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Feng T, Xie F, Lyu Y, Yu P, Chen B, Yu J, Zhang G, To KF, Tsang CM, Kang W. The arginine metabolism and its deprivation in cancer therapy. Cancer Lett 2025; 620:217680. [PMID: 40157492 DOI: 10.1016/j.canlet.2025.217680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
Arginine deprivation has emerged as a promising therapeutic strategy in cancer treatment due to the auxotrophy of certain tumors. Many cancers, such as pancreatic, colorectal, and hepatocellular carcinoma, exhibit downregulated argininosuccinate synthetase, making them reliant on external arginine sources. This dependency allows targeted therapies that deplete arginine, inhibiting tumor growth while sparing normal cells. Arginine is crucial for various cellular processes, including protein synthesis and immune function. Its deprivation affects both tumor metabolism and immune responses, potentially enhancing cancer therapy. Studies have explored using enzymes like arginine deiminase and arginase, often modified for increased stability and reduced immunogenicity, to effectively lower arginine levels in the tumor microenvironment. These approaches show promise, particularly in tumors with low argininosuccinate synthetase expression. However, the impact on immune cells and the potential for resistance highlight the need for further research. Combining arginine deprivation with other treatments might improve outcomes, offering a novel approach to combat arginine-dependent cancers.
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Affiliation(s)
- Tiejun Feng
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China
| | - Fuda Xie
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, China; CUHK-Shenzhen Research Institute, Shenzhen, China
| | - Yang Lyu
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China
| | - Peiyao Yu
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, China; CUHK-Shenzhen Research Institute, Shenzhen, China
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China
| | - Chi Man Tsang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China.
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, China; CUHK-Shenzhen Research Institute, Shenzhen, China.
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Panda PK, Paschoalini Mafra AC, Bastos AC, Cao L, Serra Bonet M, Brashears CB, Chen EY, Benedict-Hamilton HM, Ehrhardt W, Bomalaski J, Dehner C, Rogers LC, Oyama T, Van Tine BA. BCL-XL Protects ASS1-Deficient Cancers from Arginine Starvation-Induced Apoptosis. Clin Cancer Res 2025; 31:1333-1345. [PMID: 39898973 PMCID: PMC11964295 DOI: 10.1158/1078-0432.ccr-24-2548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/26/2024] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
PURPOSE Argininosuccinate synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, such as PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis. EXPERIMENTAL DESIGN The effects of ADI-PEG20 on cell-cycle regulation, apoptosis, and BCL-XL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions among BCL-XL, BAX, and BAK. In vitro synergy was determined, and in vivo efficacy was modeled. RESULTS Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell-cycle progression but did not induce significant cell death. BCL-XL was found to bind to BAX and BAK, preventing the initiation of apoptosis despite arginine starvation. Inhibition of BCL-XL allowed proapoptotic BAX and BAK to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo. CONCLUSIONS The study identifies BCL-XL as a key factor limiting the efficacy of arginine starvation therapies. Combining BCL-XL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in phase 1 clinical trials for ASS1-deficient cancers.
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Affiliation(s)
- Prashanta Kumar Panda
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Ana Carolina Paschoalini Mafra
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Alliny C.S. Bastos
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Li Cao
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
- Department of Orthopaedic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Maria Serra Bonet
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Caitlyn B. Brashears
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Ethan Yang Chen
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Heather M. Benedict-Hamilton
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - William Ehrhardt
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | | | - Carina Dehner
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Leonard C. Rogers
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Toshinao Oyama
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Brian A. Van Tine
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
- Siteman Cancer Center, St. Louis, Missouri
- Department of Pediatric Hematology/Oncology, St. Louis Children’s Hospital, St. Louis, Missouri
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Dunlap KN, Bender A, Bowles A, Bott AJ, Tay J, Grossmann AH, Rutter J, Ducker GS. SLC7A5 is required for cancer cell growth under arginine-limited conditions. Cell Rep 2025; 44:115130. [PMID: 39756034 DOI: 10.1016/j.celrep.2024.115130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/09/2024] [Accepted: 12/10/2024] [Indexed: 01/07/2025] Open
Abstract
Tumor cells must optimize metabolite acquisition between synthesis and uptake from a microenvironment characterized by hypoxia, lactate accumulation, and depletion of many amino acids, including arginine. We performed a metabolism-focused functional screen using CRISPR-Cas9 to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Using isotope tracing experiments, we show that citrulline uptake and metabolism into arginine are dependent upon expression of SLC7A5. Pharmacological inhibition of SLC7A5 blocks growth under low-arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. We identify a conditionally essential role for SLC7A5 in arginine metabolism, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be effective in the context of arginine limitation.
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Affiliation(s)
- Kyle N Dunlap
- Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - Austin Bender
- Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - Alexis Bowles
- Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - Alex J Bott
- Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Joshua Tay
- Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
| | - Allie H Grossmann
- Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Jared Rutter
- Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Gregory S Ducker
- Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
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Huang K, Han Y, Chen Y, Shen H, Zeng S, Cai C. Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy. Mol Cancer 2025; 24:7. [PMID: 39789606 PMCID: PMC11716519 DOI: 10.1186/s12943-024-02205-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025] Open
Abstract
Metabolic reprogramming within the tumor microenvironment (TME) is a hallmark of cancer and a crucial determinant of tumor progression. Research indicates that various metabolic regulators form a metabolic network in the TME and interact with immune cells, coordinating the tumor immune response. Metabolic dysregulation creates an immunosuppressive TME, impairing the antitumor immune response. In this review, we discuss how metabolic regulators affect the tumor cell and the crosstalk of TME. We also summarize recent clinical trials involving metabolic regulators and the challenges of metabolism-based tumor therapies in clinical translation. In a word, our review distills key regulatory factors and their mechanisms of action from the complex reprogramming of tumor metabolism, identified as tumor metabolic regulators. These regulators provide a theoretical basis and research direction for the development of new strategies and targets in cancer therapy based on tumor metabolic reprogramming.
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Affiliation(s)
- Kun Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yihong Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Changjing Cai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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Vonderohe C, Stoll B, Didelija I, Nguyen T, Mohammad M, Jones-Hall Y, Cruz MA, Marini J, Burrin D. Citrulline and ADI-PEG20 reduce inflammation in a juvenile porcine model of acute endotoxemia. Front Immunol 2024; 15:1400574. [PMID: 39176089 PMCID: PMC11338849 DOI: 10.3389/fimmu.2024.1400574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 07/15/2024] [Indexed: 08/24/2024] Open
Abstract
Background Arginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. In pediatric and adult patients, sepsis results in an arginine-deficient state, and the depletion of plasma arginine is associated with greater mortality. However, direct supplementation of arginine can result in the excessive production of nitric oxide (NO), which can contribute to the hypotension and macrovascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADI-PEG20, pegargiminase) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. The objective of this study was to assess the efficacy of ADI-PEG20 with and without supplemental intravenous citrulline in mitigating hypovolemic shock, maintaining tissue levels of arginine, and reducing systemic inflammation in an endotoxemic pediatric pig model. Methods Twenty 3-week-old crossbred piglets were implanted with jugular and carotid catheters as well as telemetry devices in the femoral artery to measure blood pressure, body temperature, heart rate, and respiration rate. The piglets were assigned to one of three treatments before undergoing a 5 h lipopolysaccharide (LPS) infusion protocol. Twenty-four hours before LPS infusion, control pigs (LPS; n=6) received saline, ADI-PEG20 pigs (n=7) received an injection of ADI-PEG20, and seven pigs (ADI-PEG20 + CIT pigs [n=7]) received ADI-PEG20 and 250 mg/kg citrulline intravenously. Pigs were monitored throughout LPS infusion and tissue was harvested at the end of the protocol. Results Plasma arginine levels decreased and remained low in ADI-PEG20 + CIT and ADI-PEG20 pigs compared with LPS pigs but tissue arginine levels in the liver and kidney were similar across all treatments. Mean arterial pressure in all groups decreased from 90 mmHg to 60 mmHg within 1 h of LPS infusion but there were no significant differences between treatment groups. ADI-PEG20 and ADI-PEG20 + CIT pigs had less CD45+ infiltrate in the liver and lung and lower levels of pro-inflammatory cytokines in the plasma. Conclusion ADI-PEG20 and citrulline supplementation failed to ameliorate the hypotension associated with acute endotoxic sepsis in pigs but reduced systemic and local inflammation in the lung and liver.
