directly addressed by asking if mice that lack one or both TNF receptors differ in their response to Adriamycin-induced cardiac toxicity. The results seem quite clear—wild-type mice display significantly less cardiac damage than their double-knockout counterparts when treated with Adriamycin. Therefore, it seems that the increase in TNF which occurs after Adriamycin treatment is important because it provides protection against cardiac toxicity. This leaves us with the question of how TNF does this and, more importantly, whether these findings will help us to come up with better ways to use anthracyclines in the clinic—i.e., to reduce the cardiac toxicity problem.
Based on experiments in isolated cardiac muscle cells and in whole animals, Lien et al. propose that the mechanism by which TNFR1 and TNFR2 signaling protects cardiac cells is by blocking apoptosis caused by release of mitochondrial proteins such as cytochrome c and inhibition of signaling by the Fas receptor system, which has previously been implicated in mediating anthracycline toxicity (12, 13, 17). However, the detailed mechanisms and exactly which apoptotic pathways are being inhibited by TNFR signaling are still unclear. For example, the ability of TNFR1 and TNFR2 to block the Adriamycin-induced activation of the Fas-mediated pathway is suggested by the fact that increased levels of truncated Bid are found in the double knockout mice after treatment with Adriamycin. Because Bid cleavage is normally induced by caspase-8, which is activated by the Fas pathway, this is a reasonable suggestion. However, anything that can activate caspase-8 (directly or indirectly), including any apoptotic stimulus that activates effector caspases (18) will potentially lead to Bid cleavage, hence, the increased cleavage after Adriamycin treatment that is caused by the knockout of TNF receptors could have occurred because Fas-independent apoptotic signaling is occurring in the cells. Moreover, Bid cleavage during cardiac damage caused by ischemia/reperfusion injury is caused not by caspases but rather by calpains (19), therefore, caspase-independent mechanisms of activating Bid (perhaps involving the sarcoplasmic reticulum; ref. 10) may also be important in this regard. Finally, it should be noted that the protective activity of TNFR signaling is seen after short-term exposure of a few days with a relatively high dose of Adriamycin and we do not yet know if similar effects would be found with lower doses repeatedly given over long periods of time. Recent studies examining gene expression changes caused by 12 weekly treatments of lower doses of the drug are somewhat different from those found after a single high dose (20), raising the possibility that different mechanisms may be at play under acute and chronic conditions. Although there is clearly much still to be learned, the demonstration that TNFR signaling provides protection against anthracycline-induced cardiac toxicity, both in vitro and in animals, provides a basis to generate further avenues of investigation that may broaden our armamentarium of anthracycline toxicity modifiers beyond the iron chelator, dexrazoxane (21). An old drug approached with some of our modern biotechnology tools may be further improved.
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in brain injury. Cytokine Growth Factor Rev 1999;10:119–30.[CrossRef][Medline] Kalivendi SV, Konorev EA, Cunningham S, et al. Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium. Biochem J 2005;389:527–39.[CrossRef][Medline] Cowling V, Downward J. Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ 2002;9:1046–56.[CrossRef][Medline] Chen M, Won DJ, Krajewski S, Gottlieb RA. Calpain and mitochondria in ischemia/reperfusion injury. J Biol Chem 2002;277:29181–6.Key Article
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