Glucose Deprivation Induced by Acarbose and Oncolytic Newcastle Disease Virus Promote Metabolic Oxidative Stress and Cell Death in a Breast Cancer Model.

Cancer cells are distinguished by enhanced glucose uptake and an aerobic glycolysis pathway in which its products support metabolic demands for cancer cell growth and proliferation. Inhibition of aerobic glycolysis is a smart therapeutic approach to target the progression of the cancer cell. We employed acarbose (ACA), a particular alpha-glucosidase inhibitor, to induce glucose deprivation combined with oncolytic Newcastle disease virus (NDV) to enhance antitumor activity. In this work, we used a mouse model of breast cancer with mammary adenocarcinoma tumor cells (AN3) that were treated with ACA, NDV, and a combination of both. The study included antitumor efficacy, relative body weight, glucose level, hexokinase (HK-1) level by ELISA, glycolysis product (pyruvate), total ATP, oxidative stress (ROS and reduced glutathione), and apoptosis by immunohistochemistry. The results showed significant antitumor efficacy against breast cancer after treatment with combination therapy. Antitumor efficacy was accompanied by a reduction in body weight and glucose level, HK-1 downregulation, inhibition of glycolysis products (pyruvate), total ATP, induction of oxidative stress (increase ROS and decrease reduced glutathione), and apoptotic cell death. The findings propose a novel anti-breast cancer combination involving the suppression of glycolysis, glucose deprivation, oxidative stress, and apoptosis, which can be translated clinically.

Glucose deprivation using 2-deoxyglucose and acarbose induce metabolic oxidative stress and apoptosis in female mice bearing breast cancer.

A characteristic of cancer cells is increased glucose uptake and glycolysis for energy production and hydroperoxide detoxification due to mitochondrial dysfunction. Thus, inhibition of glucose uptake and glycolysis represent smart novel therapy. We used 2-deoxyglucose (2DG) as a glycolysis inhibitor and acarbose (ACA), a specific alpha-glucosidase inhibitor, to decrease glucose uptake. Mice bearing mammary adenocarcinoma tumors were treated by 2DG and/or ACA. Relative tumor volume, tumor growth inhibition rate, relative body weight, glucose concentration, hexokinase-1 protein level by ELISA, pyruvate, and ATP (glycolysis products), reactive oxygen species (ROS), total glutathione T-GSH, apoptosis, and histopathology were measured in treated and untreated groups. Our results showed that combination therapy inhibited tumor volume and increased tumor growth inhibition rate, body weight reduction, decreasing glucose level, HK-1 level, and inhibition of glycolysis products. In addition, combination therapy induced oxidative stress, increase ROS, and decrease T-GSH. Furthermore, immunohistochemistry examination showed the broader area of apoptosis in breast cancer treated by combination agents. In conclusion, our result revealed that the novel combination inhibits glycolysis and glucose uptake and induced oxidative stress and apoptosis.