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Affiliation(s)
- Caitlin Vonderohe
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Barbara Stoll
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Inka Didelija
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Trung Nguyen
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veteran Administration Medical Center, Houston, TX, United States
| | - Mahmoud Mohammad
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Yava Jones-Hall
- Department of Pathobiology, Texas A&M College of Veterinary Medicine and Biomedical Science, College Station, TX, United States
| | - Miguel A. Cruz
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veteran Administration Medical Center, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Juan Marini
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Douglas Burrin
- USDA-ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
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Jastrząb R, Tomecki R, Jurkiewicz A, Graczyk D, Szczepankowska AK, Mytych J, Wolman D, Siedlecki P. The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase. Microb Cell Fact 2024; 23:82. [PMID: 38481270 PMCID: PMC10938756 DOI: 10.1186/s12934-024-02345-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/20/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, posing a serious public health challenge that necessitates the development of new therapeutics, therapies, and prevention methods. Among the various therapeutic approaches, interventions involving lactic acid bacteria (LAB) as probiotics and postbiotics have emerged as promising candidates for treating and preventing CRC. While human-isolated LAB strains are considered highly favorable, those sourced from environmental reservoirs such as dairy and fermented foods are also being recognized as potential sources for future therapeutics. RESULTS In this study, we present a novel and therapeutically promising strain, Lactococcus lactis ssp. lactis Lc4, isolated from dairy sources. Lc4 demonstrated the ability to release the cytostatic agent - arginine deiminase (ADI) - into the post-cultivation supernatant when cultured under conditions mimicking the human gut environment. Released arginine deiminase was able to significantly reduce the growth of HT-29 and HCT116 cells due to the depletion of arginine, which led to decreased levels of c-Myc, reduced phosphorylation of p70-S6 kinase, and cell cycle arrest. The ADI release and cytostatic properties were strain-dependent, as was evident from comparison to other L. lactis ssp. lactis strains. CONCLUSION For the first time, we unveil the anti-proliferative properties of the L. lactis cell-free supernatant (CFS), which are independent of bacteriocins or other small molecules. We demonstrate that ADI, derived from a dairy-Generally Recognized As Safe (GRAS) strain of L. lactis, exhibits anti-proliferative activity on cell lines with different levels of argininosuccinate synthetase 1 (ASS1) expression. A unique feature of the Lc4 strain is also its capability to release ADI into the extracellular space. Taken together, we showcase L. lactis ADI and the Lc4 strain as promising, potential therapeutic agents with broad applicability.
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Affiliation(s)
- Rafał Jastrząb
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
- Olimp Laboratories, Pustynia 84F, Debica, 39-200, Poland
| | - Rafał Tomecki
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
- Faculty of Biology, University of Warsaw, Miecznikowa 1, Warsaw, 02-089, Poland
| | - Aneta Jurkiewicz
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
| | - Damian Graczyk
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
| | - Agnieszka K Szczepankowska
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland
| | | | - Damian Wolman
- Olimp Laboratories, Pustynia 84F, Debica, 39-200, Poland
| | - Pawel Siedlecki
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Adolfa Pawińskiego 5A, Warsaw, 02-106, Poland.
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Zhang L, Zhai BZ, Wu YJ, Wang Y. Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment. Drug Deliv 2023; 30:1-18. [PMID: 36597205 PMCID: PMC9943254 DOI: 10.1080/10717544.2022.2144541] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Cancer is a very heterogeneous disease, and uncontrolled cell division is the main characteristic of cancer. Cancerous cells need a high nutrition intake to enable aberrant growth and survival. To do so, cancer cells modify metabolic pathways to produce energy and anabolic precursors and preserve redox balance. Due to the importance of metabolic pathways in tumor growth and malignant transformation, metabolic pathways have also been given promising perspectives for cancer treatment, providing more effective treatment strategies, and target-specific with minimum side effects. Metabolism-based therapeutic nanomaterials for targeted cancer treatment are a promising option. Numerous types of nanoparticles (NPs) are employed in the research and analysis of various cancer therapies. The current review focuses on cutting-edge strategies and current cancer therapy methods based on nanomaterials that target various cancer metabolisms. Additionally, it highlighted the primacy of NPs-based cancer therapies over traditional ones, the challenges, and the future potential.
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Affiliation(s)
- Ling Zhang
- Reproductive Medicine Center, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China,CONTACT Ling Zhang Reproductive Medicine Center, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou310014, Zhejiang, China
| | - Bing-Zhong Zhai
- Hangzhou Municipal Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310021, China
| | - Yue-Jin Wu
- Institute of Food Science and Engineering, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China
| | - Yin Wang
- Institute of Food Science and Engineering, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China,; Yin Wang Institute of Food Science and Engineering, Hangzhou Medical College, 182 Tianmushan Road, Hangzhou310013, Zhejiang, China
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Wang Y, Chen S, Wang C, Guo F. Nanocarrier-based targeting of metabolic pathways for endometrial cancer: Status and future perspectives. Biomed Pharmacother 2023; 166:115348. [PMID: 37639743 DOI: 10.1016/j.biopha.2023.115348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/10/2023] [Accepted: 08/19/2023] [Indexed: 08/31/2023] Open
Abstract
Cancer is the second-most lethal global disease, as per health reports, and is responsible for around 70% of deaths in low- and middle-income countries. Endometrial cancer is one of the emerging malignancies and has been predicted as a public health challenge for the future. Insulin resistance, obesity, and diabetes mellitus are the key metabolic factors that promote risks for the development of endometrial cancer. Various signaling pathways and associated genes are involved in the genesis of endometrial cancer, and any mutation or deletion in such related factors leads to the induction of endometrial cancer. The conventional way of drug delivery has been used for ages but is associated with poor management of cancer due to non-targeting of the endometrial cancer cells, low efficacy of the therapy, and toxicity issues as well. In this context, nanocarrier-based therapy for the management of endometrial cancer is an effective alternate choice that overcomes the problems associated with conventional therapy. In this review article, we highlighted the nanocarrier-based targeting of endometrial cancer, with a special focus on targeting various metabolic signaling pathways. Furthermore, the future perspectives of nanocarrier-based targeting of metabolic pathways in endometrial cancer were also underpinned. It is concluded that targeting metabolic signaling pathways in endometrial cancer via nanocarrier scaffolds is the future of pharmaceutical design for the significant management and treatment of endometrial cancer.
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Affiliation(s)
- Yichao Wang
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun 130000, China
| | - Siyao Chen
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun 130000, China
| | - Chunling Wang
- Medical Affairs Department, The Second Hospital of Jilin University, Changchun 130000, China
| | - Fengjun Guo
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun 130000, China.
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Wei X, Chow HY, Chong HC, Leung SL, Ho MK, Lee MY, Leung YC. Arginine Is a Novel Drug Target for Arginine Decarboxylase in Human Colorectal Cancer Cells. Int J Mol Sci 2023; 24:13741. [PMID: 37762044 PMCID: PMC10531272 DOI: 10.3390/ijms241813741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/02/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) has been proven to be highly reliant on arginine availability. Limiting arginine-rich foods or treating patients with arginine-depleting enzymes arginine deiminase (ADI) or arginase can suppress colon cancer. However, arginase and ADI are not the best drug candidates for CRC. Ornithine, the product of arginase, can enhance the supply of polyamine, which favors CRC cell growth, while citrulline, the product of ADI, faces the problem of arginine recycling due to the overexpression of argininosuccinate synthetase (ASS). Biosynthetic arginine decarboxylase (ADC), an enzyme that catalyzes the conversion of arginine to agmatine and carbon dioxide, may be a better choice as it combines both arginine depletion and suppression of intracellular polyamine synthesis via its product agmatine. ADC has anti-tumor potential yet has received much less attention than the other two arginine-depleting enzymes. In order to gain a better understanding of ADC, the preparation and the anti-cancer properties of this enzyme were explored in this study. When tested in vitro, ADC inhibited the proliferation of three colorectal cancer cell lines regardless of their ASS cellular expression. In contrast, ADC had a lesser cytotoxic effect on the human foreskin fibroblasts and rat primary hepatocytes. Further in vitro studies revealed that ADC induced S and G2/M phase cell-cycle arrest and apoptosis in HCT116 and LoVo cells. ADC-induced apoptosis in HCT116 cells followed the mitochondrial apoptotic pathway and was caspase-3-dependent. With all results obtained, we suggest that arginine is a potential target for treating colorectal cancer with ADC, and the anti-cancer properties of ADC should be more deeply investigated in the future.
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Affiliation(s)
- Xinlei Wei
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Ho-Yin Chow
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Hiu-Chi Chong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Siu-Lun Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Mei-Ki Ho
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Man-Yuen Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
- Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Yun-Chung Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
- Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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10
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Bianchi M, Rossi L, Pierigè F, Biagiotti S, Bregalda A, Tasini F, Magnani M. Preclinical and clinical developments in enzyme-loaded red blood cells: an update. Expert Opin Drug Deliv 2023; 20:921-935. [PMID: 37249524 DOI: 10.1080/17425247.2023.2219890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/26/2023] [Indexed: 05/31/2023]
Abstract
INTRODUCTION We have previously described the preclinical developments in enzyme-loaded red blood cells to be used in the treatment of several rare diseases, as well as in chronic conditions. AREA COVERED Since our previous publication we have seen further progress in the previously discussed approaches and, interestingly enough, in additional new studies that further strengthen the idea that red blood cell-based therapeutics may have unique advantages over conventional enzyme replacement therapies in terms of efficacy and safety. Here we highlight these investigations and compare, when possible, the reported results versus the current therapeutic approaches. EXPERT OPINION The continuous increase in the number of new potential applications and the progress from the encapsulation of a single enzyme to the engineering of an entire metabolic pathway open the field to unexpected developments and confirm the role of red blood cells as cellular bioreactors that can be conveniently manipulated to acquire useful therapeutic metabolic abilities. Positioning of these new approaches versus newly approved drugs is essential for the successful transition of this technology from the preclinical to the clinical stage and hopefully to final approval.
