Vanillin Prevents Doxorubicin-Induced Apoptosis and Oxidative Stress in Rat H9c2 Cardiomyocytes

Ivana Sirangelo,Angela Ragone,Antonio Giordano,Daniela Barone,Luigi Sapio,Silvio Naviglio,Clara Iannuzzi,Margherita Borriello

doi:10.3390/nu12082317

Abstract

Doxorubicin (doxo) is an effective anticancer compound in several tumor types. However, as a consequence of oxidative stress induction and ROS overproduction, its high cardiotoxicity demands urgent attention. Vanillin possesses antioxidant, antiproliferative, antidepressant and anti-glycating properties. Therefore, we investigated the potential vanillin protective effects against doxo-induced cardiotoxicity in H9c2 cells. Using multiparametric approach, we demonstrated that vanillin restored both cell viability and damage in response to doxo exposure. Contextually, vanillin decreased sub-G1 appearance and caspase-3 and PARP1 activation, reducing the doxo-related apoptosis induction. From a mechanistic point of view, vanillin hindered doxo-induced ROS accumulation and impaired the ERK phosphorylation. Notably, besides the cardioprotective effects, vanillin did not counteract the doxo effectiveness in osteosarcoma cells. Taken together, our results suggest that vanillin ameliorates doxo-induced toxicity in H9c2 cells, opening new avenues for developing alternative therapeutic approaches to prevent the anthracycline-related cardiotoxicity and to improve the long-term outcome of antineoplastic treatment.

Highlights

Classified as an anthracycline antibiotic, doxorubicin is an effective anti-neoplastic drug in a broad range of cancers, including breast cancer, leukemia, lymphoma and other solid tumors [1,2].due to its pervasive cardiotoxic effects, long-term doxo administration is usually not recommended in cancer patients
H9c2 cardiac cells were exposed for 24 h to increasing concentration of doxo and cell viability was evaluated by MTT assay [28]
H9c2 cells were exposed for 24 h to doxo in the absence and presence of vanillin, both in pre- and cotreatment conditions; thereafter, propidium iodide (PI)-stained cells were analyzed by flow cytometry assay

Summary

Introduction

Due to its pervasive cardiotoxic effects, long-term doxo administration is usually not recommended in cancer patients. Despite the beneficial effects in tumor progression, doxo-mediated cardiovascular diseases are quite frequent in long-term cancer survivors, where they may significantly contribute to heart failure and death [3,4]. Several mechanisms have been implicated in the doxo-induced cardiotoxicity, such as increased oxidative stress and lipid peroxidation, DNA damage, apoptosis and, more recently, autophagy [5]. Increased reactive oxygen species (ROS) production remains the major mechanism associated with doxo-induced oxidative stress, mitochondria injury and cellular apoptosis in cardiac cells [6,7,8,9]. The restricted antioxidant enzymes pool, especially catalases, in cardiac cells are often inadequate to counteract the ROS production amount during doxo administration [10,11]

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Conclusion