Pathophysiology of Arginases in Cancer and Efforts in Their Pharmacological Inhibition
Abstract
:1. Introduction
2. Arginases as Crucial Players in Physiology and Cancer Pathophysiology
2.1. Arginine Biosynthesis and Polyamine Production
2.2. Arginases and Proline and Glutamate Production
2.3. Arginases Control NO Production
3. Cellular Consequences of Induced Arginase Expression
3.1. Apoptosis
3.2. Cell Senescence
3.3. Autophagy
3.4. Vascularization
3.5. Immune Response and Inflammation
4. Arginases Regulate Metabolic and Mitochondria Machinery
4.1. ARG2 Regulates Oxidative Metabolism
4.2. ARG2’s Specific Role in Mitochondrial Function
5. Significance of Arginases in Non-Cancer Diseases
6. Clinical Perspectives of Arginase Inhibitors
6.1. Arginase Vaccines and Pegylated rhARG in Clinical Trials
6.2. Naturally Occurring Arginase Inhibitors
6.3. Synthetic Arginase Inhibitors
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Arginase Isoform | Substrate | Mediator | Process |
---|---|---|---|
ARG1 | L-arginine | NO | Apoptosis |
ROS | Cell senescence, apoptosis, inflammation | ||
IL-6 IL-8 | Suppression of T cells | ||
ARG2 | NO | Apoptosis | |
ROS | Cell senescence, apoptosis, inflammation | ||
IL-6 IL-8 TNF-α | Inflammation |
Compound | Clinical Trial ID | Phase of Clinical Trial | Condition or Disease |
---|---|---|---|
N(ω)-hydroxy-nor-L-arginine (nor-NOHA) | NCT02687152 | Phase I (completed) | Type 2 Diabetes Mellitus |
N(ω)-hydroxy-nor-L-arginine (nor-NOHA) | NCT02009527 | Phase I (completed) | Ischemia–Reperfusion Injury |
Numidargistat (CB-1158) | INCB001158 | Phase II (completed) | Metastatic Cancer; Colorectal Cancer; Lung Cancer; Solid Tumors; Gastric Cancer; Head and Neck Cancer; Bladder Cancer; Mesothelioma; Renal Cell Carcinoma; Urothelial Cancer |
CB-280 (chemical structure of the compound undisclosed) | NCT04279769 | Phase I (completed) | Cystic Fibrosis |
OATD-02 | NCT05759923 | Phase I (active) | Advanced/Metastatic Ovarian Carcinoma; Advanced/Metastatic Colorectal Carcinoma; Advanced/Metastatic Renal Cell Carcinoma; Advanced /Metastatic Pancreatic Carcinoma |
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Marzęta-Assas, P.; Jacenik, D.; Zasłona, Z. Pathophysiology of Arginases in Cancer and Efforts in Their Pharmacological Inhibition. Int. J. Mol. Sci. 2024, 25, 9782. https://doi.org/10.3390/ijms25189782
Marzęta-Assas P, Jacenik D, Zasłona Z. Pathophysiology of Arginases in Cancer and Efforts in Their Pharmacological Inhibition. International Journal of Molecular Sciences. 2024; 25(18):9782. https://doi.org/10.3390/ijms25189782
Chicago/Turabian StyleMarzęta-Assas, Patrycja, Damian Jacenik, and Zbigniew Zasłona. 2024. "Pathophysiology of Arginases in Cancer and Efforts in Their Pharmacological Inhibition" International Journal of Molecular Sciences 25, no. 18: 9782. https://doi.org/10.3390/ijms25189782