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Affiliation(s)
- Marzia Bianchi
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Luigia Rossi
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
- EryDel SpA, Bresso, MI, Italy
| | - Francesca Pierigè
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Sara Biagiotti
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Alessandro Bregalda
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Filippo Tasini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Mauro Magnani
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
- EryDel SpA, Bresso, MI, Italy
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11
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Chu YD, Lai MW, Yeh CT. Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment. Int J Mol Sci 2023; 24:10668. [PMID: 37445845 DOI: 10.3390/ijms241310668] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis-all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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12
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Jiménez-Alonso JJ, López-Lázaro M. Dietary Manipulation of Amino Acids for Cancer Therapy. Nutrients 2023; 15:2879. [PMID: 37447206 DOI: 10.3390/nu15132879] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Cancer cells cannot proliferate and survive unless they obtain sufficient levels of the 20 proteinogenic amino acids (AAs). Unlike normal cells, cancer cells have genetic and metabolic alterations that may limit their capacity to obtain adequate levels of the 20 AAs in challenging metabolic environments. However, since normal diets provide all AAs at relatively constant levels and ratios, these potentially lethal genetic and metabolic defects are eventually harmless to cancer cells. If we temporarily replace the normal diet of cancer patients with artificial diets in which the levels of specific AAs are manipulated, cancer cells may be unable to proliferate and survive. This article reviews in vivo studies that have evaluated the antitumor activity of diets restricted in or supplemented with the 20 proteinogenic AAs, individually and in combination. It also reviews our recent studies that show that manipulating the levels of several AAs simultaneously can lead to marked survival improvements in mice with metastatic cancers.
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Affiliation(s)
| | - Miguel López-Lázaro
- Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Sevilla, Spain
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13
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The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C. Cancer Cell Int 2023; 23:38. [PMID: 36843002 PMCID: PMC9969664 DOI: 10.1186/s12935-023-02873-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 02/14/2023] [Indexed: 02/28/2023] Open
Abstract
BACKGROUND Arginine auxotrophy constitutes a shortcoming for ~ 30% of glioblastoma multiforme (GBM). Indeed, arginine-depleting therapy using arginine deiminase from Streptococcus pyogenes (SpyADI) has proven activity against GBM in preclinical studies. The good safety profile of SpyADI renders this agent an ideal combination partner for cytostatic therapy. METHODS In this study, we combined the antineoplastic antibiotic Mithramycin A (MitA) with SpyADI to boost single-agent activity and analyzed underlying response mechanisms in-depth. RESULTS MitA monotherapy induced a time- and dose-dependent cytotoxicity in eight patient-derived GBM cell lines and had a radiosensitizing effect in all but one cell line. Combination treatment boosted the effects of the monotherapy in 2D- and 3D models. The simultaneous approach was superior to the sequential application and significantly impaired colony formation after repetitive treatment. MitA monotherapy significantly inhibited GBM invasiveness. However, this effect was not enhanced in the combination. Functional analysis identified SpyADI-triggered senescence induction accompanied by increased mitochondrial membrane polarization upon mono- and combination therapy. In HROG63, induction of lysosomes was seen after both monotherapies, indicative of autophagy. These cells seemed swollen and had a more pronounced cortically formed cytoskeleton. Also, cytochrome C and endoplasmatic reticulum-stress-associated proteins ATF4 and Calnexin were enhanced in the combination, contributing to apoptosis. Notably, no significant increases in glioma-stemness marker were seen. CONCLUSIONS Therapeutic utilization of a metabolic defect in GBM along with cytostatic therapy provides a novel combination approach. Whether this SpyADI/MitA regimen will provide a safe alternative to combat GBM, will have to be addressed in subsequent (pre-)clinical trials.
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14
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Bench-to-Bedside Studies of Arginine Deprivation in Cancer. Molecules 2023; 28:molecules28052150. [PMID: 36903394 PMCID: PMC10005060 DOI: 10.3390/molecules28052150] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/08/2023] [Accepted: 02/17/2023] [Indexed: 03/03/2023] Open
Abstract
Arginine is a semi-essential amino acid which becomes wholly essential in many cancers commonly due to the functional loss of Argininosuccinate Synthetase 1 (ASS1). As arginine is vital for a plethora of cellular processes, its deprivation provides a rationale strategy for combatting arginine-dependent cancers. Here we have focused on pegylated arginine deiminase (ADI-PEG20, pegargiminase)-mediated arginine deprivation therapy from preclinical through to clinical investigation, from monotherapy to combinations with other anticancer therapeutics. The translation of ADI-PEG20 from the first in vitro studies to the first positive phase 3 trial of arginine depletion in cancer is highlighted. Finally, this review discusses how the identification of biomarkers that may denote enhanced sensitivity to ADI-PEG20 beyond ASS1 may be realized in future clinical practice, thus personalising arginine deprivation therapy for patients with cancer.
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15
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Holz E, Darwish M, Tesar DB, Shatz-Binder W. A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future. Pharmaceutics 2023; 15:600. [PMID: 36839922 PMCID: PMC9959917 DOI: 10.3390/pharmaceutics15020600] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/04/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody-drug conjugates, peptide/protein-PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody-oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.
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Affiliation(s)
- Emily Holz
- Department of Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Martine Darwish
- Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Devin B. Tesar
- Department of Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Whitney Shatz-Binder
- Department of Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
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16
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Chu YD, Liu HF, Chen YC, Chou CH, Yeh CT. WWOX-rs13338697 genotype predicts therapeutic efficacy of ADI-PEG 20 for patients with advanced hepatocellular carcinoma. Front Oncol 2022; 12:996820. [PMID: 36530994 PMCID: PMC9756969 DOI: 10.3389/fonc.2022.996820] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 11/14/2022] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Previous studies have identified three single nucleotide polymorphisms (SNPs): GALNT14-rs9679162, WWOX-rs13338697 and rs6025211. Their genotypes are associated with therapeutic outcomes in hepatocellular carcinoma (HCC). Herein, we examined whether these SNP genotypes could predict the clinical outcome of HCC patients treated with ADI-PEG 20. METHODS Totally 160 patients with advanced HCC, who had previously been enrolled in clinical trials, including 113 receiving ADI-PEG 20 monotherapy (cohort-1) and 47 receiving FOLFOX/ADI-PEG 20 combination treatment (cohort-2), were included retrospectively. RESULTS The WWOX-rs13338697-GG genotype was associated with favorable overall survival in cohort-1 patients (P = 0.025), whereas the rs6025211-TT genotype was associated with unfavorable time-to-tumor progression in cohort-1 (P = 0.021) and cohort-1 plus 2 patients (P = 0.008). As ADI-PEG 20 can reduce plasma arginine levels, we examined its pretreatment levels in relation to the WWOX-rs13338697 genotypes. Pretreatment plasma arginine levels were found to be significantly higher in patients carrying the WWOX-rs13338697-GG genotype (P = 0.006). We next examined the association of the WWOX-rs13338697 genotypes with WWOX tissue protein levels in 214 paired (cancerous/noncancerous) surgically resected HCC tissues (cohort-3). The WWOX-rs13338697-GG genotype was associated with decreased tissue levels of WWOX and ASS1. Mechanistic studies showed that WWOX and ASS1 levels were downregulated in hypoxic HCC cells. Silencing WWOX to mimic low WWOX protein expression in HCC in patients with the WWOX-rs13338697-GG genotype, enhanced HIF1A increment under hypoxia, further decreased ASS1, and increased cell susceptibility to ADI-PEG 20. COMCLUSION In summary, the WWOX-rs13338697 and rs6025211 genotypes predicted treatment outcomes in ADI-PEG 20-treated advanced HCC patients. The WWOX-rs13338697-GG genotype was associated with lower tissue WWOX and ASS1 levels and higher pretreatment plasma arginine levels, resembling an arginine auxotrophic phenotype requires excessive extracellular arginine supply. Silencing WWOX to mimic HCC with the WWOX-rs13338697-GG genotype further stimulated HCC cell response to hypoxia through increased HIF1A expression, leading to further reduction of ASS1 and thus increased cell susceptibility to ADI-PEG 20.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hui-Fen Liu
- Polaris Pharmaceuticals, Inc., Polaris Group, Taipei, Taiwan
| | - Yi-Chen Chen
- Polaris Pharmaceuticals, Inc., Polaris Group, Taipei, Taiwan
| | - Chun-Hung Chou
- Polaris Pharmaceuticals, Inc., Polaris Group, Taipei, Taiwan
- Ph.D. Program for Biotechnology Industry, College of Life Sciences, China Medical University, Taichung, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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17
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Pokrovsky VS, Abo Qoura L, Morozova E, Bunik VI. Predictive markers for efficiency of the amino-acid deprivation therapies in cancer. Front Med (Lausanne) 2022; 9:1035356. [PMID: 36405587 PMCID: PMC9669297 DOI: 10.3389/fmed.2022.1035356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Amino acid deprivation therapy (AADT) is a promising strategy for developing novel anticancer treatments, based on variations in metabolism of healthy and malignant cells. L-asparaginase was the first amino acid-degrading enzyme that received FDA approval for the treatment of acute lymphoblastic leukemia (ALL). Arginase and arginine deiminase were effective in clinical trials for the treatment of metastatic melanomas and hepatocellular carcinomas. Essential dependence of certain cancer cells on methionine explains the anticancer efficacy of methionine-g-lyase. Along with significant progress in identification of metabolic vulnerabilities of cancer cells, new amino acid-cleaving enzymes appear as promising agents for cancer treatment: lysine oxidase, tyrosine phenol-lyase, cysteinase, and phenylalanine ammonia-lyase. However, sensitivity of specific cancer cell types to these enzymes differs. Hence, search for prognostic and predictive markers for AADT and introduction of the markers into clinical practice are of great importance for translational medicine. As specific metabolic pathways in cancer cells are determined by the enzyme expression, some of these enzymes may define the sensitivity to AADT. This review considers the known predictors for efficiency of AADT, emphasizing the importance of knowledge on cancer-specific amino acid significance for such predictions.
