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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

Authors

  • Tin-Lun Lam,

    1.  Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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    • These authors contributed equally to this work.

  • Gabriel K. Y. Wong,

    1.  Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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    • These authors contributed equally to this work.

  • Ho-Yin Chow,

    1.  Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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  • Hiu-Chi Chong,

    1.  Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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  • Tsz-Lung Chow,

    1.  Bio-Cancer Treatments International Ltd., Hong Kong Science Park, Bio-informatics Building, Hong Kong, China
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  • Sui-Yi Kwok,

    1.  Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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  • Paul N. M. Cheng,

    1.  Bio-Cancer Treatments International Ltd., Hong Kong Science Park, Bio-informatics Building, Hong Kong, China
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  • Denys N. Wheatley,

    1.  Bio-Cancer Treatments International Ltd., Hong Kong Science Park, Bio-informatics Building, Hong Kong, China
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  • Wai-Hung Lo,

    1.  Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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  • Yun-Chung Leung

    1.  Department of Applied Biology and Chemical Technology and Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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Y. C. Leung, e-mail: bctleung@polyu.edu.hk; W. H. Lo, e-mail: bctlo@polyu.edu.hk

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 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.

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