Effects of age on multidrug resistance protein expression and doxorubicin accumulation in cardiac and skeletal muscle

Abstract

1. Doxorubicin (DOX) is a highly effective and commonly used anthracycline antibiotic used to treat cancer patients. The side effects of DOX are manifested in a more delayed manner in children and multidrug resistant proteins (MRPs) may factor into this phenomenon. MRPs are known to extrude DOX and may factor into the degree of cardiac DOX accumulation. 2. The purpose of this study was to examine age-related differences in muscle MRP expression and DOX accumulation. 3. Female Sprague-Dawley rats were randomly selected to receive a 15-mg DOX/kg body weight bolus injection (i.p.) at various ages. 4. Cardiac and extensor digitorum longus DOX accumulation was markedly increased as animals aged from 4 to 24 weeks. In contrast, no differences in soleus accumulation were observed. A significant age-related reduction in MRP-2 and MRP-7 expression was detected in cardiac and extensor digitorum longus tissues with no age differences in MRP-1 expression in any tissues analyzed. MRP-6 was not detected in any tissues. 5. These data suggest that aging is associated with increased DOX accumulation and an age-related decrease in MRP expression may be a factor.

Skeletal Muscle an Active Compartment in the Sequestering and Metabolism of Doxorubicin Chemotherapy

“…Previous studies have focused on the accumulation of DOX in the heart, liver, spleen, lung, brain and kidney [ 30 – 34 ]. However very few have investigated the accumulation in skeletal muscle [ 7 , 35 , 36 ]. The accumulation of DOX was observed in the muscle at each time point regardless of the administered dose.…”

Current Insights into Cellular Senescence and Myotoxicity Induced by Doxorubicin: The Role of Exercise and Growth Factors

“…Doxorubicin is a chemotherapeutic drug widely used against a variety of malignancies such as acute leukaemia, non-Hodgkin lymphomas, Hodgkin's disease, breast cancer, lung cancer, childhood solid tumours and sarcomas [1,2]. Doxorubicin is an antibiotic (i.e.…”

“…Increased ROS enhances p53-DNA binding to activate the DNA cross-linking and caspase signaling and results in DNA damage and apoptosis [1]. However, the doxorubicin non-specific mechanism of action has deleterious effects on healthy cells and tissues that restrict its clinical use [2]. As a matter of fact, several studies have shown that doxorubicin induces cellular senescence in various cell types [11][12][13][14].…”

“…In addition to cachexia, sarcopenia (i. e. loss of skeletal muscle mass and strength) represents a comorbidity during cancer that affects the quality of life and increases the mortality rates of cancer patients [1,9]. Among the main side effects of doxorubicin are nausea, hair and weight loss, fatigue, vasculature and liver toxicity, cardiotoxicity and, last but not least, skeletal muscle atrophy [1,2,6,15].…”

Exercise training does not affect anthracycline antitumor efficacy while attenuating cardiac dysfunction

“…We have previously shown that exercise provides cardioprotection against DOX-induced cardiotoxicity and that this protection is associated with reduced accumulation of DOX within cardiac tissue (25). Reduced accumulation may be related to the expression of multidrug resistance proteins (MRPs) (16), which have been shown to be upregulated by exercise (13,14,31). MRPs are located in the cellular plasma membrane where they efflux a broad range of substrates, including chemotherapeutic agents, such as DOX.…”