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.

Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts

“…It should be pointed out, however, that using the same rate constant between each transit compartment would not have accounted for the different duration of each cell-cycle phase (17,26,27). This was addressed by using the baseline phase density in the cell line (18,20) to fix the values of the rate constants, k G 1 S , k SG 2 , and k MG 1 . The resulting impact on model prediction is 2-fold: (i) the model was able to account for the expected difference in transit time between the different cell-cycle compartments, and (ii) it could predict a different duration of inhibition of each phase arising from a single dose of LY2835219.…”

“…First, the biomarker model was recalibrated by adjusting the intercompartmental rate constants based on the observed initial phase distribution of the A375 cell line. This resulted in baseline proportions of early G 1 (P 0 ), late G 1 (p-Rb 0 ), S (TopoIIa 0 ), and G 2 -M phases (pHH3 0 ) of 59.7, 14.9, 20.7, and 4.7%, respectively (20), assuming early G 1 -phase represents 80% of total G 1 -phase density. The new parameter values for the rate constants, k G 1 S , k SG 2 , and k MG 1 , are given in Table 1.…”

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

“…[7][8][9][10] BCT-100 has shown significant benefit against solid tumors in preclinical studies and early-phase clinical trials. 8 Here, we characterize the mechanisms of dependence of AML blasts on arginine and the potential for arginine depletion with BCT-100 as a therapeutic approach.…”

Arginine enzymatic deprivation and diet restriction for cancer treatment

“…Recombinant human arginase (rhArg) demonstrated significant cytotoxicity in hepatocellular carcinoma and melanoma, in vitro and in vivo (Cheng et al, 2007;Lam et al, 2009;Lam et al, 2010). In contrast to ADI-PEG20, the sensitivity to rhArg in hepatocellular carcinoma and melanoma is independent of ASS expression.…”

“…To overcome the short circulatory half-life of arginase, rhArg(Mn)-PEG5000 was developed and investigated with in vivo and in vitro studies in HCC (Lam et al, 2010). RhArg(Mn)-PEG5000 was effective in inhibiting growth of HCC cell lines as well as melanoma cell lines, with IC50 ranging from 0.1-2 IU/ ml.…”