Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model.

Chhanda Bose,Sanjay Awasthi,Marjan Boerma,Sharda P Singh,Rajendra Sharma,Helen Beneš,Martin Hauer-Jensen,Partha Mukhopadhyay

doi:10.1371/journal.pone.0193918

Abstract

Breast cancer is the most common malignancy in women of the Western world. Doxorubicin (DOX) continues to be used extensively to treat early-stage or node-positive breast cancer, human epidermal growth factor receptor-2 (HER2)-positive breast cancer, and metastatic disease. We have previously demonstrated in a mouse model that sulforaphane (SFN), an isothiocyanate isolated from cruciferous vegetables, protects the heart from DOX-induced toxicity and damage. However, the effects of SFN on the chemotherapeutic efficacy of DOX in breast cancer are not known. Present studies were designed to investigate whether SFN alters the effects of DOX on breast cancer regression while also acting as a cardioprotective agent. Studies on rat neonatal cardiomyocytes and multiple rat and human breast cancer cell lines revealed that SFN protects cardiac cells but not cancer cells from DOX toxicity. Results of studies in a rat orthotopic breast cancer model indicated that SFN enhanced the efficacy of DOX in regression of tumor growth, and that the DOX dosage required to treat the tumor could be reduced when SFN was administered concomitantly. Additionally, SFN enhanced mitochondrial respiration in the hearts of DOX-treated rats and reduced cardiac oxidative stress caused by DOX, as evidenced by the inhibition of lipid peroxidation, the activation of NF-E2-related factor 2 (Nrf2) and associated antioxidant enzymes. These studies indicate that SFN not only acts synergistically with DOX in cancer regression, but also protects the heart from DOX toxicity through Nrf2 activation and protection of mitochondrial integrity and functions.

Highlights

Breast cancer is the most common malignancy in western women
NF-E2related factor 2 (Nrf2) activity was measured in nuclear extracts by an Nrf2-DNA-binding ELISA kit on nuclear fractions prepared from cardiac tissue and cells using Trans AM Nrf2 Kits (Active Motif) as we have reported before [51]
We found that SFN (4 mg/kg, 5 days/week) protected against mortality and cardiac dysfunction induced by DOX (5 mg/kg x 4, total 20 mg/kg)

Summary

Introduction

Breast cancer is the most common malignancy in western women. Doxorubicin (DOX) is used to treat early-stage or node-positive breast cancer, human epidermal growth factor. The KEAP1-Nrf2-ARE antioxidant system is a principal means by which cells respond to oxidative and xenobiotic stresses by activating antioxidant and anti-electrophile enzymes [25, 26]. In this system, the transcription factor Nrf binds to the antioxidant response element (ARE) of several target genes. Since the hearts of cancer patients are generally under oxidative and electrophilic stress generated by cancer therapy, and are likely stressed because of the oxidative and inflammatory responses elicited by cancer [38,39,40,41,42], we tested the effects of DOX and SFN in a rat breast cancer model. Since DOX has been shown to cause an elevation in the serum levels of cytokines TNF-α and IL-6 due to the disruption of the intestinal epithelium, enabling the leakage of endotoxin from gut microflora into the circulation [43, 44], and since SFN can attenuate inflammation [45, 46], we examined inflammatory cytokine levels in our rat model

Ethics statement

Data availability and statistical analysis

Results

Methods

Discussion