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Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis
Author(s) -
Lam TinLun,
Wong Gabriel K. Y.,
Chow HoYin,
Chong HiuChi,
Chow TszLung,
Kwok SuiYi,
Cheng Paul N. M.,
Wheatley Denys N.,
Lo WaiHung,
Leung YunChung
Publication year - 2011
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2010.00798.x
Subject(s) - arginase , cell cycle checkpoint , cell cycle , apoptosis , melanoma , cell growth , arginine deiminase , cancer research , in vivo , in vitro , arginine , cell culture , biology , biochemistry , microbiology and biotechnology , amino acid , genetics
Summary 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 r ecombinant form of h uman arg inase 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 G 2 /M phases, in contrast to the G 2 /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.