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Affiliation(s)
- Vadim S. Pokrovsky
- Laboratory of Experimental Oncology, Research Institute of Molecular and Cellular Medicine, People’s Friendship University of Russia (RUDN University), Moscow, Russia
- Laboratory of Combined Treatment, N.N. Blokhin National Medical Research Center of Oncology of Ministry of Health of Russian Federation, Moscow, Russia
- Department of Biotechnology, Sirius University of Science and Technology, Sochi, Russia
- *Correspondence: Vadim S. Pokrovsky,
| | - Louay Abo Qoura
- Laboratory of Experimental Oncology, Research Institute of Molecular and Cellular Medicine, People’s Friendship University of Russia (RUDN University), Moscow, Russia
| | - Elena Morozova
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Victoria I. Bunik
- A.N. Belozersky Institute of Physicochemical Biology, M.V. Lomonosov Moscow State University, Moscow, Russia
- Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, Russia
- Department of Biological Chemistry, Sechenov First Moscow State Medical University, Moscow, Russia
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18
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Ping Y, Shen C, Huang B, Zhang Y. Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity. Cells 2022; 11:3103. [PMID: 36231064 PMCID: PMC9562038 DOI: 10.3390/cells11193103] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/09/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
Abstract
T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.
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Affiliation(s)
- Yu Ping
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Chunyi Shen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Bo Huang
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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19
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Sun N, Zhao X. Argininosuccinate synthase 1, arginine deprivation therapy and cancer management. Front Pharmacol 2022; 13:935553. [PMID: 35910381 PMCID: PMC9335876 DOI: 10.3389/fphar.2022.935553] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/29/2022] [Indexed: 12/13/2022] Open
Abstract
Metabolic reprogramming is an emerging hallmark of tumor cells. In order to survive in the nutrient-deprived environment, tumor cells rewire their metabolic phenotype to provide sufficient energy and build biomass to sustain their transformed state and promote malignant behaviors. Amino acids are the main compositions of protein, which provide key intermediate substrates for the activation of signaling pathways. Considering that cells can synthesize arginine via argininosuccinate synthase 1 (ASS1), arginine is regarded as a non-essential amino acid, making arginine depletion as a promising therapeutic strategy for ASS1-silencing tumors. In this review, we summarize the current knowledge of expression pattern of ASS1 and related signaling pathways in cancer and its potential role as a novel therapeutic target in cancer. Besides, we outline how ASS1 affects metabolic regulation and tumor progression and further discuss the role of ASS1 in arginine deprivation therapy. Finally, we review approaches to target ASS1 for cancer therapies.
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Affiliation(s)
- Naihui Sun
- Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xing Zhao
- Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Xing Zhao,
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20
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Chan PY, Phillips MM, Ellis S, Johnston A, Feng X, Arora A, Hay G, Cohen VML, Sagoo MS, Bomalaski JS, Sheaff MT, Szlosarek PW. A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma. Pigment Cell Melanoma Res 2022; 35:461-470. [PMID: 35466524 PMCID: PMC9322321 DOI: 10.1111/pcmr.13042] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/14/2022]
Abstract
Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI‐PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose‐expansion study of patients with argininosuccinate synthetase (ASS1)‐deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m2) and Cis (75 mg/m2) every 3 weeks plus weekly intramuscular ADI (36 mg/m2), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1‐deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression‐free survival of 3.0 months (range, 1.3–8.1) and a median overall survival of 11.5 months (range, 3.2–36.9). Despite anti‐ADI‐PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re‐expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti‐metabolite strategies.
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Affiliation(s)
- Pui Ying Chan
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.,Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK
| | - Melissa M Phillips
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Stephen Ellis
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | | | - Xiaoxing Feng
- Polaris Pharmaceuticals Inc, San Diego, California, USA
| | - Amit Arora
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Gordon Hay
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Victoria M L Cohen
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Mandeep S Sagoo
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK.,NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK
| | | | - Michael T Sheaff
- Department of Histopathology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Peter W Szlosarek
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.,Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
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21
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Riess C, del Moral K, Fiebig A, Kaps P, Linke C, Hinz B, Rupprecht A, Frank M, Fiedler T, Koczan D, Troschke-Meurer S, Lode HN, Engel N, Freitag T, Classen CF, Maletzki C. Implementation of a combined CDK inhibition and arginine-deprivation approach to target arginine-auxotrophic glioblastoma multiforme cells. Cell Death Dis 2022; 13:555. [PMID: 35717443 PMCID: PMC9206658 DOI: 10.1038/s41419-022-05006-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 05/18/2022] [Accepted: 06/08/2022] [Indexed: 01/21/2023]
Abstract
Constitutive activation of cyclin-dependent kinases (CDKs) or arginine auxotrophy are hallmarks of Glioblastoma multiforme (GBM). The latter metabolic defect renders tumor cells vulnerable to arginine-depleting substances, such as arginine deiminase from Streptococcus pyogenes (SpyADI). Previously, we confirmed the susceptibility of patient-derived GBM cells towards SpyADI as well as CDK inhibitors (CDKis). To improve therapeutic effects, we here applied a combined approach based on SpyADI and CDKis (dinaciclib, abemaciclib). Three arginine-auxotrophic patient-derived GBM lines with different molecular characteristics were cultured in 2D and 3D and effects of this combined SpyADI/CDKi approach were analyzed in-depth. All CDKi/SpyADI combinations yielded synergistic antitumoral effects, especially when given sequentially (SEQ), i.e., CDKi in first-line and most pronounced in the 3D models. SEQ application demonstrated impaired cell proliferation, invasiveness, and viability. Mitochondrial impairment was demonstrated by increasing mitochondrial membrane potential and decreasing oxygen consumption rate and extracellular acidification rate after SpyADI/abemaciclib monotherapy or its combination regimens. The combined treatment even induced autophagy in target cells (abemaciclib/SpyADI > dinaciclib/SpyADI). By contrast, the unfolded protein response and p53/p21 induced senescence played a minor role. Transmission electron microscopy confirmed damaged mitochondria and endoplasmic reticulum together with increased vacuolization under CDKi mono- and combination therapy. SEQ-abemaciclib/SpyADI treatment suppressed the DSB repair system via NHEJ and HR, whereas SEQ-dinaciclib/SpyADI treatment increased γ-H2AX accumulation and induced Rad51/Ku80. The latter combination also activated the stress sensor GADD45 and β-catenin antagonist AXIN2 and induced expression changes of genes involved in cellular/cytoskeletal integrity. This study highlights the strong antitumoral potential of a combined arginine deprivation and CDK inhibition approach via complex effects on mitochondrial dysfunction, invasiveness as well as DNA-damage response. This provides a good starting point for further in vitro and in vivo proof-of-concept studies to move forward with this strategy.
