posted on 2023-04-03, 18:21authored byYijun Cai, Jeremy P.H. Chow, Yu-On Leung, Xiaoxu Lu, Chak-Ho Yuen, Wing Lun Lee, Ka-Chun Chau, Liz L. Yang, Raymond M.H. Wong, Justin Y.T. Lam, Daniel T.L. Chow, Steven H.K. Chung, Sui-Yi Kwok, Yun-chung Leung
ASS1 expression in AML cell lines and normal fibroblast
Funding
New Epsilon Innovation Limited
AML
Hong Kong Polytechnic University
History
ARTICLE ABSTRACT
Recent studies have revealed that targeting amino acid metabolic enzymes is a promising strategy in cancer therapy. Acute myeloid leukemia (AML) downregulates the expression of argininosuccinate synthase (ASS1), a recognized rate-limiting enzyme for arginine synthesis, and yet displays a critical dependence on extracellular arginine for survival and proliferation. This dependence on extracellular arginine, also known as arginine auxotrophy, suggests that arginine deprivation would be a treatment strategy for AML. NEI-01, a novel arginine-depleting enzyme, is capable of binding to serum albumin to extend its circulating half-life, leading to a potent anticancer activity. Here we reported the preclinical activity of NEI-01 in arginine auxotrophic AMLs. NEI-01 efficiently depleted arginine both in vitro and in vivo. NEI-01-induced arginine deprivation was cytotoxic to arginine auxotrophic AML cells through induction of cell-cycle arrest and apoptosis. Furthermore, the potent anti-leukemia activities of NEI-01 were observed in three different types of mouse models including human cell line-derived xenograft, mouse cell line-derived homografts in syngeneic mice and patient-derived xenograft. This preclinical data provide strong evidence to support the potential use of NEI-01 as a therapeutic approach in AML treatment.