wzb117 and Breast-Neoplasms

Breast cancer is the frequently diagnosed cancer and the leading cancer death among women. The growing tumour of the breast is composed of both normoxic and hypoxic cells, and the heterogeneity of tumour affects the targeted treatment strategies against breast cancer. The functional and therapeutic status of the Warburg effect is mostly recognized, and the genes involved in glycolysis have become a target for anticancer therapeutic strategies. Glut-1 is essential for basal glucose uptake among the glucose transporters and could act as a potential target for anticancer therapy. In the present study, we explored the alteration in the metabolic phenotype of SKBR-3 cells, representing HER-2 overexpressed breast cancer cell line, with Glut-1 inhibition by a synthetic small molecule inhibitor WZB117 in the presence or absence of cobalt chloride (CoCl

Topics: Breast Neoplasms; Cell Line, Tumor; Female; Glucose; Glycolysis; Humans; Hypoxia; Phenotype

The tolerance to adriamycin of cancer as a common and stubborn obstacle occurred during curing breast cancer patients needs to be overcome. In the present study, we explored whether inhibiting the glucose transporter 1 (GLUT1) could restore the activity of adriamycin in breast cancer cell line MCF-7 resistant to adriamycin and the possible underlying mechanisms. Adriamycin-resistant cell line MCF-7/ADR was selected stepwise from the parental MCF-7 cells and the level of GLUT1 was measured. Then, the MCF-7/ADR cells were incubated with adriamycin, WZB117 (a specific GLUT1 inhibitor), or both. The viability, proliferation and apoptosis of cells and the level of glucose and lactate were measured, respectively. Finally, the cytosolic and mitochondrial proteins were isolated and the activity of the adenosine monophosphate-activated protein kinase (AMPK)/phosphorylated AMPK, mammalian target of rapamycin (mTOR)/phosphorylated mTOR, and apoptotic-related protein BCL-2-associated X protein (BAX), Bcl-2 was assayed by western blot. We found that WZB117 resensitized MCF-7/ADR to adriamycin and increased BAX translocated to mitochondria, which through activation of AMPK and inhibition of mTOR in a high probability. Inhibition of the GLUT1 could partially restore the antineoplastic effects of adriamycin in the adriamycin-resistant MCF-7 cell line possibly through activating the AMPK, downregulating the mTOR pathway, and increasing the BAX translocation to mitochondria.

Topics: AMP-Activated Protein Kinases; Antineoplastic Combined Chemotherapy Protocols; bcl-2-Associated X Protein; Breast Neoplasms; Cell Growth Processes; Cell Movement; Doxorubicin; Drug Synergism; Female; Glucose; Glucose Transporter Type 1; Humans; Hydroxybenzoates; MCF-7 Cells; Mitochondria; TOR Serine-Threonine Kinases

Breast cancer is the most common type of cancer with high incidence in women. Currently, identifying new therapies that selectively inhibit tumor growth without damaging normal tissue are a major challenge of cancer research. One of the features of cancer cells is that they do not consume more oxygen even under normal oxygen circumstances but prefer to aerobic glycolysis through the enhanced catabolism of glucose and glutamine. In this study, we investigate the mechanisms of the radioresistance in breast cancer cells.. Human breast cancer cells MDA-MB-231 and MCF-7 were treated with radiation alone, Glut1 inhibitor alone or the combination of both to evaluate cell glucose metabolism and apoptosis. By the establishment of radioresistant cell line, we investigate the mechanisms of the combined treatments of radiation with Glut1 inhibitor in the radioresistant cells.. The glucose metabolism and the expression of Glut1 are significantly stimulated by radiotherapy. We report the radioresistant breast cancer cells exhibit upregulated Glut1 expression and glucose metabolism. In addition, we observed overexpression of Glut1 renders breast cancer cells resistant to radiation and knocking down of Glut1 sensitizes breast cancer cells to radiation. We treated breast cancer cells with radiation and WZB117 which inhibits Glut1 expression and glucose metabolism and found the combination of WZB117 and radiation exhibits synergistically inhibitory effects on breast cancer cells. Finally, we demonstrate the inhibition of Glut1 re-sensitizes the radioresistant cancer cells to radiation.. This study reveals the roles of Glut1 in the radiosensitivity of human breast cancer. It will provide new mechanisms and strategies for the sensitization of cancer cells to radiotherapy through regulation of glucose metabolism.

Topics: Breast Neoplasms; Cell Culture Techniques; Cell Survival; Female; Glucose; Glucose Transporter Type 1; Humans; Hydroxybenzoates; Immunohistochemistry; MCF-7 Cells; Radiation Tolerance; Radiation-Sensitizing Agents; Real-Time Polymerase Chain Reaction; Transfection