Hyperglycemic and hyper insulin condition is the signature symptoms for type two diabetes which is the most favorable condition for the development of a cancer. Women with type two diabetes (T2D) have 20- 27% higher risk to develop breast cancer, including triple negative breast cancer (TNBC). Hyperglycemic and/or hyper insulin condition leads to the therapy resistance, and according to ‘Warburg’s effect’ cancer cells consume high amount of glucose as compared to normal cells, via aerobic glycolysis process. To combat this condition currently several clinical studies are underway, with the combination therapy of T2D and chemotherapy drugs e.g., metformin and erlotinib. The major drawback of such T2D drugs is that they do not affect cancer cells under hyperglycemic and hyper insulin conditions. These T2D drugs including metformin, work via AMP-activated protein kinase (AMPK) activation to switch aerobic glycolysis to oxidative phosphorylation. To address this challenge, we have developed a novel AMPK activator (SU-18) which selectively induces an oxidative phosphorylation in TNBC cells, and glycolysis in normal cells. We found that SU-18 induces G2/M phase arrest, mitochondrial stress and apoptosis in TNBC cells similar to metformin, but at 1000 of the concentration. This drig selectively reduces the glucose consumption, lactate and ATP production in TNBC cells, where as the normal cells act opposite to this. We found that SU-18 acts through AMPK activation, which otherwise gets eliminated in the presence of AMPK inhibitor (compound c). It also improves the blood glucose level in hyperglycemic mice, and inhibits the tumor growth and progression. Comparative studies with metformin suggest that SU-18 works irrespective of hyperglycemic and insulin conditions, whereas metformin is ineffective under these conditions. FDG-PET analysis further supports our findings that treatment with SU-18 reduces the FDG accumulation in tumor cells. Overall, our study provides strong basis for clinical development of SU-18 for TNBC patients.

Novel glycolysis inhibitor improves the therapeutic regimen for triple negative breast cancer under hyperglycemic condition

2019 Fall National Meeting

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