The arginase inhibitor Nω−hydroxy−nor−arginine (nor−NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target

• DOI: 10.1371/journal.pone.0205254
• Publication Date: 2018-10-11T17:43:07Z
• Authors: King Pan Ng; Aditi Manjeri; Lin Ming Lee; Zhu En Chan; Chin Yee Tan; Qiancheng Darren Tan; A'Qilah Majeed; Kian Leong Lee; Charles Chuah; Toshio Suda; S. Tiong Ong
• Keywords: HEK 293 cells

Cancer cells, including in chronic myeloid leukemia (CML), depend on the hypoxic response to persist hosts and evade therapy. Accordingly, there is significant interest drugging cancer-specific responses. However, a major challenge identifying differential druggable responses between leukemic normal cells. Previously, we found that arginase 2 (ARG2), an enzyme of urea cycle, overexpressed CML but not progenitors. ARG2 target hypoxia inducible factors (HIF1-α HIF2-α), required for generation polyamines which are cell growth. We therefore explored if clinically-tested inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) would be effective against cells under conditions. Remarkably, nor-NOHA effectively induced apoptosis ARG2-expressing normoxia. Co-treatment with overcame hypoxia-mediated resistance towards BCR-ABL1 kinase inhibitors. While itself promising targeting response, unexpectedly its anti-leukemic activity was independent inhibition. Genetic ablation using CRISPR/Cas9 had no effect viability their sensitivity nor-NOHA. This discrepancy further evidenced by distinct effects knockouts cellular respiration. In conclusion, show has off-target among Since been employed clinical trials, widely used studies endothelial dysfunction, immunosuppression metabolism, diverse biological must cautiously evaluated before attributing ARG