Non-invasive MRI tumor imaging and synergistic anticancer effect of HSP90 inhibitor and glycolysis inhibitor in RIP1-Tag2 transgenic pancreatic tumor model

Abstract

To utilize non-invasive MRI imaging for real-time testing the synergistic effects of HSP90 inhibitor and glycolysis inhibitor for pancreatic cancer therapy in spontaneous pancreatic cancer mouse model. Transgenic RIP1-Tag2 spontaneous pancreatic cancer mice were treated with geldanamycin (GA, 5 mg/kg) and /or 3-Bromo-pyruvate (3-BrPA, 5 mg/kg) from 8 to 12 weeks of age. Non-invasive MRI imaging measured and calculated the total tumor mass and volumes in real-time and compared to ex vivo tumors size. Serum VEGF levels were measured by ELISA. HSP 90 client protein levels (AKT and VEGF) were measured by western blots. RIP-Tag2 transgenic mice developed pancreatic tumors from 8 to 12 weeks of age. Non-invasive MRI imaging detected primary tumors in pancreas and metastasis in intestine and mesenterium with minimal resolution of 20 mm(3). VEGF, AKT, hexokinase II, and Hsp90 were expressed in the pancreatic cancer tissues from RIP1-Tag2 transgenic mice. Combination of GA and 3-BrPA decreased serum VEGF levels by 70% compared to control group. Non-invasive MRI imaging showed that combination of GA and 3-BrPA inhibited pancreatic tumor and metastasis by more than 90% and significantly prolonged life span of RIP1-Tag2 transgenic pancreatic cancer mice. The synergistic effect of geldanamycin and 3-BrPA is through inhibition of two different pathways on HSP90 for its client protein degradation and on HK II for energy metabolism. Non-invasive MRI imaging revealed synergistic effects of Hsp90 inhibitors and glycolysis inhibitors, which may provide a new therapeutic option for pancreatic cancer therapy.