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Int. J. Mol. Sci. 2017, 18(6), 1175; doi:10.3390/ijms18061175

The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma

1
Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
2
Chulabhorn Graduate Institute, Laksi, Bangkok 10210, Thailand
3
Division of Hematology/Oncology, Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA
4
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
5
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA
6
Center of Excellence on Environmental Health, Toxicology (EHT), Ministry of Education, Bangkok 10300, Thailand
7
Laboratory Unit of Pathology, Chulabhorn Hospital, Laksi, Bangkok 10210, Thailand
8
Department of Surgery, Faculty of Medicine, Khonkaen University, Khonkaen 40000, Thailand
9
Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
*
Authors to whom correspondence should be addressed.
Academic Editor: Terrence Piva
Received: 30 March 2017 / Revised: 18 May 2017 / Accepted: 26 May 2017 / Published: 1 June 2017
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
View Full-Text   |   Download PDF [9726 KB, uploaded 22 June 2017]   |  

Abstract

Argininosuccinate synthetase (ASS), a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC). Similar to previous reports, we have found the decrease in ASS expression in poorly differentiated HCC. These ASS(-) tumors are auxotrophic for arginine. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine, has shown activity in these tumors, but the antitumor effect is not robust and hence combination treatment is needed. Herein, we have elucidated the effectiveness of ADI-PEG20 combined with 5-Fluorouracil (5-FU) in ASS(-)HCC by targeting urea cycle and pyrimidine metabolism using four HCC cell lines as model. SNU398 and SNU387 express very low levels of ASS or ASS(-) while Huh-1, and HepG2 express high ASS similar to normal cells. Our results showed that the augmented cytotoxic effect of combination treatment only occurs in SNU398 and SNU387, and not in HepG2 and Huh-1 (ASS(+)) cells, and is partly due to reduced anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP), myeloid leukemia cell differentiation protein (Mcl-1) and B-cell lymphoma-2 (Bcl-2). Importantly, lack of ASS also influences essential enzymes in pyrimidine synthesis (carbamoyl-phosphate synthetase2, aspartate transcarbamylase and dihydrooratase (CAD) and thymidylate synthase (TS)) and malate dehydrogenase-1 (MDH-1) in TCA cycle. ADI-PEG20 treatment decreased these enzymes and made them more vulnerable to 5-FU. Transfection of ASS restored these enzymes and abolished the sensitivity to ADI-PEG20 and combination treatment. Overall, our data suggest that ASS influences multiple enzymes involved in 5-FU sensitivity. Combining ADI-PEG20 and 5-FU may be effective to treat ASS(-)hepatoma and warrants further clinical investigation. View Full-Text
Keywords: ASS(-)Hepatocellular carcinoma; ADI-PEG20; 5-FU; thymidylate synthase; ASS re-expression; pyrimidine metabolism ASS(-)Hepatocellular carcinoma; ADI-PEG20; 5-FU; thymidylate synthase; ASS re-expression; pyrimidine metabolism
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Thongkum, A.; Wu, C.; Li, Y.-Y.; Wangpaichitr, M.; Navasumrit, P.; Parnlob, V.; Sricharunrat, T.; Bhudhisawasdi, V.; Ruchirawat, M.; Savaraj, N. The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma. Int. J. Mol. Sci. 2017, 18, 1175.

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