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Affiliation(s)
- Christin Riess
- grid.413108.f0000 0000 9737 0454University Children’s Hospital, Rostock University Medical Center, Ernst-Heydemann-Straße 8, 18057 Rostock, Germany ,grid.413108.f0000 0000 9737 0454Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany
| | - Katharina del Moral
- grid.413108.f0000 0000 9737 0454University Children’s Hospital, Rostock University Medical Center, Ernst-Heydemann-Straße 8, 18057 Rostock, Germany
| | - Adina Fiebig
- grid.413108.f0000 0000 9737 0454Institute for Medical Microbiology, Virology, and Hygiene, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany
| | - Philipp Kaps
- grid.413108.f0000 0000 9737 0454University Children’s Hospital, Rostock University Medical Center, Ernst-Heydemann-Straße 8, 18057 Rostock, Germany ,grid.413108.f0000 0000 9737 0454Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany ,grid.413108.f0000 0000 9737 0454Institute for Medical Microbiology, Virology, and Hygiene, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany
| | - Charlotte Linke
- grid.413108.f0000 0000 9737 0454University Children’s Hospital, Rostock University Medical Center, Ernst-Heydemann-Straße 8, 18057 Rostock, Germany
| | - Burkhard Hinz
- grid.413108.f0000 0000 9737 0454Institute for Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany
| | - Anne Rupprecht
- grid.413108.f0000 0000 9737 0454Institute for Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany
| | - Marcus Frank
- grid.413108.f0000 0000 9737 0454Medical Biology and Electron Microscopy Center, Rostock University Medical Center, Rostock, Germany ,grid.10493.3f0000000121858338Department of Life, Light & Matter, University of Rostock, Rostock, Germany
| | - Tomas Fiedler
- grid.413108.f0000 0000 9737 0454Institute for Medical Microbiology, Virology, and Hygiene, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany
| | - Dirk Koczan
- grid.10493.3f0000000121858338Institute for Immunology, University of Rostock, 18055 Rostock, Germany
| | - Sascha Troschke-Meurer
- grid.5603.0Department of Pediatric Oncology and Hematology, University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany
| | - Holger N. Lode
- grid.5603.0Department of Pediatric Oncology and Hematology, University Medicine Greifswald, Ferdinand-Sauerbruch-Strasse, 17475 Greifswald, Germany
| | - Nadja Engel
- grid.413108.f0000 0000 9737 0454Department of Oral and Maxillofacial Surgery, Facial Plastic Surgery, Rostock University Medical Center, Rostock, Germany
| | - Thomas Freitag
- grid.413108.f0000 0000 9737 0454Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany
| | - Carl Friedrich Classen
- grid.413108.f0000 0000 9737 0454University Children’s Hospital, Rostock University Medical Center, Ernst-Heydemann-Straße 8, 18057 Rostock, Germany
| | - Claudia Maletzki
- grid.413108.f0000 0000 9737 0454Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany
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22
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Kraehenbuehl L, Holland A, Armstrong E, O’Shea S, Mangarin L, Chekalil S, Johnston A, Bomalaski JS, Erinjeri JP, Barker CA, Francis JH, Wolchok JD, Merghoub T, Shoushtari AN. Pilot Trial of Arginine Deprivation Plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma. Cancers (Basel) 2022; 14:cancers14112638. [PMID: 35681616 PMCID: PMC9179243 DOI: 10.3390/cancers14112638] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Uveal melanoma is a rare subtype of malignant melanoma. It is known to rapidly metastasize, with the liver being the most frequently affected organ. Due to differences from melanoma arising in the skin, such as a lower number of mutations, it responds poorly to immune checkpoint blockade, a treatment approach reinvigorating the patient’s immune system to eliminate the cancer. We here investigated the safety and tolerability of a new combination treatment consisting of two established immunotherapy medications (ipilimumab and nivolumab) with the addition of an experimental arginine depleting medication, pegylated arginine deiminase (ADI-PEG 20), which is thought to make uveal melanoma more amenable to immunotherapy. This novel treatment approach was found to be safe and well-tolerated but did not improve the clinical outcome beyond the expected limited efficacy of approved immunotherapy alone. Abstract Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases.
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Affiliation(s)
- Lukas Kraehenbuehl
- Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (L.K.); (A.H.); (L.M.); (S.C.); (J.D.W.); (T.M.)
| | - Aliya Holland
- Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (L.K.); (A.H.); (L.M.); (S.C.); (J.D.W.); (T.M.)
| | - Emma Armstrong
- Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (E.A.); (S.O.)
| | - Sirinya O’Shea
- Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (E.A.); (S.O.)
| | - Levi Mangarin
- Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (L.K.); (A.H.); (L.M.); (S.C.); (J.D.W.); (T.M.)
| | - Sara Chekalil
- Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (L.K.); (A.H.); (L.M.); (S.C.); (J.D.W.); (T.M.)
| | - Amanda Johnston
- Polaris Pharmaceuticals, Inc., San Diego, CA 92121, USA; (A.J.); (J.S.B.)
| | - John S. Bomalaski
- Polaris Pharmaceuticals, Inc., San Diego, CA 92121, USA; (A.J.); (J.S.B.)
| | - Joseph P. Erinjeri
- Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA;
| | - Christopher A. Barker
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA;
| | - Jasmine H. Francis
- Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA;
| | - Jedd D. Wolchok
- Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (L.K.); (A.H.); (L.M.); (S.C.); (J.D.W.); (T.M.)
- Weill Cornell Medical College; New York, NY 10065, USA
| | - Taha Merghoub
- Ludwig Collaborative and Swim Across America Laboratory, Parker Institute for Cancer Immunotherapy, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (L.K.); (A.H.); (L.M.); (S.C.); (J.D.W.); (T.M.)
- Weill Cornell Medical College; New York, NY 10065, USA
| | - Alexander N. Shoushtari
- Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; (E.A.); (S.O.)
- Weill Cornell Medical College; New York, NY 10065, USA
- Correspondence: ; Tel.: +1-646-888-4161
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23
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Chung SF, Tam SY, Kim CF, Chong HC, Lee LMY, Leung YC. Mono-PEGylated thermostable Bacillus caldovelox arginase mutant (BCA-M-PEG20) induces apoptosis, autophagy, cell cycle arrest and growth inhibition in gastric cancer cells. Invest New Drugs 2022; 40:895-904. [PMID: 35857203 PMCID: PMC9395487 DOI: 10.1007/s10637-022-01265-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/31/2022] [Indexed: 12/15/2022]
Abstract
Gastric cancer is one of the most common malignant solid tumors in the world, especially in Asia with high mortality due to a lack of effective treatment. The potential usage of the newly constructed arginine-depleting enzyme-mono-PEGylated Bacillus caldovelox arginase mutant (BCA-M-PEG20), an effective drug against multiple cancer cell lines such as cervical and lung cancers, for the treatment of gastric cancer was demonstrated. Our results indicated that BCA-M-PEG20 significantly inhibited argininosuccinate synthetase (ASS)-positive gastric cancer cells, MKN-45 and BGC-823, while another arginine-depleting enzyme, arginine deiminase (ADI, currently under Phase III clinical trial), failed to suppress the growth of gastric cancer cells. In vitro studies demonstrated that BCA-M-PEG20 inhibited MKN-45 cells by inducing autophagy and cell cycle arrest at the S phase under 0.58 U/mL (IC<sub>50</sub> values). Significant caspase-dependent apoptosis was induced in MKN-45 after the treatment with 2.32 U/mL of BCA-M-PEG20. In vivo studies showed that administrations of BCA-M-PEG20 at 250 U/mouse twice per week significantly suppressed about 50% of tumor growth in the MKN-45 gastric cancer xenograft model. Taken together, BCA-M-PEG20 demonstrated a superior potential to be an anti-gastric cancer drug.
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Affiliation(s)
- Sai-Fung Chung
- grid.16890.360000 0004 1764 6123Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Suet-Ying Tam
- grid.16890.360000 0004 1764 6123Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Chi-Fai Kim
- grid.16890.360000 0004 1764 6123Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Hiu-Chi Chong
- grid.16890.360000 0004 1764 6123Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Leo Man-Yuen Lee
- grid.16890.360000 0004 1764 6123Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Yun-Chung Leung
- grid.16890.360000 0004 1764 6123Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Centre for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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24
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Johnson RL, Cummings M, Thangavelu A, Theophilou G, de Jong D, Orsi NM. Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment. Cancers (Basel) 2021; 13:6231. [PMID: 34944851 PMCID: PMC8699358 DOI: 10.3390/cancers13246231] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/03/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.
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Affiliation(s)
- Racheal Louise Johnson
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Michele Cummings
- Leeds Institute of Medical Research, St. James’s University Hospital, Leeds LS9 7TF, UK; (M.C.); (N.M.O.)
| | - Amudha Thangavelu
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Georgios Theophilou
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Diederick de Jong
- Department Gynaecological Oncology, St. James’s University Hospital, Leeds LS9 7TF, UK; (A.T.); (G.T.); (D.d.J.)
| | - Nicolas Michel Orsi
- Leeds Institute of Medical Research, St. James’s University Hospital, Leeds LS9 7TF, UK; (M.C.); (N.M.O.)
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25
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Yao S, Janku F, Koenig K, Tsimberidou AM, Piha-Paul SA, Shi N, Stewart J, Johnston A, Bomalaski J, Meric-Bernstam F, Fu S. Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors. Cancer Med 2021; 11:340-347. [PMID: 34841717 PMCID: PMC8729058 DOI: 10.1002/cam4.4446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 01/30/2023] Open
Abstract
Background Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI‐PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI‐PEG 20 and PLD in patients with metastatic solid tumors. Methods Patients with advanced ASS1‐deficient solid tumors were enrolled in this phase 1 trial of ADI‐PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI‐PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. Results Of 15 enrolled patients, 9 had metastatic HER2‐negative breast carcinoma. We observed no dose‐limiting toxicities or treatment‐related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression‐free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti‐ADI‐PEG 20 antibodies by week 8 in one third of patients. Conclusion Concurrent IM injection of ADI‐PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1‐deficient solid tumors. Further evaluation of this combination is under discussion.
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Affiliation(s)
- Shuyang Yao
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA.,Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA
| | | | | | | | - Nai Shi
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA
| | - John Stewart
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - John Bomalaski
- Polaris Pharmaceuticals, Inc., San Diego, California, USA
| | | | - Siqing Fu
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA
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26
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Toro MD, Gozzo L, Tracia L, Cicciù M, Drago F, Bucolo C, Avitabile T, Rejdak R, Nowomiejska K, Zweifel S, Yousef YA, Nazzal R, Romano GL. New Therapeutic Perspectives in the Treatment of Uveal Melanoma: A Systematic Review. Biomedicines 2021; 9:biomedicines9101311. [PMID: 34680428 PMCID: PMC8533164 DOI: 10.3390/biomedicines9101311] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/15/2021] [Accepted: 09/21/2021] [Indexed: 12/13/2022] Open
Abstract
Uveal melanoma (UM) is a rare disease, but the most common primary intraocular cancer, mostly localized in the choroid. Currently, the first-line treatment options for UM are radiation therapy, resection, and enucleation. However, although these treatments could potentially be curative, half of all patients will develop metastatic disease, whose prognosis is still poor. Indeed, effective therapeutic options for patients with advanced or metastatic disease are still lacking. Recently, the development of new treatment modalities with a lower incidence of adverse events, a better disease control rate, and new therapeutic approaches, have merged as new potential and promising therapeutic strategies. Additionally, several clinical trials are ongoing to find new therapeutic options, mainly for those with metastatic disease. Many interventions are still in the preliminary phases of clinical development, being investigated in phase I trial or phase I/II. The success of these trials could be crucial for changing the prognosis of patients with advanced/metastatic UM. In this systematic review, we analyzed all emerging and available literature on the new perspectives in the treatment of UM and patient outcomes; furthermore, their current limitations and more common adverse events are summarized.
