Chia-Ying Lien

Exercise Preconditioning Protects against Doxorubicin-Induced Cardiac Dysfunction

UNLABELLED The clinical use of the chemotherapeutic drug doxorubicin (DOX) is limited due to a dose-dependent cardiotoxicity. Evidence is mounting that exercise protects against DOX-related cardiac dysfunction, and as such, it may be possible that prior endurance training promotes defense against DOX cardiotoxicity. PURPOSE To examine the effects of exercise preconditioning on acute DOX-induced cardiotoxicity, and to determine whether any observed cardioprotection was associated with myosin heavy chain (MHC) isoform alterations. METHODS Male Sprague-Dawley rats trained on a motorized treadmill, had access to voluntary running wheels, or remained sedentary for 10 wk prior to being injected with either saline or 10 mg.kg(-1) DOX. Left ventricular function was then assessed in vivo using transthoracic echocardiography and ex vivo using the isolated working heart at 5 and 10 d after injection. Additionally, left ventricular MHC isoform expression was analyzed as a possible mechanism to explain exercise-induced cardioprotection. RESULTS DOX treatment promoted significant in vivo and ex vivo cardiac dysfunction at 5 and 10 d after injection in sedentary animals, and this dysfunction was associated with an upregulation of the beta-MHC isoform. Exercise preconditioning protected against DOX-induced cardiac dysfunction at 5 and 10 d after injection by attenuating beta-MHC upregulation. CONCLUSION Endurance training prior to DOX treatment protects against acute DOX cardiotoxicity for up to 10 d, and this protection can potentially be explained by a preservation of MHC isoform distribution.

Exercise Preconditioning Provides Long-Term Protection Against Early Chronic Doxorubicin Cardiotoxicity

Acute doxorubicin (DOX) cardiotoxicity can be attenuated by exercise preconditioning, but little is known of whether this cardioprotection continues beyond 10 days post-DOX administration. The purpose of this study was to determine the effects of exercise preconditioning on early chronic DOX-induced cardiotoxicity. Male rats were randomly assigned to sedentary, treadmill, or wheel running groups. Treadmill and wheel running animals participated in a progressive treadmill training protocol or voluntary wheel running, respectively, for 10 weeks. Following the intervention, animals were further randomized to receive either DOX (sedentary + DOX, treadmill + DOX, wheel running + DOX) or saline (sedentary + saline, treadmill + saline, wheel running + saline). All animals then remained sedentary for 4 weeks. A 22% reduction in fractional shortening was observed in left ventricles from previously sedentary animals receiving DOX when compared with sedentary + saline. This degree of decline was not observed in treadmill + DOX and wheel running + DOX. Sedentary + DOX possessed significantly depressed mitral and aortic valve blood flow velocities when compared with sedentary + saline, but these decrements were not observed in treadmill + DOX and wheel running + DOX. Ex vivo analysis revealed that left ventricular developed pressure and maximal rate of pressure development were significantly lower in sedentary + DOX when compared to sedentary + saline. Treadmill and wheel running prior to DOX treatment protected against these decrements. Exercise cardioprotection was associated with preserved myosin heavy chain but not sarcoendoplasmic reticulum Ca2+ ATPase 2a expression. In conclusion, 10 weeks of prior exercise protected against early chronic DOX cardiotoxicity suggesting that training status may be a determining factor in the degree of late-onset cardiotoxicity experienced by cancer patients undergoing treatment with DOX.

Exercise training mitigates anthracycline-induced chronic cardiotoxicity in a juvenile rat model.

Childhood cancer survivors are at greater risk of cardiovascular complications once they reach adulthood. Anthracyclines may be a major contributor to these delayed‐onset complications, yet their use continues because of favorable clinical outcomes. Exercise has been shown to protect against anthracycline cardiotoxicity, yet it is unclear whether exercise can protect against delayed‐onset cardiotoxicity when treatment is initiated in childhood. The aim of the present study was to determine if exercise training provides cardioprotection in a juvenile rat model of delayed‐onset anthracycline cardiotoxicity.

Anandamide preserves cardiac function and geometry in an acute doxorubicin cardiotoxicity rat model.

