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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Non-invasive MRI imaging revealed synergistic effects of Hsp90 inhibitors and glycolysis inhibitors, which may provide a new therapeutic option for pancreatic cancer therapy.
Cao
Xianhua
X
Division of Pharmaceutics, School of Pharmacy, Ohio State University, 500 W. 12th Ave., Columbus, OH 43210, USA.
Jia
Guang
G
Zhang
Tao
T
Yang
Ming
M
Wang
Bing
B
Wassenaar
Peter A
PA
Cheng
Hao
H
Knopp
Michael V
MV
Sun
Duxin
D
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006019:Glycolysis / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D011773:Pyruvates / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D000952:Antigens, Polyomavirus Transforming; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007328:Insulin; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D011773:Pyruvates; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C017092:bromopyruvate; D006593:Hexokinase; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C001277:geldanamycin