The Effect of N-Acetylcysteine Administration to Prevent Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients

Khazdooz, Hamid; Nourian, Mahyar; Jalaeikhoo, Hasan; Rajaeinejad, Mohsen; Moghadam, Adel Johari; Iranpour, Mostafa; Naghoosi, Hamed; Tofangchiha, Shahnaz

doi:10.30699/acadpub.mci.3.3.16

Cited by 2 publications

(1 citation statement)

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“…Aortic segments were randomly divided and received either PBS as vehicle (1:100), DOX (1 μM), a combination of DOX (1 μM) and DEXRA (10 μM), or a combination of DOX (1 μM) and the antioxidant Nacetylcysteine (NAC; 10 μM) for 16h. A NAC dose of 10 μM was chosen as a NAC to DOX ratio of 10 to 1 has shown effective capability in attenuating DOX-induced ROS formation and prevent cardiotoxicity in both patients and rodent experimental models [31][32][33]. DEXRA and NAC were administered 15 minutes prior to DOX addition to allow the uptake of DEXRA and NAC first.…”

Section: Competing Interestsmentioning

confidence: 99%

Dexrazoxane does not mitigate early vascular toxicity induced by doxorubicin in mice

Bosman,

Krüger,

Favere

et al. 2023

PLoS ONE

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Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established in vivo and ex vivo model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg/kg) or DOX with DEXRA (40 mg/kg) to male C57BL6/J mice. In parallel, vascular reactivity was evaluated after ex vivo incubation (16h) of murine aortic segments with DOX (1 μM) or DOX with DEXRA (10 μM). In both in vivo and ex vivo experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the ex vivo setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-IIβ (TOP-IIβ), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 μM), a reactive oxygen species (ROS) scavenger, was evaluated ex vivo. NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-IIβ-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.

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Section: Competing Interestsmentioning

confidence: 99%