2-methoxyestradiol sensitizes tamoxifen-resistant MCF-7 breast cancer cells via downregulating HIF-1α.

The clinical studies for breast cancer (BC) are now assessing the efficacy of 2-Methoxyestradiol (2-ME), a naturally occurring derivative of estradiol. Our study aimed to explore the potential of combining the 2-ME and tamoxifen (TAM) on sensitization of TAM-resistant cells using LCC2 the TAM-resistant cells as a model and comparing the results to the sensitive cells MCF-7. Sulphorhodamine-B (SRB) assay is used to examine the 2-ME chemo-sensitizing impact on the cytotoxicity of TAM on LCC2 cells. Colorimetric assay kits were used to assess the level of the apoptosis-related markers caspases 3, Bcl2, and Bax in cell lysate. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was measured using western blotting. Total cholesterol and triglyceride (TG) levels were examined colorimetrically, using the BIOLABO kit. The use of 2-ME enhanced the cytotoxic effects of TAM and effectively reversed TAM resistance. This was achieved by inhibiting the expression of HIF-1α, while concurrently increasing the levels of apoptotic marker caspase-3, as well as the pro-apoptotic protein Bax. Additionally, there was a reduction in the levels of Bcl2, an anti-apoptotic protein. Furthermore, a reduction in TG and cholesterol levels was noted. Our findings show that HIF-1α plays an important role in TAM resistance and that suppression of HIF-1α by 2-ME-mediated sensitization of BC-resistant cells to TAM. Therefore, the concurrent administration of TAM/2-ME might potentially serve as a viable therapeutic approach to address TAM resistance and enhance the overall therapy efficacy for patients with BC.

Attia YM ，Mokhlis HA ，Ismail A ，Doghish AS ，Sobhy MH ，Hassanein SS ，El-Dakroury WA ，Mariee AD ，Salama SA ，Sharaky M ... -  《-》

Comment on "2-methoxyestradiol sensitizes tamoxifen-resistant MCF-7 breast cancer cells via downregulating HIF-1α".

Chellapandian H ，Jeyachandran S 《-》

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

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.

Chen Y ，Zhang J ，Zhang M ，Song Y ，Zhang Y ，Fan S ，Ren S ，Fu L ，Zhang N ，Hui H ，Shen X ... -  《Clinical and Translational Medicine》

Comment on, "2-methoxyestradiol sensitizes tamoxifen-resistant MCF-7 breast cancer cells via downregulating HIF-1α".

Chellapandian H ，Jeyachandran S 《SURGEON-JOURNAL OF THE ROYAL COLLEGES OF SURGEONS OF EDINBURGH AND IRELAND》

Expression of the CD59 Glycoprotein Precursor is Upregulated in an Estrogen Receptor-alpha (ER-α)-Negative and a Tamoxifen-Resistant Breast Cancer Cell Line In Vitro.

Xiong H ，Jin X ，You C 《MEDICAL SCIENCE MONITOR》