Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals

Dirks‐Naylor, Amie J.; Kouzi, Samir A.; Bero, Joseph D.; Phan, Diep T; Taylor, Heather N.; Whitt, Stephanie D.; Mabolo, Raean

doi:10.1111/fcp.12073

Cited by 29 publications

(11 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specifically, it was demonstrated that the loss of OPA1 in cells can cause disorganization of the mitochondrial inner membrane, release of cytochrome c and apoptosis (Olichon et al, 2003). In regards to treatment with DOX, previous studies have demonstrated reductions in the fusion proteins Mfn1/2 and OPA1 (Dirks-Naylor et al, 2014). Indeed, our results also show a decrease in OPA1 concentration after DOX administration that is specific to the SS mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Effects of doxorubicin on cardiac muscle subsarcolemmal and intermyofibrillar mitochondria

et al. 2017

View full text Add to dashboard Cite

Doxorubicin (DOX) is a highly effective chemotherapeutic used in the treatment of a broad spectrum of malignancies. However, clinical use of DOX is highly limited by cumulative and irreversible cardiomyopathy that occurs following DOX treatment. The pathogenesis of DOX-induced cardiac muscle dysfunction is complex. However, it has been proposed that the etiology of this myopathy is related to mitochondrial dysfunction, as a result of the dose-dependent increase in the mitochondrial accumulation of DOX. In this regard, cardiac muscle possesses two morphologically distinct populations of mitochondria. Subsarcolemmal (SS) mitochondria are localized just below the sarcolemma, whereas intermyofibrillar (IMF) mitochondria are found between myofibrils. Mitochondria in both regions exhibit subtle differences in biochemical properties, giving rise to differences in respiration, lipid composition, enzyme activities and protein synthesis rates. Based on the heterogeneity of SS and IMF mitochondria, we hypothesized that acute DOX administration would have distinct effects on each cardiac mitochondrial subfraction. Therefore, we isolated SS and IMF mitochondria from the hearts of female Sprague-Dawley rats 48 h after administration of DOX. Our results demonstrate that while SS mitochondria appear to accumulate greater amounts of DOX, IMF mitochondria demonstrate a greater apoptotic and autophagic response to DOX exposure. Thus, the divergent protein composition and function of the SS and IMF cardiac mitochondria result in differential responses to DOX, with IMF mitochondria appearing more susceptible to damage after DOX treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of doxorubicin on cardiac muscle subsarcolemmal and intermyofibrillar mitochondria

et al. 2017

View full text Add to dashboard Cite

show abstract

“…DOX is widely used for cancer therapy [38]. However, it has been recognized to have a toxic effect on noncancerous tissue such as the heart [13,39], liver, kidneys [22], as well as the brain [40], and its poisonous effect is related to its dose [38]. This is why the drug's use for cancer treatment is limited based on its undesired impact on healthy tissue.…”

Section: Cytotoxic Effect Of Doxorubicin On Noncancerous Tissuesmentioning

confidence: 99%

“…This is why the drug's use for cancer treatment is limited based on its undesired impact on healthy tissue. Unfortunately, the mechanism of its toxic effect on noncancerous tissue has been not understood so far [38,39].…”

Section: Cytotoxic Effect Of Doxorubicin On Noncancerous Tissuesmentioning

confidence: 99%

“…Based on our best knowledge of the mechanisms associated with apoptosis, oxidative stress, and mitochondrial dysfunction, to avoid undesired toxicity it has been suggested to use some form of antioxidant. Unfortunately, antioxidant therapy has failed to accomplish the drug's toxicity effect in many tissues, particularly the heart and liver according to clinical data [39]. This is why any approaches to use the drug clinically may reduce its toxic effects on noncancerous mass.…”

Section: Cytotoxic Effect Of Doxorubicin On Noncancerous Tissuesmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial Dysfunction Associated with Doxorubicin

Güven¹,

Sevgiler²,

Taşkın³

2018

Mitochondrial Diseases

View full text Add to dashboard Cite

Cancer prevalence is scaling up each year. Anthracycline groups are still the best chemotherapeutic agent. The most popular anticancer drug in the group is doxorubicin (DOX). Unfortunately, DOX has potent toxicity on noncancerous tissues, e.g., heart, kidneys, etc. However, it is well documented that the severest toxicity of the drug affects heart tissue. Of course, some reasons have been suggested why and/or how the heart is so vulnerable to toxicity. The primary mechanism responsible for DOX's cardiospecific toxicity remains unidentified so far; however, mitochondrial dysfunction induced by DOX is now considered one of the leading reasons for DOX's toxicities and undesired side effects. Mitochondrial reactive oxygen production in the heart is a significant contributor to developing mitochondrial dysfunction-exposed DOX based on a variety of evidence. The objective of this review chapter is to critically evaluate and highlight the role of mitochondria in the development of DOX-induced cardiotoxicity. TurkeyMitochondrial Dysfunction Associated with Doxorubicin http://dx.doi.org/10.5772/intechopen.80284 353

show abstract

“…Currently, doxorubicin is the most widely used drug against liver cancer either as single agent or in combination with other chemotherapeutics like cisplatin [10]. However, the outcomes of the existing conventional chemotherapeutic drugs remain considerably low due to their severe toxicity on normal hepatocytes [11,12]. Therefore, alternative therapeutic agents without or with low hepatotoxicity are highly desirable.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of interferon‐β on hepatocellular carcinoma HepG2 via Akt/STAT phosphorylation

Ethiraj

Veerappan²,

Samuel³

et al. 2015

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

Conventional chemotherapy fails to cure metastatic hepatoma mainly due to its high hepatotoxicity. Currently, doxorubicin is the most widely used drug against liver cancer either as single agent or in combination with other chemotherapeutics such as cisplatin. It is limited due to their severe toxicity on normal hepatocytes. Therefore, alternative therapeutic agents without or with low hepatotoxicity are highly desirable. Interferons are a family of cytokines that potently demonstrate antiviral, immunomodulatory, and antiproliferative activities. It also exerts direct cytotoxic effects on tumor cells. The purpose of this study was to examine the in vitro cytotoxicity of interferon-β on HepG2 cells. We revealed the presence of binding receptor of interferon-β in HepG2 cells. The dose-dependent inhibition on cell proliferation was observed. We demonstrated that IFN-β exhibited significant cytotoxicity in HepG2 cells mainly through phosphorylation of signal transducers and activators of transcription 2. The activation of Akt was suppressed. The stimulation of pro-apoptotic protein expression of Bax, inhibition of anti-apoptotic protein expression of Bcl-2, activation of cleaved caspases 9 and 3 was found at increasing concentrations. In conclusion, our results suggest that interferon-β has potential to inhibit cell proliferation dose dependently. Increased concentrations of interferon-β influenced apoptosis via mitochondrial pathway through inhibition of p-Akt.

show abstract

Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals

Cited by 29 publications

References 45 publications

Effects of doxorubicin on cardiac muscle subsarcolemmal and intermyofibrillar mitochondria

Effects of doxorubicin on cardiac muscle subsarcolemmal and intermyofibrillar mitochondria

Mitochondrial Dysfunction Associated with Doxorubicin

Inhibitory effects of interferon‐β on hepatocellular carcinoma HepG2 via Akt/STAT phosphorylation

Contact Info

Product

Resources

About