Baicalin Enhances Chemosensitivity to Doxorubicin in Breast Cancer Cells via Upregulation of Oxidative Stress-Mediated Mitochondria-Dependent Apoptosis.

Mei-Yi Lin,Hsiu-Chung Ou,Kun-Ling Tsai,Hsiu-I Chen,Wan-Ching Chou,Hui-Ching Cheng,Wan-Ting Cheng

doi:10.3390/antiox10101506

Mei-Yi Lin, Hsiu-Chung Ou + Show 5 more

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https://doi.org/10.3390/antiox10101506

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Abstract

Doxorubicin (Dox) is an effective anthracycline anticancer drug. However, recent studies have revealed that Dox resistance is a highly critical issue, and a significant reason for treatment failure. Baicalin is a flavonoid component in the roots of Scutellaria baicalensis Georgi; however, whether baicalin can increase chemosensitivity in breast cancers is still unclear. In this study, we found that cellular apoptosis occurs when excessive intracellular ROS is generated, triggered by the dual intervention of baicalin and doxorubicin, which increases intracellular calcium [Ca2+]i concentrations. Increased [Ca2+]i concentrations decrease the mitochondrial membrane potential (△Ψm), thereby causing cellular apoptosis. Pretreatment with NAC (ROS inhibitor) or BATBA (Ca2+ chelator) reduces baicalin-induced chemosensitivity. The findings of this study demonstrate that the effect of baicalin on Dox treatment could enhance cytotoxicity toward breast cancer cells via the ROS/[Ca2+]i-mediated intrinsic apoptosis pathway—thus potentially lessening the required dosage of doxorubicin, and further exploring associated mechanisms in combined treatments for breast cancer clinical interventions in the future.

Highlights

IntroductionDoxorubicin (Dox), one of the most effective anticancer drugs in the anthracycline class, is constantly utilized in the clinical treatment of breast cancer; it contributes to the irreversible side-effect of cardiotoxicity—characterized by the loss of myofibrils, dilated sarcoplasmic reticulum, swelling of mitochondria, cytoplasmic vacuolization, and increased number of lysosomes, which is a species-independent final morphologic impairment [1]
We found that cytochrome c expression levels were enhanced in or BATBA reduced baicalin-promoted apoptosis under Dox treatment, suggesting that baicalin enhances apoptosis under Dox treatment through upregulation of reactive oxygen species (ROS)/[Ca2+ ]i
The outcomes of the study reveal that baicalin could effectively enhance anticancer ability via cellular apoptosis through an ROS/endoplasmic reticulum (ER) stress/mitochondrial intrinsic pathway in stubborn breast cancer cells

Summary

Introduction

Doxorubicin (Dox), one of the most effective anticancer drugs in the anthracycline class, is constantly utilized in the clinical treatment of breast cancer; it contributes to the irreversible side-effect of cardiotoxicity—characterized by the loss of myofibrils, dilated sarcoplasmic reticulum, swelling of mitochondria, cytoplasmic vacuolization, and increased number of lysosomes, which is a species-independent final morphologic impairment [1]. Dox is taken as a single-agent treatment, with an average response rate of around 50% and a reported maximal response rate of 80% [2]. Many compounds extracted from natural products present chemopreventive properties and show a potent sensitization function in variant cancer cells [5]. Baicalin (C21 H18 O11 ; 5,6,7-trihydroxyflavone 7-O-beta-D-glucuronide) is one of the flavonoid components present in the roots of Scutellaria baicalensis Georgi, with a concentration ranging from 8.1% to

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