Glycolytic Inhibition with 3Bromopyruvate (3BP) and Ketogenic Diet Increases Survival in a Mouse Model of Anaplastic Thyroid Cancer
Abha Aggarwal, Bixiao Zhao, Jessica Marshall, Matthew Nehs
Brigham and Women's Hospital, Boston, MA
Background: Anaplastic thyroid cancer/ATC is a fatal malignancy characterized by glucose dependency for energy metabolism and rapid cellular proliferation. Hexokinase2/HK2 is a critical glycolytic enzyme. We hypothesized that HK2-inhibitor (3Bromopyruvate/3BP) and/or a Ketogenic Diet (low carbohydrate-high fat) could decrease tumor growth in ATC.
Methods: In-vivo, nude-mice were orthotopically injected with ATC line-8505C (n=8/group). Group1 and Group2 were fed standard chow (SD, n=9) or ketogenic diet (KD); Group3 was given SD plus 3BP (intraperitoneally); Group4 was fed KD with 3BP. Tumor volume, ketones, glucose, and survival were measured (8 weeks). In-vitro, 8505C cells were cultured in High Glucose/HG (25mM), Low Glucose/LG (3mM), HG plus 3BP (200uM), and LG plus 3BP. Proliferation, invasion, and migration assays were performed.
Results: In-vivo, KD+3BP decreased tumor volume compared to SD (20.8mm3, +/-16.1 vs. 51.9mm3, +/-35.4, p<0.05) and KD (62.0mm3 +/-50.5, p<0.05). Treatment with KD+3BP increased survival compared to SD (p=0.006, ptrend=0.007) and KD (p=0.009, ptrend =0.009). In-vitro, LG reduced proliferation (1.4 vs. 2.0 OD, p<0.002) and invasion (96.1 vs. 143.1 Relative Fluorescent Units/RFUs, p<0.001) compared to HG. This was further amplified with the addition of LG+3BP for proliferation (0.22 vs. 1.4, p<0.0001) and invasion (38.5 vs. 96.1 RFUs, p<0.0001) compared to LG. Migration decreased with LG+3BP compared to HG (491.3 vs. 876.7, p<0.0001).
Conclusion: 3Bromopyruvate combined with the ketogenic diet significantly decreased tumor volume and increased survival in an ATC-mouse model. In-vitro, 3BP plus low-glucose decreased proliferation and invasion. The ketogenic diet combined with metabolic glycolytic inhibition may be an effective adjuvant treatment for ATC.
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