Abstract
The moderate anticancer effect of arginine deprivation in clinical trials has been linked to an induced argininosuccinate synthetase (ASS1) expression in initially ASS1-negative tumors, and ASS1-positive cancers are anticipated as non-responders. Our previous studies indicated that arginine deprivation and low doses of the natural arginine analog canavanine can enhance radioresponse. However, the efficacy of the proposed combination in the presence of extracellular citrulline, the substrate for arginine synthesis by ASS1, remains to be elucidated, in particular for malignant cells with positive and/or inducible ASS1 as in colorectal cancer (CRC). Here, the physiological citrulline concentration of 0.05 mM was insufficient to overcome cell cycle arrest and radiosensitization triggered by arginine deficiency. Hyperphysiological citrulline (0.4 mM) did not entirely compensate for the absence of arginine and significantly decelerated cell cycling. Similar levels of canavanine-induced apoptosis were detected in the absence of arginine regardless of citrulline supplementation both in 2-D and advanced 3-D assays, while normal colon epithelial cells in organoid/colonosphere culture were unaffected. Notably, canavanine tremendously enhanced radiosensitivity of arginine-starved 3-D CRC spheroids even in the presence of hyperphysiological citrulline. We conclude that the novel combinatorial targeting strategy of metabolic-chemo-radiotherapy has great potential for the treatment of malignancies with inducible ASS1 expression.
Highlights
Arginine is a multifaceted amino acid, which is required for protein synthesis, and for the production of many other cellular metabolites, e.g. urea, nitric oxide, polyamines, proline, glutamate, creatine, and agmatine [1]
It is widely anticipated that arginine deprivationbased therapy is exclusively applicable for ASS1‐negative tumor entities as they cannot rely on plasma citrulline for arginine synthesis [4, 6]
colorectal cancer (CRC) were excluded as therapy responders based on an early work of Dillon et al, who demonstrated ASS1 expression in 46 out of 47 human CRC tissue samples CRCs [7]
Summary
Arginine is a multifaceted amino acid, which is required for protein synthesis, and for the production of many other cellular metabolites, e.g. urea, nitric oxide, polyamines, proline, glutamate, creatine, and agmatine [1]. The metabolism of this amino acid is a complex process with tissue and organ-specific patterns [2, 3]. The non-proteinogenic amino acid citrulline, which is supplied via the blood/plasma, is a key arginine precursor and becomes more relevant for cell survival under arginine shortage [2, 4]. The therapeutic potential of arginine deprivation has been established in clinical trials for melanomas and hepatocellular carcinomas [12,13,14,15]; trials on other ASS1-deficient malignancies are underway (e.g. leukemia (NCT01910012), lymphoma (NCT01910025), prostate cancer (NCT01497925, NCT02285101) etc., all from (http://clinicaltrials.gov)
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