Cancer Therapy–Induced Cardiotoxicity: Basic Mechanisms and Potential Cardioprotective Therapies

Hahn, Virginia S.; Lenihan, Daniel J.; Ky, Bonnie

doi:10.1161/jaha.113.000665

Cited by 228 publications

(176 citation statements)

References 147 publications

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“…Subsequent to the clinical trials showing cardiotoxicity from trastuzumab use, emerging research found that HER2 receptors expressed in the membranes of adult cardiomyocytes have an important role in transmitting growth and survival signals 62. In response to the ligand, neuregulin‐1, ErbB2 forms heterodimers that activate cell hypertrophy and survival pathways through activation of the phosphoinositide 3‐kinase and protein kinase A pathways as well as the mitogen‐activated protein kinase cascade 60, 63. In murine models, deletion of ErbB2 leads to development of spontaneous dilated cardiomyopathy and makes these mice more sensitive to triggers of cardiomyopathy such as pressure overload and anthracyclines 64, 65.…”

Section: Pathophysiologymentioning

confidence: 99%

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

Florido

Smith

Cuomo

et al. 2017

JAHA

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Section: Pathophysiologymentioning

confidence: 99%

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

Florido

Smith

Cuomo

et al. 2017

JAHA

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“…These studies further suggest that the chronic manifestations of DOXinduced cardiotoxicity may result from myocardial injuries associated with acute DOX exposure [18]. Thus far multiple mechanisms of DOX-induced cardiotoxicity have been proposed in the literature [19][20][21][22][23][24][25][26]. Among the proposed mechanisms, DOXinduced generation of reactive oxygen species (ROS) is the central mediator of numerous direct and indirect cardiac adverse consequences.…”

Section: Doxorubicin-induced Cardiotoxicitymentioning

confidence: 99%

“…Effective new interventions for alleviating the cardiotoxic effects of DOX are expected to occur in two different ways; either exploiting the tissue-specific differences between cancerous tissues and the cardiomyocyte/cardiac endothelium or affecting the cardiotoxic mechanisms without disrupting antitumor pathways [25]. Currently, a number of potential cardioprotective therapies are under active investigation for treating and/or preventing DOXinduced cardiotoxicity.…”

Section: ) Impairment Of Prosurvival Signalingmentioning

confidence: 99%

“…These include exercise training, HMG-CoA reductase inhibitors, betablockers, angiotensin receptor blockers, ACE inhibitors, and bivalent neuregulin. Of the potential cardioprotective strategies that are being investigated, aerobic exercise training is the only nonpharmacologic strategy that promises to attenuate DOX-induced cardiac dysfunction significantly [24,25,49].…”

Section: ) Impairment Of Prosurvival Signalingmentioning

confidence: 99%

“…However, based on these studies, a number of potential molecular mechanisms have been proposed to explain the protective properties of exercise training against DOX-induced cardiac damage [24,25,[49][50][51][52][53][54][55][56][57][58][59]. The following is a brief description of these proposed mechanisms: Modulation of calpain activation has also been implicated in exercise-induced protection against DOX cardiotoxicity [64].…”

Section: Table 1 Continued…mentioning

confidence: 99%

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Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity

Kouzi

Uddin

2016

J Pharm Pharm Sci

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Doxorubicin is one of the most commonly used cytotoxic anticancer drugs against several cancers. Although a highly effective anticancer drug, the clinical use of doxorubicin is severely limited by its cardiotoxicity which results in morbidity, poor quality of life, and premature mortality. Only very few clinically accepted methods to minimize doxorubicin-induced cardiac injury are available today, but none of them have proven to be completely successful. Due to limited alternative strategies, a number of potential cardioprotective therapies are currently being investigated for treating and/or preventing doxorubicin-induced cardiotoxicity. Of these potential strategies, aerobic exercise training is the only nonpharmacologic strategy that shows a great deal of promise. Although there are no published human clinical trials, evidence from numerous animal studies suggests that aerobic exercise training, administered prior to, during and/or following doxorubicin therapy, is protective against doxorubicin-induced cardiac injury. Protective properties of exercise training against the cardiotoxicity of doxorubicin have been attributed to a number of potential molecular mechanisms including: enhancing the production of endogenous antioxidant machineries; regulating proapoptotic signaling; stimulating the release, mobilization and homing of cardiac progenitor cells; limiting myocyte turnover; eliciting favorable adaptations in myocardial calcium handling and preventing calcium overload; modulating cardiac AMPK activity; downregulating cardiac autophagy/lysosomal signaling; and reducing myocardial doxorubicin accumulation. Further preclinical and clinical research is needed to decipher and refine the molecular mechanisms underlying the cardioprotective effects of exercise training, as well as to define the nature and magnitude of the effect of exercise on doxorubicin-induced cardiotoxicity in cancer patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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The efficacy and cardiac toxicity of different‐dose pegylated liposomal doxorubicin in elderly patients with diffuse large B lymphoma

Chen

Zhou

et al. 2022

Cancer Medicine

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Objectives In order to explore the impact of pegylated liposomal doxorubicin (PLD) dose intensity on survival outcomes of newly diagnosed elderly patients with diffuse large B‐cell lymphoma (DLBCL), we performed a retrospective study to compare the efficacy and adverse effects of RCEOP (70 mg/m2), RCdOP (20–30 mg/m2) and RCDOP (30–45 mg/m2). The optimal PLD dose of patients with different clinical characteristics of subgroups was explored to provide a clue for the selection of clinical PLD dose. Methods A total of 335 DLBCL patients (60–85 years old) who were newly diagnosed and completed at least four cycles of RCE(D)OP were selected. The patients were mainly divided into RCEOP (126 cases) (epirubicin 70 mg/m2), RCdOP (151 cases) (PLD 20–30 mg/m2) and RCdOP (58 cases) (PLD 30–45 mg/m2). The effects of different doses of PLD on clinical efficacy, cardiotoxicity and prognosis of patients were retrospectively analyzed. Subgroup analysis was performed to compare the clinical characteristics of different subgroups. Results Our study showed that PLD and epirubicin had similar efficacy (overall survival (OS) p = 0.776; progression‐free survival (PFS) p = 0.959). RCDOP (30–45 mg/m2 PLD) group had a higher complete remission (CR) rate of 75.9% compared with RCdOP (20–30 mg/m2 PLD) group (P D vs. d = 0.018). In the overall population, there was no significant difference in survival between RCDOP and RCdOP groups (OS P D vs. d = 0.661; PFS P D vs. d = 0.212). In patients with underlying cardiovascular diseases, the PFS of the RCDOP group was significantly better than the RCdOP group (p = 0.043). Meanwhile, patients in the RCDOP group tended to have a better prognosis than those in the RCEOP group (OS: RCDOP vs. RCEOP p = 0.054, PFS: RCDOP vs. RCEOP p = 0.053). There was no significant difference in the incidence of cardiotoxicity and other adverse events among the three groups. For the low‐risk (age‐adjusted‐International Prognostic Index = 0/1) old patients without cardiovascular disease, RCdOP was considered a better strategy in OS (p = 0.020). Conclusion In the general population, the CR rate in the RCDOP group was significantly higher than that in the RCdOP group (p = 0.018). For elderly DLBCL patients with cardiovascular disease, the effect benefit brought by the PLD dose was more obvious, and the PFS of the RCDOP group was significantly better than that of the RCdOP group (p = 0.043). Full dose of PLD is an efficient alternative in the treatment of patients with preexisting cardiovascular diseases.

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Cancer Therapy–Induced Cardiotoxicity: Basic Mechanisms and Potential Cardioprotective Therapies

Cited by 228 publications

References 147 publications

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity

The efficacy and cardiac toxicity of different‐dose pegylated liposomal doxorubicin in elderly patients with diffuse large B lymphoma

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