Joseph D. Bero’s research while affiliated with Wingate University and other places

Doxorubicin (Dox) is one of the most effective chemotherapeutic agents used in the treatment of several types of cancer. However the use is limited by cardiotoxicity. Despite extensive investigation into the mechanisms of toxicity and preventative strategies, Dox-induced cardiotoxicity still remains a major cause of morbidity and mortality in cancer survivors. Thus, continued research into preventative strategies is vital. Short-term fasting has proven to be cardioprotective against a variety of insults. Despite the potential, only a few studies have been conducted investigating its ability to prevent Dox-induced cardiotoxicity. However, all show proof-of-principle that short-term fasting is cardioprotective against Dox. Fasting affects a plethora of cellular processes making it difficult to discern the mechanism(s) translating fasting to cardioprotection, but may involve suppression of insulin and insulin-like growth factor-1 signaling with stimulated autophagy. It is likely that additional mechanisms also contribute. Importantly, the literature suggests that fasting may enhance the antitumor activity of Dox. Thus, fasting is a regimen that warrants further investigation as a potential strategy to prevent Dox-induced cardiotoxicity. Future research should aim to determine the optimal regimen of fasting, confirmation that this regimen does not interfere with the antitumor properties of Dox, as well as the underlying mechanisms exerting the cardioprotective effects.

Doxorubicin (Dox) is an effective chemotherapeutic agent, but known to cause cardiac and hepatic toxicity. Mechanisms of toxicity have not been clearly identified, but shown to involve oxidative stress and mitochondrial dysfunction. However, antioxidant supplementation have only shown modest protection from Dox-induced toxicity in clinical trials. Therefore, further research is required to discern alternative mechanisms that may also play an important role in Dox-induced toxicity. Thus, we aimed to investigate the role of mitochondrial fusion and fission in Dox-induced hepatic toxicity, which has not yet been investigated. Six-week old male F344 rats were injected IP with 20 mg/kg of Dox or saline. Once administered, both groups of animals were fasted with no food or water until sacrifice 24 hours later. Dox decreased content of primary regulators of mitochondrial fusion (OPA1, MFN1, and MFN2) with no effect on regulators of fission (DRP1 and FIS1), thus shifting the balance favoring mitochondrial fission. Moreover, it was determined that mitochondrial fission was likely not coupled to cell proliferation or cytochrome c release leading to activation of mitochondrial-mediated apoptotic signaling. Rather, mitochondrial fission may be coupled to mitophagy and may be an adaptive response to protect against Dox-induced hepatic toxicity. This is the first study to report the role of altered mitochondrial dynamics and mitophagy machinery in Dox-induced hepatic injury. This article is protected by copyright. All rights reserved.

Doxorubicin (DOX) is an effective chemotherapeutic agent, but with known toxicity which limits its lifetime dosage. In various experimental models, cellular stress has been shown to alter proteome lysine acetylation status, causing deacetylation which was associated with a pro‐apoptotic environment. The effects of DOX on proteome lysine acetylation status and expression of related sirtuins is unknown, thus we aimed to determine these effects in heart and liver of treated animals. Male F344 rats were injected IP with 20 mg/kg of DOX or saline. Once treated, all animals were fasted with no food or water until sacrifice 24 hours later. DOX treatment caused significant deacetylation in heart and liver. DOX did not affect the expression of sirtuin 1 or 3 in either tissue. Western analysis of sirtuin 1 revealed a prominent band of ~40kDa in liver, but not heart. Further, DOX treatment increased the content of this species. It has been reported in chondrocytes that sirtuin 1 can be cleaved into a ~75kDa protein which can bind to cytochrome c and inhibit apoptosis. The ~40 kDa fragment may be the remaining cleaved fragment detected by the antibody used. In conclusion, DOX induces proteome lysine deacetylation, which may be due to other deacetylases. Further, liver, but not heart, may be another tissue type that produces a 75 kDa product of sirtuin 1 as a mechanism to protect against apoptosis and is responsive to DOX treatment.

Doxorubicin (DOX) is a chemotherapeutic agent known to cause cardiac and hepatic toxicity. Mechanisms of toxicity include induction of oxidative stress and apoptosis. While mechanisms of cardiotoxicity have been extensively studied, much less is known about hepatic toxicity. Although the effect of DOX on markers of oxidative stress in the liver has been previously described, none of the studies controlled for the anorexic effects of DOX. Anorexia can deplete glutathione and cause oxidative stress in the liver. Thus, we aimed to delineate the effects of DOX‐induced oxidative stress from the effects of anorexia. Furthermore, the effect of DOX on vitamin D receptor (VDR) expression is not known. Therefore, a second aim was to make this determination. Male F344 rats were injected IP with 20 mg/kg of DOX or saline. Once treated, all animals were fasted with no food or water until sacrifice 24 hours later. Total glutathione content was elevated and protein carbonyls were decreased, with no change in Mn superoxide dismutase content, compared to control animals at 24 hr post treatment. These results differ from those previously reported and may be due to the differences in experimental design. Furthermore, content of VDR was increased in the DOX group compared to controls. In summary, improved oxidative stress status and increased VDR expression at 24 hr may be due to a rebound response.

Doxorubicin (DOX) is an effective chemotherapeutic agent, but known to cause cardiotoxicitv via induction of oxidative stress and apoptosis. DOX also causes hepatic toxicity, although mechanisms have not been as extensively described. Currently, the mechanism of DOX induced hepatic apoptosis is unknown. Moreover, despite the anorexic effects of DOX very few studies have controlled for this and, therefore, it is not clear whether changes in apoptosis markers and signaling in vivo are due to direct or indirect effects of DOX. Thus, we aimed to determine the early effects of DOX on expression and activation of apical caspases in heart and liver and to delineate these effects from mal consumption of food and water. Male F344 rats were injected IP with 20 mg/kg of DOX or saline. Once treated, all animals were fasted with no food or water until sacrifice 24 hours later. DOX did not affect expression or activation of caspase‐1, ‐8, ‐9, ‐12 in the heart at 24‐hour post treatment. However, DOX increased procaspase‐9 expression and caspase‐12 activation in liver. These results may suggest that at an early time point after acute DOX administration, the liver seems more vulnerable to DOX‐induced apoptosis compared to the heart. This may be explained by higher concentrations of DOX in liver compared to heart and/or the increased resistance to apoptosis in post‐mitotic cardiomyocytes compared to mitotic hepatocytes.