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Affiliation(s)
- Mario Damiano Toro
- Department of Ophthalmology, University of Zurich, 8091 Zurich, Switzerland; (M.D.T.); (S.Z.)
- Department of General and Pediatric Ophthalmology, Medical University of Lublin, 20079 Lublin, Poland; (R.R.); (K.N.)
| | - Lucia Gozzo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Clinical Pharmacology Unit, Regional Pharmacovigilance Centre, University Hospital of Catania, 95123 Catania, Italy
- Correspondence: ; Tel.: +39-095-3781757
| | - Luciano Tracia
- Plastic and Reconstructive Surgery Department, American Hospital Dubai, Dubai, United Arab Emirates;
| | - Marco Cicciù
- Department of Biomedical and Dental Sciences, Morphological and Functional Images, University of Messina, AOU ‘G. Martino’, 98124 Messina, Italy;
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Clinical Pharmacology Unit, Regional Pharmacovigilance Centre, University Hospital of Catania, 95123 Catania, Italy
- Centre for Research and Consultancy in HTA and Drug Regulatory Affairs (CERD), University of Catania, 95123 Catania, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
| | - Teresio Avitabile
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy;
| | - Robert Rejdak
- Department of General and Pediatric Ophthalmology, Medical University of Lublin, 20079 Lublin, Poland; (R.R.); (K.N.)
| | - Katarzyna Nowomiejska
- Department of General and Pediatric Ophthalmology, Medical University of Lublin, 20079 Lublin, Poland; (R.R.); (K.N.)
| | - Sandrine Zweifel
- Department of Ophthalmology, University of Zurich, 8091 Zurich, Switzerland; (M.D.T.); (S.Z.)
| | - Yacoub A. Yousef
- Department of Surgery/Ophthalmology, King Hussein Cancer Center, Amman 11941, Jordan;
| | | | - Giovanni Luca Romano
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (F.D.); (C.B.); (G.L.R.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
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27
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Comito F, Marchese PV, Ricci AD, Tober N, Peterle C, Sperandi F, Melotti B. Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives. Future Oncol 2021; 17:4583-4606. [PMID: 34431316 DOI: 10.2217/fon-2021-0318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.
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Affiliation(s)
- Francesca Comito
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna.,Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Paola Valeria Marchese
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Angela Dalia Ricci
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Nastassja Tober
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Chiara Peterle
- Department of Experimental, Diagnostic & Specialty Medicine, S. Orsola-Malpighi University Hospital of Bologna 40138, Italy
| | - Francesca Sperandi
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
| | - Barbara Melotti
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna
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28
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Kumari N, Bansal S. Arginine depriving enzymes: applications as emerging therapeutics in cancer treatment. Cancer Chemother Pharmacol 2021; 88:565-594. [PMID: 34309734 DOI: 10.1007/s00280-021-04335-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022]
Abstract
Cancer is the second leading cause of death globally. Chemotherapy and radiation therapy and other medications are employed to treat various types of cancer. However, each treatment has its own set of side effects, owing to its low specificity. As a result, there is an urgent need for newer therapeutics that do not disrupt healthy cells' normal functioning. Depriving nutrient or non/semi-essential amino acids to which cancerous cells are auxotrophic remains one such promising anticancer strategy. L-Arginine (Arg) is a semi-essential vital amino acid involved in versatile metabolic processes, signaling pathways, and cancer cell proliferation. Hence, the administration of Arg depriving enzymes (ADE) such as arginase, arginine decarboxylase (ADC), and arginine deiminase (ADI) could be effective in cancer therapy. The Arg auxotrophic cancerous cells like hepatocellular carcinoma, human colon cancer, leukemia, and breast cancer cells are sensitive to ADE treatment due to low expression of crucial enzymes argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and ornithine transcarbamylase (OCT). These therapeutic enzyme treatments induce cell death through inducing autophagy, apoptosis, generation of oxidative species, i.e., oxidative stress, and arresting the progression and expansion of cancerous cells at certain cell cycle checkpoints. The enzymes are undergoing clinical trials and could be successfully exploited as potential anticancer agents in the future.
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Affiliation(s)
- Neha Kumari
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology Waknaghat, Solan, 173234, Himachal Pradesh, India
| | - Saurabh Bansal
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology Waknaghat, Solan, 173234, Himachal Pradesh, India.
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29
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Cheng PNM, Liu AM, Bessudo A, Mussai F. Safety, PK/PD and preliminary anti-tumor activities of pegylated recombinant human arginase 1 (BCT-100) in patients with advanced arginine auxotrophic tumors. Invest New Drugs 2021; 39:1633-1640. [PMID: 34287772 DOI: 10.1007/s10637-021-01149-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/01/2021] [Indexed: 10/20/2022]
Abstract
Background The study determined the safety, pharmacokinetics/pharmacodynamics (PK/PD), and recommended Phase II dose of BCT-100 for arginine auxotrophic tumours in a non-Chinese population. Methods This is a Phase I, 3 + 3 dose-escalation, open-label, multi-centre study in two arginine auxotrophic cancers-Malignant Melanoma (MM) and Castration Resistant Prostate Cancer (CRPC). Patients were enrolled to receive weekly intravenous BCT-100. The dose cohorts were respectively 0.5 mg/kg, 1.0 mg/kg, 1.7 mg/kg and 2.7 mg/kg. Results There were 14 MM and 9 CRPC patients, 16 males and 7 females with a median age of 71. No dose-limiting toxicities were reported. Among all the AEs, 18 were drug-related (mostly were Grade 1). Although there were individual variations in PKs amongst the patients in each cohort, the median arginine level was maintained at 2.5 µM (lower limit of quantification) in all 4 cohorts of patients after the second BCT-100 injection. Therapeutic Arginine Depletion was found in the 1.7 and 2.7 mg/kg/week cohorts when anti-tumor activities were observed. The two cohorts had a similar AUC (20,947 and 19,614 h*µg/ml respectively). Since the 2.7 mg/kg/week cohort had a more sustained arginine depletion for 2 weeks, the 2.7 mg/kg/week dose is chosen as the future phase II dose. There were two complete remissions (1 MM & 1 CRPC), 1PR (MM) and 2 stable diseases with a disease control rate (CR + PR + SD) of 5/23 (22%). Conclusions BCT-100 is safe in a non-Chinese population and has anti-tumor activities in both MM and CRPC. Weekly BCT-100 at 2.7 mg/kg is defined as the optimal biological dose for future clinical phase II studies.
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Affiliation(s)
- Paul N M Cheng
- Bio-Cancer Treatment International Ltd, Hong Kong, China.
| | - Angela M Liu
- Bio-Cancer Treatment International Ltd, Hong Kong, China
| | - Alberto Bessudo
- California Cancer Associates for Research and Excellence, Fresno, CA, US
| | - Francis Mussai
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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Chen CL, Hsu SC, Ann DK, Yen Y, Kung HJ. Arginine Signaling and Cancer Metabolism. Cancers (Basel) 2021; 13:3541. [PMID: 34298755 PMCID: PMC8306961 DOI: 10.3390/cancers13143541] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/01/2021] [Accepted: 07/12/2021] [Indexed: 12/19/2022] Open
Abstract
Arginine is an amino acid critically involved in multiple cellular processes including the syntheses of nitric oxide and polyamines, and is a direct activator of mTOR, a nutrient-sensing kinase strongly implicated in carcinogenesis. Yet, it is also considered as a non- or semi-essential amino acid, due to normal cells' intrinsic ability to synthesize arginine from citrulline and aspartate via ASS1 (argininosuccinate synthase 1) and ASL (argininosuccinate lyase). As such, arginine can be used as a dietary supplement and its depletion as a therapeutic strategy. Strikingly, in over 70% of tumors, ASS1 transcription is suppressed, rendering the cells addicted to external arginine, forming the basis of arginine-deprivation therapy. In this review, we will discuss arginine as a signaling metabolite, arginine's role in cancer metabolism, arginine as an epigenetic regulator, arginine as an immunomodulator, and arginine as a therapeutic target. We will also provide a comprehensive summary of ADI (arginine deiminase)-based arginine-deprivation preclinical studies and an update of clinical trials for ADI and arginase. The different cell killing mechanisms associated with various cancer types will also be described.
