Function of Norleual in Pancreatic Cancer

2018-08-18

Introduction 

Norleual is a potent inhibitor of the HGF/Met system, which inhibited the prosurvival effects of HGF and suppressed lung colonization in a murine melanoma cell model. The activation step of HGF was blocked, representing a novel therapeutic approach to the treatment of HGF/Met sensitive cancers, including pancreatic cancer.

Pharmacologic action

The binding of a H3-Hinge peptide sequence to the HGF and direct bind to HGF was inhibited by norleual. It competes with HGF for binding to c-Met, antagonizes HGF-dependent c-Met signaling activity in vitro. Norleual blocks HGF induced proliferation, invasion, cell scattering and wound closure in vitro. Norleual also inhibits ex vivo angiogenesis and attenuates melanoma lung colonization in vivo. In norleual, the reduced peptide bond increases the rotatability around the 3-4-position, making the molecule more flexible. This may permit norleual to emulate hinge conformations in HGF that are normally induced by tertiary structure (kringles) to facilitate its interaction with the c-Met. Norleual was evaluated using viability testing and cell sorting tags to identify living, dead and apoptotic cells, it can inhibit the growth and survival of several cell lines including pancreatic cancer cells.

Function

Norleual sensitized pancreatic cancer cells to gemcitabine both in vitro and in vivo. Norleual can inhibit MSP-dependent signaling and migration in pancreatic cancer cells, likely due to the substantial sequence homology between HGF and MSP. It acts a dual antagonist of HGF and MSP, if norleual treatment may sensitize pancreatic cancer cells to gemcitabine because of inhibition of the prosurvival effects of the MSP/Ron and HGF/Met systems. Norleual sensitized the pancreatic cancer cells to gemcitabine-induced cell death, likely by inhibiting the activity of growth factors present in the serum. Norleual treatment sensitized the pancreatic cancer cells to gemcitabine-induced cell death. Norleual sensitized the pancreatic tumor cells to gemcitabine treatment and reduced tumor burden compared with vehicle or either drug alone.

Pharmacokinetics and metabolism

Norleual increased the cytotoxic effect of gemcitabine at several doses in each cell line.

References:

1. B. J. Yamamoto, P. D. Elias, J. A. Masino, B. D. Hudson, A. T. McCoy, Z. J. Anderson, M. D. Varnum, M. F. Sardinia, J. W. Wright, and J. W. Harding. The Angiotensin IV Analog Nle-Tyr-Leu-(CH2-NH2)3-4-HisPro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/cMet Inhibitor. J. Pharmacol. Exp. Ther. 2010, 333 (1) :161-173.

2. Yamamoto BJ, Elias PD, Masino JA, Hudson BD, McCoy AT, Anderson ZJ, et al. The angiotensin IV analog Nle-Tyr-Leu-psi-(CH2-NH2)3-4-His-Pro-Phe (norleual) can act as a hepatocyte growth factor/c-Met inhibitor. J. Pharmacol. Exp. Ther. 2010, 333:161-173.

3. Gherardi E, Sandin S, Petoukhov MV, Finch J, Youles ME, Ofverstedt LG, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc. Natl. Acad. 2006, 103:4046-4051.

4. Church KJ, Vanderwerff BR, Riggers RR, McMicheal MD, MateoVictoriano B, Sukumar SR, et al. Analogs of the hepatocyte growth factor and macrophage stimulating protein hinge regions act as Met and Ron dual inhibitors in pancreatic cancer cells. Anti-Cancer Drugs. 2016, 27:766-779.

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