Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis.

Abstract

Melanoma has been shown to require arginine for growth, thus providing a potential Achilles' heel for therapeutic exploitation. Our investigations show that arginine depletion, using a recombinant form of human arginase I (rhArg), efficiently inhibits the growth of mammalian melanoma cell lines in vitro. These cell lines are consistently deficient in ornithine transcarbamylase (OTC) expression, correlating with their sensitivity to rhArg. Cell cycle distribution of A375 human melanoma cells treated with rhArg showed a remarkable dual-phase cell cycle arrest in S and G₂/M phases, in contrast to the G₂/M single-phase arrest observed with arginine deiminase (ADI), another arginine-degrading enzyme. rhArg and ADI both induced substantial apoptosis in A375 cells, accompanied by global modulation of cell cycle- and apoptosis-related transcription. Moreover, PEGylated rhArg dramatically inhibited the growth of A375 and B16 melanoma xenografts in vivo. Our results establish for the first time that (PEGylated) rhArg is a promising candidate for effective melanoma treatment, with fewer safety issues than ADI. Insight into the mechanism behind the antiproliferative activity of rhArg could inform us in designing combination therapies for future clinical trials.

• Authors: Tin-Lun Lam, Gabriel K Y Wong, Ho-Yin Chow, Hiu-Chi Chong, Tsz-Lung Chow, Sui-Yi Kwok, Paul N M Cheng, Denys N Wheatley, Wai-Hung Lo, Yun-Chung Leung
• Journal: Pigment cell & melanoma research (Pigment Cell Melanoma Res) Vol. 24 Issue 2 Pg. 366-76 (Apr 2011) ISSN: 1755-148X [Electronic] England
• PMID: 21029397 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 John Wiley & Sons A/S.

Chemical References

• Recombinant Proteins
• raf Kinases
• Arginase

Topics

• Animals
• Apoptosis (drug effects)
• Arginase (genetics, pharmacology, therapeutic use)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Clinical Trials as Topic
• Humans
• Melanoma (drug therapy, pathology, physiopathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Recombinant Proteins (genetics, pharmacology, therapeutic use)
• Skin Neoplasms (drug therapy, pathology, physiopathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• raf Kinases (antagonists & inhibitors)