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Affiliation(s)
- Chia-Lin Chen
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 350, Miaoli County, Taiwan;
| | - Sheng-Chieh Hsu
- Institute of Biotechnology, National Tsing-Hua University, Hsinchu 30035, Taiwan;
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Miaoli County, Taiwan
| | - David K. Ann
- Department of Diabetes and Metabolic Diseases Research, Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;
| | - Yun Yen
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan;
| | - Hsing-Jien Kung
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 350, Miaoli County, Taiwan;
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan;
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
- Comprehensive Cancer Center, Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA 95817, USA
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Bhingarkar A, Vangapandu HV, Rathod S, Hoshitsuki K, Fernandez CA. Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias. Front Oncol 2021; 11:694526. [PMID: 34277440 PMCID: PMC8281237 DOI: 10.3389/fonc.2021.694526] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/15/2021] [Indexed: 12/24/2022] Open
Abstract
Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.
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Affiliation(s)
- Aboli Bhingarkar
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United States
| | - Hima V. Vangapandu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United States
| | - Sanjay Rathod
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United States
| | - Keito Hoshitsuki
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Christian A. Fernandez
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, United States
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32
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Tsai HJ, Hsiao HH, Hsu YT, Liu YC, Kao HW, Liu TC, Cho SF, Feng X, Johnston A, Bomalaski JS, Kuo MC, Chen TY. Phase I study of ADI-PEG20 plus low-dose cytarabine for the treatment of acute myeloid leukemia. Cancer Med 2021; 10:2946-2955. [PMID: 33787078 PMCID: PMC8085967 DOI: 10.1002/cam4.3871] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 03/05/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Most acute myeloid leukemia (AML) cells are argininosuccinate synthetase‐deficient. Pegylated arginine deiminase (ADI‐PEG20) monotherapy depletes circulating arginine, thereby selectively inducing tumor cell death. ADI‐PEG20 was shown to induce complete responses in ~10% of relapsed/refractory or poor‐risk AML patients. We conducted a phase I, dose‐escalation study combining ADI‐PEG20 and low‐dose cytarabine (LDC) in AML patients. Patients received 20 mg LDC subcutaneously twice daily for 10 days every 28 days and ADI‐PEG20 at 18 or 36 mg/m2 (dose levels 1 and 2) intramuscularly weekly. An expansion cohort for the maximal tolerated dose of ADI‐PEG20 was planned to further estimate the toxicity and preliminary response of this regimen. The primary endpoints were safety and tolerability. The secondary endpoints were time on treatment, overall survival (OS), overall response rate (ORR), and biomarkers (pharmacodynamics and immunogenicity detection). Twenty‐three patients were included in the study, and seventeen patients were in the expansion cohort (dose level 2). No patients developed dose‐limiting toxicities. The most common grade III/IV toxicities were thrombocytopenia (61%), anemia (52%), and neutropenia (30%). One had an allergic reaction to ADI‐PEG20. The ORR in 18 evaluable patients was 44.4%, with a median OS of 8.0 (4.5‐not reached) months. In seven treatment‐naïve patients, the ORR was 71.4% and the complete remission rate was 57.1%. The ADI‐PEG20 and LDC combination was well‐tolerated and resulted in an encouraging ORR. Further combination studies are warranted. (This trial was registered in ClinicalTrials.gov as a Ph1 Study of ADI‐PEG20 Plus Low‐Dose Cytarabine in Older Patients With AML, NCT02875093).
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Affiliation(s)
- Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hui-Hua Hsiao
- Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ya-Ting Hsu
- Division of Hematology, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Chang Liu
- Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiao-Wen Kao
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan
| | - Ta-Chih Liu
- Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Hematology-Oncology and Cancer Center, Chang Bing Show Chwan Hospital, Changhua, Taiwan
| | - Shih-Feng Cho
- Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Xiaoxing Feng
- Polaris Pharmaceuticals, Inc, Polaris Group, San Diego, CA, USA
| | - Amanda Johnston
- Polaris Pharmaceuticals, Inc, Polaris Group, San Diego, CA, USA
| | | | - Ming-Chung Kuo
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Linkou, Taiwan
| | - Tsai-Yun Chen
- Division of Hematology, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
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Zhao Z, Zhang P, Li W, Wang D, Ke C, Liu Y, Ho JCM, Cheng PNM, Xu S. Pegylated Recombinant Human Arginase 1 Induces Autophagy and Apoptosis via the ROS-Activated AKT/mTOR Pathway in Bladder Cancer Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5510663. [PMID: 33791071 PMCID: PMC7996046 DOI: 10.1155/2021/5510663] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/22/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023]
Abstract
Bladder cancer is one of the most commonly diagnosed cancers worldwide, especially in males. Current therapeutic interventions, including surgery, radiation therapy, chemotherapy, and immunotherapy, have not been able to improve the clinical outcome of bladder cancer patients with satisfaction. Recombinant human arginase (rhArg, BCT-100) is a novel agent with great anticancer effects on arginine-auxotrophic tumors. However, the effects of BCT-100 on bladder cancer remain unclear. In this study, the in vitro anticancer effects of BCT-100 were assessed using four bladder cancer cell lines (J82, SCaBER, T24, and 5637), while the in vivo effects were evaluated by establishing T24 nude mice xenograft models. Intracellular arginine level was observed to be sharply decreased followed by the onset of apoptotic events. Furthermore, BCT-100 was found to induce H2O2 production and mitochondrial membrane depolarization, leading to the release of mitochondrial cytochrome c and Smac to the cytosol. Treatment with BCT was observed to upregulate the expression of LC3B and Becllin-1, but downregulate the expression of p62 in a time-dependent manner. Autophagic flux was also observed upon BCT-100 treatment. Besides, the phosphorylation of the AKT/mTOR pathway was suppressed in a time-dependent fashion in BCT-100-treated T24 cells. While N-acetyl-L-cysteine was shown to alleviate BCT-100-induced apoptosis and autophagy, chloroquine, MK-2206, and rapamycin were found to potentiate BCT-100-triggered apoptosis. Finally, BCT-100 was demonstrated to induce autophagy and apoptosis via the ROS-mediated AKT/mTOR signaling pathway in bladder cancer cells.
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Affiliation(s)
- Zhuyun Zhao
- Department of Burn and Plastic Surgery, Shenzhen Longhua District Central Hospital, Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Peng Zhang
- Department of Pharmacy, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, China
| | - Wei Li
- Department of Urology, Shenzhen Longhua District Central Hospital, Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Dengchuan Wang
- Office of Medical Ethics, Shenzhen Longhua District Central Hospital, Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Changneng Ke
- Department of Burn and Plastic Surgery, Shenzhen Longhua District Central Hospital, Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Yueming Liu
- Department of Burn and Plastic Surgery, Shenzhen Longhua District Central Hospital, Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, Guangdong, China
| | - James Chung-Man Ho
- Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China
| | - Paul Ning-Man Cheng
- Bio-Cancer Treatment International, 511-513, Bioinformatics Building, Hong Kong Science Park, Tai Po, Hong Kong SAR, China
| | - Shi Xu
- Department of Burn and Plastic Surgery, Shenzhen Longhua District Central Hospital, Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, Guangdong, China
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Shreyash N, Sonker M, Bajpai S, Tiwary SK. Review of the Mechanism of Nanocarriers and Technological Developments in the Field of Nanoparticles for Applications in Cancer Theragnostics. ACS APPLIED BIO MATERIALS 2021; 4:2307-2334. [PMID: 35014353 DOI: 10.1021/acsabm.1c00020] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer cannot be controlled by the usage of drugs alone, and thus, nanotechnology is an important technique that can provide the drug with an impetus to act more effectively. There is adequate availability of anticancer drugs that are classified as alkylating agents, hormones, or antimetabolites. Nanoparticle (NP) carriers increase the residence time of the drug, thereby enhancing the survival rate of the drug, which otherwise gets washed off owing to the small size of the drug particles by the excretory system. For example, for enhancing the circulation, a coating of nonfouling polymers like PEG and dextran is done. Famous drugs such as doxorubicin (DOX) are commonly encapsulated inside the nanocomposite. The various classes of nanoparticles are used to enhance drug delivery by aiding it to fight against the tumor. Targeted therapy aims to attack the cells with features common to the cancer cells while minimizing damage to the normal cell, and these therapies work in one in four ways. Some block the cancer cells from reproducing newer cells, others release toxic substances to kill the cancer cells, some stimulate the immune system to destroy the cancer cells, and some block the growth of more blood vessels around cancer cells, which starve the cells of the nutrients, which is needed for their growth. This review aims to testify the advancements nanotechnology has brought in cancer therapy, and its statements are supported with recent research findings and clinical trial results.
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Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies. Br J Cancer 2021; 124:1533-1539. [PMID: 33674736 DOI: 10.1038/s41416-020-01230-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/02/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20. RESULTS We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively). CONCLUSION Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.
