Journal of Liver Cancer

Original Article

Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma: Jin Sun Kim, Won-Mook Choi, Ha-Il Kim, Sung Won Chung, Jonggi Choi, Danbi Lee, Kang Mo Kim; J Liver Cancer. 2025;25(1):79-90. Published online January 14, 2025; DOI: https://doi.org/10.17998/jlc.2024.12.27

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Backgrounds/Aims
Hepatocellular carcinoma (HCC) is a malignant cancer with an increasing incidence worldwide. Although numerous efforts have been made to identify effective therapies for HCC, current strategies have limitations. We present a new approach for targeting L-arginine and argininosuccinate synthetase 1 (ASS1).
Methods
ASS1 expression in HCC cell lines and primary hepatocytes was detected using polymerase chain reaction and western blotting. Proliferation, migration, signaling pathways, and nitric oxide production in HCC cell lines were measured using MTS, colony formation, wound healing, Western blot, and Griess assays.
Results
ASS1 expression varied among the HCC cell lines, and cisplatin cytotoxicity was ASS1-dependent. L-arginine alone induced apoptosis in HCC cell lines, regardless of ASS1 expression; however, its effect was enhanced in ASS1-expressing HCC cell lines. Cisplatin cytotoxicity also increased, suggesting that L-arginine acts as a sensitizer to cisplatin in HCC cell lines. ASS1 and L-arginine produced nitric oxide and inhibited key proliferation- and survival-related signaling pathways such as PI3K/Akt and MAPK. Additionally, ASS1 and L-arginine reduced the expression of PKM1 and PKM2 in the glycolysis pathway.
Conclusions
Our study revealed that ASS1 and L-arginine exhibited anticancer effects in HCC and sensitized cisplatin-resistant HCC cells to chemotherapy. The combination of ASS1 and L-arginine significantly enhanced the anticancer effects, even in HCC cell lines with low or absent ASS1 expression. These findings highlight the critical roles of arginine and ASS1 in HCC and suggest that increasing arginine availability could be a promising therapeutic strategy.

Citations

Citations to this article as recorded by

Antitumor role of L-arginine and argininosuccinate synthetase 1 in hepatocellular carcinoma: direct and immunological mechanisms
Hyuk Soo Eun
Journal of Liver Cancer.2025; 25(1): 1. CrossRef
Metabolic-immune microenvironment crosstalk mediating ICI resistance in MASH-HCC
Yi Ju, Kequan Xu, Xi Chen, Tiangen Wu, Yufeng Yuan
Trends in Endocrinology & Metabolism.2025;[Epub] CrossRef

Case Reports

A Case of Hemolytic Uremic Syndrome after Cisplatin Based Transarterial Chemoembolization: Chang Hyeon Seok, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee; Journal of the Korean Liver Cancer Study Group. 2012;12(2):169-171. Published online September 30, 2012

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Abstract PDF: Hemolytic uremic syndrome (HUS) is a rare condition compromising the clinical triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. HUS may be associated with a variety of etiologies, and chemotherapeutic agents have also been reported to be associated with HUS, including mitomycin, cisplatin, bleomycin, and most recently gemcitabine. HUS also has been observed in association with a number of disseminated malignancies in adults, most typically adenocarcinoma of the stomach and breast. But there was no case report of HUS after cisplatin based transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). We experienced a case of HUS after cisplatin based TACE and reported this case with several literature reviews.

Two Cases of Hepatocellular Carcinoma with Extrahepatic Metastasis Who Showed Complete Remission Following Doxorubicin and Cisplatin (AP) Combination Chemotherapy in Reduced Dosage: Seung Bum Nam, Chul Ju Han, Ho Jin Lee, Youn Joo Kim, Ki Young Yang, Su Cheol Park, Jin Kim, Yu Cheol Kim; Journal of the Korean Liver Cancer Study Group. 2010;10(1):55-60. Published online June 30, 2010

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Abstract PDF: The effect of systemic chemotherapy in patients with advanced HCC is very limited, not only in regard to poor response to cytotoxic chemotherapeutic agents but also poor tolerance to therapy and related adverse effects. Herein, we report two
case
s of hepatocellular carcinoma (HCC) with extrahepatic metastasis who achieved complete remission following administration of doxorubicin and cisplatin in reduced dosage. The first case was a 41-year-old male who had HCC with multiple lung and intraabdominal lymph nodes metastasis. After 9 cycles of chemotherapy with 50% reduced dosage, he achieved a complete remission of both primary and metastatic lesions. He showed no evidence of disease for 11 more months during follow-up and still lives without recurrence. The second case was a 61-year-old female who had HCC with inferior vena cava thrombosis and multiple lung metastasis. After one cycle of treatment with 25% reduced dosage, she underwent life-threatening toxicities and poor tolerance to chemotherapy and further treatment was discontinued. However, she achieved a complete remission of both primary and metastatic lesions. Following 26 months of recurrence free period, she suffered from a recurrent tumor near previously treated lesion, which was successfully treated by TACE and radiation therapy. This modified doxorubicin and cisplatin regimen in reduced dosage could be used as means of evading life threatening toxicity and selecting out responders to systemic chemotherapy with reduced risk.

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