We investigated the use of the endocannabinoid anandamide as a means of cardioprotection against doxorubicin-induced cardiac dysfunction. Male rats received doxorubicin with or without anandamide pretreatment. Cardiac function was assessed in vivo using transthoracic echocardiography and ex vivo using the isolated working heart 5 days posttreatment. Doxorubicin administration without anandamide pretreatment resulted in a decline in fractional shortening (P < .05) and left ventricular wall thickness when compared to controls (P < .05). Ex vivo cardiac function analysis revealed a reduction in left ventricular developed pressure in hearts from animals receiving doxorubicin without anandamide pretreatment when compared to controls (P < .05). Left ventricles from animals receiving anandamide pretreatment before doxorubicin administration did not exhibit depressed fractional shortening, ventricular wall thickness, or developed pressure when compared to controls (P > .05). These results suggest that a potential therapy for doxorubicin-induced cardiotoxicity involves targeting the endogenous cannabinoid system.

Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity

The use of exercise to minimize doxorubicin (DOX)-induced cardiotoxicity is gaining attention. However, very few clinically relevant reports exist investigating the effects of exercise performed during and following DOX treatments. The purpose of this study, therefore, was to examine the effects of voluntary wheel running during and following DOX treatment using two models of late-onset DOX cardiotoxicity in the rat. Female Sprague-Dawley rats received either DOX or saline injections using one of two separate treatment regimens. These regimens involved either daily or weekly DOX injections with cumulative doses for both protocols totaling 15 mg/kg. Daily DOX injections were 1 mg/kg and lasted for 15 consecutive days while weekly DOX injections were 2.5 mg/kg and lasted for six consecutive weeks with control animals receiving matched saline injection regimens. Immediately following the initial DOX/saline injection, animals were randomly housed in cages with voluntary running wheels or standard rat cages throughout DOX/saline treatments and continued until reaching 10 weeks. Cardiac function was then assessed using echocardiography and an isolated working heart model, and myosin heavy chain (MHC) isoform distribution was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When compared wth controls, daily DOX treatment resulted in reduced running wheel distances at weeks 2-10 (P < 0.05), and weekly DOX treatment resulted in reduced running wheel distances at weeks 2, 6 and 10 (P < 0.05). Nonetheless, wheel running during and following daily and weekly DOX dosing protected against DOX-induced cardiotoxicity by preserving maximal mitral and aortic blood flow velocities, left ventricular developed pressure and MHC isoform expression. In conclusion, the overall reduced volume of activity during and following daily and weekly DOX treatments attenuated DOX-induced cardiac dysfunction suggesting that low-volume endurance training may be an effective rehabilitative approach in minimizing DOX cardiotoxicity in cancer patients.

Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat.

Purpose: Doxorubicin (DOX) is an effective antineoplastic agent with well-characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. Methods: Sprague–Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation. Results: Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function. Conclusions: These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

Voluntary wheel running in growing rats does not protect against doxorubicin-induced osteopenia.

There is growing concern regarding the long-term negative side effects of chemotherapy in childhood cancer survivors. Doxorubicin (DOX) is commonly used in the treatment of childhood cancers and has been shown to be both cardiotoxic and osteotoxic. It is unclear whether exercise can attenuate the negative skeletal effects of this chemotherapy. Rat pups were treated with saline or DOX. Animals remained sedentary or voluntarily exercised. After 10 weeks, femoral bone mineral content and bone mineral density were measured using dual-energy x-ray absorptiometry. Cortical and cancellous bone architecture was then evaluated by microcomputed tomography. DOX had a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture. Treatment with DOX resulted in shorter femora and lower femoral bone mineral content and bone mineral density, lower cross-sectional volume, cortical volume, marrow volume, cortical thickness, and principal (IMAX, IMIN) and polar (IPOLAR) moments of inertia in the femur diaphysis, and lower cancellous bone volume/tissue volume, trabecular number, and trabecular thickness in the distal femur metaphysis. Exercise failed to protect bones from the damaging effects of DOX. Other modalities may be necessary to mitigate the deleterious skeletal effects that occur in juveniles undergoing treatment with anthracyclines.

Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin.

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague-Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)(-1)·d(-1) by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (-21% and -27%), maximal rate of pressure development (-29% and -32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

Oral treatment with the herbal formula B307 alleviates cardiac toxicity in doxorubicin-treated mice via suppressing oxidative stress, inflammation, and apoptosis.

Objective This study aimed to investigate whether the herbal formula B307 could alleviate doxorubicin (DOX)-induced acute cardiotoxicity. If so, we further unraveled possible molecular mechanisms of cardiac protection under treatment with the herbal formula B307. Methods Before the animal experiment, we examined relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307. To test whether oral treatment with the herbal formula B307 could alleviate cardiotoxicity, equal volumes of B307 (50 mg/kg) or saline (sham treatment) were administered to 20-week-old male mice once daily for 14 consecutive days. Then, DOX (10 mg/kg; ip) was administered to male mice under B307 and sham treatments at 22–23 weeks of age. Cardiac functions in these mice were assessed via echocardiography at 23–24 weeks of age. Then, expressions of oxidative stress, inflammation, and apoptosis-related proteins were examined in the heart tissue by immunohistochemistry and Western blotting at 24–25 weeks of age. Apart from this, mortality rate and body weight were measured during the experiment. Results In vitro, the relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307 had shown no obvious change at doses of 10–160 ng/mL. Furthermore, the relative viabilities of Huh7 cancer cells were significantly reduced under DOX treatment but showed no significant change under DOX only and DOX plus B307 treatment. In vivo, the mortality rate, body weight, and cardiac function of DOX-treated mice were obviously improved under oral treatment with the herbal formula B307. Furthermore, cardiac expressions of endothelial nitric oxide synthase, superoxide dismutase 2, and B-cell lymphoma 2 were significantly enhanced, but tumor necrosis factor alpha, NFKB1 (p50 and its precursor, p105), neurotrophin-3, Bcl-2-associated X protein, calpain, caspase 12, caspase 9, and caspase 3 were significantly suppressed in DOX-treated mice under oral treatment with the herbal formula B307. Conclusion Our results revealed that oral treatment with the herbal formula B307 may provide cardioprotection in DOX-treated mice via suppressing oxidative stress, inflammation, and apoptosis in heart tissue. We believe that the herbal formula B307 may be developed as a potential alternative treatment for cancer patients under DOX treatment.

Effects of voluntary wheel running on goserelin acetate-induced bone degeneration

A common treatment option for many breast and prostate cancer patients is the use of a luteinizing hormone-releasing hormone agonist such as goserelin acetate (GA) which reduces sex hormone levels. This treatment, however, is associated with bone degeneration, and exercise has been suggested as a means of preventing this side effect. Little is known about the effects of low intensity, low volume exercise on GA-induced bone loss. The purpose of this study, therefore, was to investigate the effects of voluntary wheel running on bone architecture in growing male (M) and female (F) rats receiving GA treatment. Rats received an 8-week GA treatment or placebo (CON) and were either housed in cages equipped with voluntary running wheels (WR) or remained sedentary (SED) in standard cages throughout the experimental period. Following treatments, tibiae were excised and analyzed for cortical bone (cross-sectional volume, cortical volume, marrow volume, cortical thickness) and cancellous bone (bone volume/total volume, trabecular number, trabecular thickness, trabecular spacing) using micro-computed tomography. Treatment with GA resulted in a significant reduction in running wheel distances in both sexes throughout the study period (P<0.05). GA treatment had no effect on cortical bone architecture in neither sex (P>0.05). Cancellous bone degeneration, however, was observed in M and F SED+GA (P<0.05). No significant differences were observed in M WR+GA animals in bone volume/total volume, trabecular number and trabecular spacing when compared to M SED+CON (P>0.05). In F WR+GA, trabecular thickness did not differ from that of F SED+CON (P>0.05), and trabecular spacing was found to be significantly lower than F SED+GA (P<0.05). The current report indicates that 8 weeks of GA treatment promotes cancellous bone degeneration, and voluntary wheel running provides no clear osteoprotection in growing male and female rats.