Direct effects of doxorubicin on skeletal muscle contribute to fatigue

Norren, Klaske van; Helvoort, Ardy van; Argilés, Josep Μ.; Tuijl, Sjoerd van; Arts, K.; Gorselink, M.; Laviano, Alessandro; Kegler, Diane; Haagsman, Henk P.; Beek, Eline M. van der

doi:10.1038/sj.bjc.6604858

Cited by 106 publications

(91 citation statements)

References 15 publications

(21 reference statements)

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“…However, use of antioxidants has had disappointing outcomes in both humans and animals, and a third of patients administered dexrazoxane (to prevent ironmediated ROS production) still develop heart failure, suggesting the coexistence of non-ROS-mediated actions (van Dalen et al, 2009). There is mounting evidence that anthracycline-induced dysfunction of cardiomyocyte Ca 21 signaling pathways contributes to the cardiotoxicity (Zorzato et al, 1985;Abramson et al, 1988;Ondrias et al, 1990;Feng et al, 1999;Charlier et al, 2005;Park et al, 2005;van Norren et al, 2009;Gilliam and St Clair, 2011;Hanna et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In vitro experiments show that anthracyclines can stimulate and inhibit RyR Ca 21 release in both cardiac and skeletal muscle (Abramson et al, 1988;Pessah et al, 1990;Olson et al, 2000), and reduce the Ca 21 -binding capacity of CSQ2 (Kang et al, 2010), and they are believed to compromise SERCA2A function (van Norren et al, 2009) in skeletal muscle. In addition to binding directly to RyR2 and CSQ2, anthracyclines are also thought to decrease the number of reactive thiol groups on RyR2 directly, or indirectly via increased ROS production (Abramson et al, 1988;Hanna et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A

et al. 2014

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The use of anthracycline chemotherapeutic drugs is restricted owing to potentially fatal cardiotoxic side effects. It has been hypothesized that anthracycline metabolites have a primary role in this cardiac dysfunction; however, information on the molecular interactions of these compounds in the heart is scarce. Here we provide novel evidence that doxorubicin and its metabolite, doxorubicinol, bind to the cardiac ryanodine receptor (RyR2) and to the sarco/endoplasmic reticulum Ca 21 ATPase (SERCA2A) and deleteriously alter their activity. Both drugs (0.01 mM-2.5 mM) activated single RyR2 channels, and this was reversed by drug washout. Both drugs caused a secondary inhibition of RyR2 activity that was not reversed by drug washout. Preincubation with the reducing agent dithiothreitol (DTT, 1 mM) prevented drug-induced inhibition of channel activity. Doxorubicin and doxorubicinol reduced the abundance of thiol groups on RyR2, further indicating that oxidation reactions may be involved in the actions of the compounds. Ca 21 uptake into sarcoplasmic reticulum vesicles by SERCA2A was inhibited by doxorubicinol, but not doxorubicin. Unexpectedly, in the presence of DTT, doxorubicinol enhanced the rate of Ca 21 uptake by SERCA2A. Together the evidence provided here shows that doxorubicin and doxorubicinol interact with RyR2 and SERCA2A in similar ways, but that the metabolite acts with greater efficacy than the parent compound. Both compounds modify RyR2 and SERCA2A activity by binding to the proteins and also act via thiol oxidation to disrupt SR Ca 21 handling. These actions would have severe consequences on cardiomyocyte function and contribute to clinical symptoms of acute anthracycline cardiotoxicity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A

et al. 2014

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“…A study conducted in mice in 2009 showed that with increasing doses of doxorubicin, there was a decrease in the maximum contractile force and velocity with an increase in relaxation time of skeletal muscle, making it more susceptible to fatigue. [8] In addition, Fabris et al showed in a rat model that skeletal muscle may play an important role in the sequestration of doxorubicin, and direct myocyte injury may occur in response to the development of reactive oxygen species. [9] To our knowledge, this is the first reported case of exertional ACS in a female.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy and extreme exercise: A potentially dangerous combination

Gandhi

Roy

2016

CRIM

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Acute exertional compartment syndrome of the thighs is extremely rare. It should be considered in patients who present with myalgia and swelling after vigorous exercise. We present a case of a 35-year-old female athlete with breast cancer who had received one cycle of chemotherapy. The patient presented with diffuse myalgias in her thighs after an exercise session. She was diagnosed with chemotherapy induced compartment syndrome of the bilateral thighs with resultant rhabdomyolysis and acute kidney injury. She required continuous venovenous hemodialysis. The patient suffered a cardiac arrest and could not be resuscitated. This case draws attention to the potential myotoxocity of certain chemotherapeutic agents. It also demonstrates acute compartment syndrome as a rare but devastating consequence of extreme physical training associated with certain chemotherapeutic agents. As many of our patients are adopting vigorous exercise routines, it is important for physicians to be aware of acute exertional compartment syndrome, as it necessitates a high degree of clinical suspicion.

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“…Alessandro Laviano emphasized the various effects of anticancer treatment: (1) that tumor response is often associated with improvement of cachexia-related symptoms [8,12], (2) that anticancer treatment can deteriorate energy intake [16,24], and (3) that chemotherapeutic agents can directly affect skeletal muscle [25]. These data suggest that continuous monitoring of patients' nutritional intake [4], weight, and associated symptoms (e.g., early satiety, fatigue) is of value.…”

Section: Introductionmentioning

confidence: 99%