These authors contributed equally to this work.
Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis
Article first published online: 6 DEC 2010
© 2010 John Wiley & Sons A/S
Pigment Cell & Melanoma Research
Volume 24, Issue 2, pages 366–376, April 2011
How to Cite
Lam, T.-L., Wong, G. K. Y., Chow, H.-Y., Chong, H.-C., Chow, T.-L., Kwok, S.-Y., Cheng, P. N. M., Wheatley, D. N., Lo, W.-H. and Leung, Y.-C. (2011), Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis. Pigment Cell & Melanoma Research, 24: 366–376. doi: 10.1111/j.1755-148X.2010.00798.x
- Issue published online: 10 MAR 2011
- Article first published online: 6 DEC 2010
- Accepted manuscript online: 28 OCT 2010 07:57AM EST
- PUBLICATION DATA Received 26 July 2010, revised and accepted for publication 23 October 2010, published online 28 October 2010
- PEGylated enzyme;
- cell cycle;
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.