Baicalein resensitizes tamoxifen‐resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia‐inducible factor‐1α

Abstract

Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM‐resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM‐resistant cells. It also enhanced the TAM‐induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan–Meier plotter database showed that HIF‐1α expression was inversely correlated with TAM therapeutic response in NCI‐60 cancer cells and breast cancer patients. HIF‐1α expression was increased in TAM‐resistant cells due to an increase in mRNA levels and reduced ubiquitin‐mediated degradation. Baicalein reduced HIF‐1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase‐mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia‐response element, and transcriptional activity of HIF‐1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF‐1α‐targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF‐1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM‐induced mitochondrial apoptotic pathway. The HIF‐1α stabilizer dimethyloxallyl glycine prevented the baicalein‐induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM‐induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF‐1α–mediated aerobic glycolysis and mitochondrial dysfunction.

Advances in Anti-Cancer Activities of Flavonoids in Scutellariae radix: Perspectives on Mechanism

“…Recent findings by Chen and his colleagues suggested that baicalein significantly enhanced the oral-bioavailability of tamoxifen (TAM). The nuclear translocation and transcriptional activity of hypoxia-inducible factor-1α (HIF-1α) were reduced by baicalein, which contributed to the downregulation of HIF-1α–mediated glycolysis uptake and recovered the number and shape of mitochondria as well as their ability to generate ROS, and thus re-sensitized breast cancer cells to TAM treatment [ 103 ]. As a critical chemotherapeutic agent currently utilized in the treatment of a wide range of cancers, cisplatin exerts its cytotoxic effects in tumor cells primarily through the production of deoxyribonucleic acid-platinum complexes and the subsequent deoxyribonucleic acid damage response [ 104 ].…”

Regulation of Cell Signaling Pathways and Non-Coding RNAs by Baicalein in Different Cancers

“…TLR4 activation led to an increase in the levels of HIF1α and VEGF, which were reversed by baicalein. Importantly, baicalein substantially reduced NF-κB phosphorylation in the tumor tissues of CRC-bearing xenograft mouse models [ 113 ].…”

Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy

“…It also interfered with HIF-1α inhibition of mitochondrial biosynthesis. This increased the mitochondrial DNA content, restored the ROS, and thus increased the tamoxifen-induced mitochondrial apoptotic pathway [ 166 ].…”