Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy

Moruno-Manchon, Jose F.; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Townley, Debra; Nagaraja, Archana S.; Pradeep, Sunila; Mangala, Lingegowda S.; Sood, Anil K.; Tsvetkov, Andrey S.

doi:10.1016/j.mcn.2017.11.014

Cited by 37 publications

(25 citation statements)

References 88 publications

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“…The behavior of larvae treated with 50 µg/ml of DOX could be a result of both effects observed for lower and higher concentrations and was observed as a movement similar to the untreated control. These results are in accordance with previous works which showed that DOX induced cytotoxic effects in vitro in primary cultured neurons, and in vivo produced neurotoxic effects in the brain of mice and rat (Kosoko et al, 2017;Moruno-Manchon et al, 2018). Even though DOX poorly crosses the bloodbrain barrier (BBB) in humans, it still arrives at the brain at doses sufficient to cause neurotoxicity (Kesler and Blayney, 2016).…”

Section: Accepted Manuscriptsupporting

confidence: 92%

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Calienni

Cagel

Montanari

et al. 2018

Toxicology and Applied Pharmacology

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Doxorubicin (DOX) hydrochloride is a powerful anthracycline antibiotic used for the treatment of various types of malignancies, particularly ovarian and metastatic breast cancer. However, DOX presents severe side effects, such as hepatotoxicity, nephrotoxicity, dose-limiting myelosuppression, brain damage and cardiotoxicity. A liposomal formulation, Doxil®, was approved by the FDA, which has managed to reduce the number of cardiac events in patients with metastatic breast cancer. However, in comparison to free DOX, Doxil® has not shown significant improvements regarding survival. We have previously designed DOX-loaded mixed micelles (MMDOX) composed of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and Tetronic® T1107. To assess the potential toxic effects of this novel formulation, in this work the zebrafish (Danio rerio) model was used to evaluate its in vivo toxicity and teratogenicity. This study evaluated and compared the effects of DOX exposure from different formulations (free DOX, MMDOX and Doxil®) on the swimming activity, morphological alterations, cardiac rhythm, lethality rate and DOX biodistribution. MMDOX showed lower lethal effects, morphological alterations and neurotoxic effects than the free drug. This study shows the potential of the MMDOX to be an effective DOX-delivery system because it could reduce the side effects.

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Section: Accepted Manuscriptsupporting

confidence: 92%

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Calienni

Cagel

Montanari

et al. 2018

Toxicology and Applied Pharmacology

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“…Cortices from rat embryos (E17 and E18) were dissected, dissociated, and plated on 24-well tissue-culture plates (4 × 10 5 per well) coated with poly- d -lysine (BD Biosciences, San Jose, CA) as described 17 , 23 , 73 , 74 . Primary cortical neurons were grown in Neurobasal Medium (Life Technologies, Carlsbad, CA) supplemented with B-27 (Life Technologies), GlutaMAX (Life Technologies), and penicillin–streptomycin (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

Sphingosine kinase 1-associated autophagy differs between neurons and astrocytes

Moruno-Manchon

Uzor²,

Ambati

et al. 2018

Cell Death Dis

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Autophagy is a degradative pathway for removing aggregated proteins, damaged organelles, and parasites. Evidence indicates that autophagic pathways differ between cell types. In neurons, autophagy plays a homeostatic role, compared to a survival mechanism employed by starving non-neuronal cells. We investigated if sphingosine kinase 1 (SK1)-associated autophagy differs between two symbiotic brain cell types—neurons and astrocytes. SK1 synthesizes sphingosine-1-phosphate, which regulates autophagy in non-neuronal cells and in neurons. We found that benzoxazine autophagy inducers upregulate SK1 and neuroprotective autophagy in neurons, but not in astrocytes. Starvation enhances SK1-associated autophagy in astrocytes, but not in neurons. In astrocytes, SK1 is cytoprotective and promotes the degradation of an autophagy substrate, mutant huntingtin, the protein that causes Huntington’s disease. Overexpressed SK1 is unexpectedly toxic to neurons, and its toxicity localizes to the neuronal soma, demonstrating an intricate relationship between the localization of SK1’s activity and neurotoxicity. Our results underscore the importance of cell type-specific autophagic differences in any efforts to target autophagy therapeutically.

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“…Furthermore, eNOS expression, which is associated with the function of HUVECs (51), was reinstated by treatment with Ator. Alteration in the cellular microenvironment ultimately leads to cell aging (54). In the current study, Ator delayed Ang II-induced aging by maintaining cellular homeostasis.…”

Section: Discussionmentioning

confidence: 51%

Atorvastatin reverses the dysfunction of human umbilical vein endothelial cells induced by angiotensin II

et al. 2018

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Statins exert pleiotropic effects on endothelial cells, in addition to lowering cholesterol. This study evaluated angiotensin II (Ang II)-induced dysfunction in human umbilical vein endothelial cells (HUVECs), and the effects of atorvastatin (Ator) on induced HUVECs in vitro. The cytotoxicity of Ang II and Ator was determined by the MTT assay. A series of cellular responses were screened, including oxidative stress, cellular apoptosis, inflammatory response, autophagy, expression of endothelial nitric oxide synthase and the angiogenic function of HUVECs. Ator returned these cellular responses to a normal level. The present study also examined cellular organelle dysfunction. In HUVECs, Ang II triggered mitochondrial damage, as demonstrated by a decreased mitochondrial membrane potential, while Ator attenuated this Ang II-induced damage. The observed cellular dysfunction may cause endothelial senescence due to excessive cell injury. The current study examined several aging markers, which revealed that these disorders of cellular functions triggered endothelial senescence, which was delayed by Ator. Ator also suppressed Ang II-induced angiogenesis damage. The data presented in this study strongly suggested that Ang II induced a series of processes that lead to cellular dysfunction in HUVECs, including oxidative stress, inflammation, and mitochondrial damage, leading to apoptosis and endothelial senescence. However, Ator significantly reversed these effects and modulated intracellular stability. The present study indicated that Ator serves an antagonistic role against HUVEC dysfunction and may potentially prevent several diseases, including coronary disease and atherosclerosis, by maintaining cellular homeostasis.

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Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy

Cited by 37 publications

References 88 publications

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Zebrafish (Danio rerio) model as an early stage screening tool to study the biodistribution and toxicity profile of doxorubicin-loaded mixed micelles

Sphingosine kinase 1-associated autophagy differs between neurons and astrocytes

Atorvastatin reverses the dysfunction of human umbilical vein endothelial cells induced by angiotensin II

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