Abstract
It is well established that cancer cells depend upon aerobic glycolysis to provide the energy they need to survive and proliferate. However, anti‐glycolytic agents have yielded few positive results in human patients, in part due to dose‐limiting side effects. Here, we discovered the unexpected anti‐cancer efficacy of Polydatin (PD) combined with 2‐deoxy‐D‐glucose (2‐DG), which is a compound that inhibits glycolysis. We demonstrated in two breast cell lines (MCF‐7 and 4T1) that combination treatment with PD and 2‐DG induced cell apoptosis and inhibited cell proliferation, migration and invasion. Furthermore, we determined the mechanism of PD in synergy with 2‐DG, which decreased the intracellular reactive oxygen (ROS) levels and suppressed the PI3K/AKT pathway. In addition, the combined treatment inhibited the glycolytic phenotype through reducing the expression of HK2. HK2 deletion in breast cancer cells thus improved the anti‐cancer activity of 2‐DG. The combination treatment also resulted in significant tumour regression in the absence of significant morphologic changes in the heart, liver or kidney in vivo. In summary, our study demonstrates that PD synergised with 2‐DG to enhance its anti‐cancer efficacy by inhibiting the ROS/PI3K/AKT/HIF‐1α/HK2 signalling axis, providing a potential anti‐cancer strategy.
Highlights
While recent advances have been made in cancer therapies and can‐ cer diagnostic methods, most cancer remains an incurable disease with highly mortality in many parts of the world.[1,2] Previous studies suggest that patient death results mostly from cancer cell metas‐ tasis to distant organs and chemotherapy plays an imperative role in metastatic cancer treatment.[3,4] Several agents that are currently used for chemotherapy, such as vinorelbine, Paclitaxel and anthra‐ cyclines, obviously induce cancer cell apoptosis, but they cause excessive damage to normal cells, leading to various serious side effects.[5,6] the development of novel therapeutic strategies that are safe and effective depends on a deeper understanding of the differences between cancer cells and normal cells
We found that NAC inhibited PI3K/AKT compared to other groups in breast cancer cells (Figure 4C,D)
In further studies we examined other markers of glycolysis, such as glucose transporter 1 (GLUT1) and Lactate dehydrogenase A (LDH‐A) (Figure 5A,B), and the results were consistent with the changes of HK2
Summary
While recent advances have been made in cancer therapies and can‐ cer diagnostic methods, most cancer remains an incurable disease with highly mortality in many parts of the world.[1,2] Previous studies suggest that patient death results mostly from cancer cell metas‐ tasis to distant organs and chemotherapy plays an imperative role in metastatic cancer treatment.[3,4] Several agents that are currently used for chemotherapy, such as vinorelbine, Paclitaxel and anthra‐ cyclines, obviously induce cancer cell apoptosis, but they cause excessive damage to normal cells, leading to various serious side effects.[5,6] the development of novel therapeutic strategies that are safe and effective depends on a deeper understanding of the differences between cancer cells and normal cells. A series of cancer cell behaviours, such as infinite proliferation and metastasis, consume a large amount of energy To acclimatise to this situation, cancer cells must elevate their glucose up‐take due to glycolysis being less effective than oxidative phosphorylation in the adenosine triphosphate (ATP) yield.[8]. 2‐deoxy‐D‐glucose (2‐DG) is one of the most effective anti‐gly‐ colytic agents It is phosphorylated by hexokinase (HK), which is the first rate‐limiting enzyme of glycolysis and subsequently inhibits the pentose‐phosphate pathway (NAPDH) and ATP generation.9,11 2‐DG can change the redox state of the cell, or the generation of free radicals and disorder the cell cycle and induce apoptosis.[12]. Whether PD can promote the anti‐cancer effects of 2‐DG by regulating glucose metabolism, inhibiting the PI3K/AKT pathway or other mechanisms has aroused great interest. We evaluated the anti‐cancer effect of PD, 2‐DG and their co‐treatment in breast cancer cell lines (4T1 and MCF‐7) and elucidated the underlying molecular mechanisms
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