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Guo D, Ji X, Luo J. Rational nanocarrier design towards clinical translation of cancer nanotherapy. Biomed Mater 2021; 16. [DOI: 10.1088/1748-605x/abe35a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/04/2021] [Indexed: 02/06/2023]
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Mohammad MA, Didelija IC, Stoll B, Nguyen TC, Marini JC. Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs. Am J Physiol Endocrinol Metab 2021; 320:E641-E652. [PMID: 33427052 PMCID: PMC7988784 DOI: 10.1152/ajpendo.00472.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (n = 7) and ADI-PEG20 treated (n = 8) pigs during the postprandial period. In addition, blood pressure was monitored by telemetry, and multiple tissues were collected to determine arginine concentration. Plasma arginine was depleted immediately after ADI-PEG20 administration, with an increase in plasma citrulline concentration (P < 0.01). The depletion of arginine did not affect (P > 0.10) blood pressure, whole body protein synthesis, or urea production. Despite the lack of circulating arginine in ADI-PEG20-treated pigs, most tissues were able to maintain concentrations similar (P > 0.10) to those in Control animals. The kinetics of citrulline and arginine indicated the high citrulline turnover and regeneration of arginine through the citrulline recycling pathway. ADI-PEG20 administration resulted in an absolute and almost instantaneous depletion of circulating arginine, thus reducing global availability without affecting cardiovascular parameters and protein metabolism. The citrulline produced from the deimination of arginine was in turn utilized by the citrulline recycling pathway restoring local tissue arginine availability.NEW & NOTEWORTHY Pegylated arginine deiminase depletes circulating arginine, but the citrulline generated is utilized by multiple tissues to regenerate arginine and sustain local arginine availability. Preempting the arginine depletion that occurs as result of sepsis and trauma with arginine deiminase offers the possibility of maintaining tissue arginine availability despite negligible plasma arginine concentrations.
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Affiliation(s)
- Mahmoud A Mohammad
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
- Food Science and Nutrition Department, National Research Centre, Giza, Egypt
| | - Inka C Didelija
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Barbara Stoll
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Trung C Nguyen
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Juan C Marini
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
- Pediatric Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
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Choi JW, Hua TNM. Impact of Lifestyle Behaviors on Cancer Risk and Prevention. J Lifestyle Med 2021; 11:1-7. [PMID: 33763336 PMCID: PMC7957047 DOI: 10.15280/jlm.2021.11.1.1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 12/03/2020] [Indexed: 12/21/2022] Open
Abstract
Cancer incidences are rising globally. Therefore, in order to prevent and treat cancer, understanding cancer pathology is crucial. Tumors reprogram their metabolic phenotype to meet their needs for bioenergy, biosynthesis, and redox control. Alteration of the metabolic pathway has been proposed as the hallmark of cancer and explains the distinction between normal and cancer cells concerning nutrient utilization. Changes in the metabolism of nutrients such as glucose, amino acid, and fatty acid are associated with cancer risk. Luckily, this can be controlled with lifestyle modifications. Improvements in lifestyle behaviors to reduce cancer risks include a healthy diet, calorie restriction, and regular physical activity. This review begins with the understandings of metabolic reprogramming in cancer. Then, there will be evidence on the correlation between lifestyle factors and altered nutrient metabolism suggesting an application of lifestyle intervention for cancer risk reduction.
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Affiliation(s)
- Jong-Whan Choi
- Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Tuyen N M Hua
- Department of Biochemistry, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
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Zhang Y, Chung SF, Tam SY, Leung YC, Guan X. Arginine deprivation as a strategy for cancer therapy: An insight into drug design and drug combination. Cancer Lett 2021; 502:58-70. [PMID: 33429005 DOI: 10.1016/j.canlet.2020.12.041] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/07/2020] [Accepted: 12/27/2020] [Indexed: 12/18/2022]
Abstract
Extensive studies have shown that cancer cells have specific nutrient auxotrophy and thus have much a higher demand for certain nutrients than normal cells. Amino acid deprivation has attracted much attention in cancer therapy with positive outcomes from clinical trials. Arginine, as one of the conditionally essential amino acids, plays a pivotal role in cellular division and metabolism. Since many types of cancer cells exhibit decreased expression of argininosuccinate synthetase and/or ornithine transcarbamylase, they are auxotrophic for arginine, which makes arginine deprivation an accessible choice for cancer treatment. Arginine deiminase (ADI) and human arginase (hArg) are the two major protein drugs used for arginine deprivation and are undergoing many clinical trials. However, the clinical application of ADI and hArg is facing some common problems, including their short half-lives, immunogenicity and inconsistent production, which underlines the importance of improving these drugs using protein engineering techniques. Thus, we systematically review the latest studies of protein engineering and anti-cancer studies based on in vitro, in vivo and clinical models of ADI and hArg, and we include the latest studies on drug combinations consisting of ADI/hArg with chemotherapeutic drugs.
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Affiliation(s)
- Yu Zhang
- School of Medical Instruments and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China; Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Center for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China; Shanghai Engineering Research Center for Food Rapid Detection, Shanghai, China
| | - Sai-Fung Chung
- Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Center for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Suet-Ying Tam
- Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Center for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - Yun-Chung Leung
- Department of Applied Biology and Chemical Technology, Lo Ka Chung Research Center for Natural Anti-Cancer Drug Development and State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
| | - Xiao Guan
- School of Medical Instruments and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China.
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Qi H, Wang Y, Yuan X, Li P, Yang L. Selective extracellular arginine deprivation by a single injection of cellular non-uptake arginine deiminase nanocapsules for sustained tumor inhibition. NANOSCALE 2020; 12:24030-24043. [PMID: 33291128 DOI: 10.1039/d0nr06823c] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The metabolic enzyme-based arginine deprivation represents a tremendous opportunity to treat argininosuccinate synthetase (ASS1)-deficient tumors. Arginine deiminase (ADI), a typical representative, has aroused great interest. To date, the functional modification of ADI, such as PEGylation, has been applied to improve its weakness significantly, reducing its immunogenicity and extending its blood circulation time. However, the advantages of ADI, such as the cellular non-uptake property, are often deprived by current modification methods. The cellular non-uptake property of ADI only renders extracellular arginine degradation that negligibly influences normal cells. However, current-functionalized ADIs can be readily phagocytized by cells, causing the imbalance of intracellular amino acids and the consequent damage to normal cells. Therefore, it is necessary to exploit a new method that can simultaneously improve the weakness of ADI and maintain its advantage of cellular non-uptake. Here, we utilized a kind of phosphorylcholine (PC)-rich nanocapsule to load ADI. These nanocapsules possessed extremely weak cellular interaction and could avoid uptake by endothelial cells (HUVEC), immune cells (RAW 264.7), and tumor cells (H22), selectively depriving extracellular arginine. Besides, these nanocapsules increased the blood half-life time of ADI from the initial 2 h to 90 h and efficiently avoided its immune or inflammatory responses. After a single injection of ADI nanocapsules into H22 tumor-bearing mice, tumors were stably suppressed for 25 d without any detectable side effects. This new strategy first realizes the selective extracellular arginine deprivation for the treatment of ASS1-deficient tumors, potentially promoting the clinical translation of metabolic enzyme-based amino acid deprivation therapy. Furthermore, the research reminds us that the functionalization of drugs can not only improve its weakness but also maintain its advantages.
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Affiliation(s)
- Hongzhao Qi
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
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Tu MJ, Duan Z, Liu Z, Zhang C, Bold RJ, Gonzalez FJ, Kim EJ, Yu AM. MicroRNA-1291-5p Sensitizes Pancreatic Carcinoma Cells to Arginine Deprivation and Chemotherapy through the Regulation of Arginolysis and Glycolysis. Mol Pharmacol 2020; 98:686-694. [PMID: 33051382 PMCID: PMC7673485 DOI: 10.1124/molpharm.120.000130] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer cells are dysregulated and addicted to continuous supply and metabolism of nutritional glucose and amino acids (e.g., arginine) to drive the synthesis of critical macromolecules for uncontrolled growth. Recent studies have revealed that genome-derived microRNA (miRNA or miR)-1291-5p (miR-1291-5p or miR-1291) may modulate the expression of argininosuccinate synthase (ASS1) and glucose transporter protein type 1 (GLUT1). We also developed a novel approach to produce recombinant miR-1291 agents for research, which are distinguished from conventional chemo-engineered miRNA mimics. Herein, we firstly demonstrated that bioengineered miR-1291 agent was selectively processed to high levels of target miR-1291-5p in human pancreatic cancer (PC) cells. After the suppression of ASS1 protein levels, miR-1291 perturbed arginine homeostasis and preferably sensitized ASS1-abundant L3.3 cells to arginine deprivation therapy. In addition, miR-1291 treatment reduced the protein levels of GLUT1 in both AsPC-1 and PANC-1 cells, leading to a lower glucose uptake (deceased > 40%) and glycolysis capacity (reduced approximately 50%). As a result, miR-1291 largely improved cisplatin efficacy in the inhibition of PC cell viability. Our results demonstrated that miR-1291 was effective to sensitize PC cells to arginine deprivation treatment and chemotherapy through targeting ASS1- and GLUT1-mediated arginolysis and glycolysis, respectively, which may provide insights into understanding miRNA signaling underlying cancer cell metabolism and development of new strategies for the treatment of lethal PC. SIGNIFICANCE STATEMENT: Many anticancer drugs in clinical use and under investigation exert pharmacological effects or improve efficacy of coadministered medications by targeting cancer cell metabolism. Using new recombinant miR-1291 agent, we revealed that miR-1291 acts as a metabolism modulator in pancreatic carcinoma cells through the regulation of argininosuccinate synthase- and glucose transporter protein type 1-mediated arginolysis and glycolysis. Consequently, miR-1291 effectively enhanced the efficacy of arginine deprivation (pegylated arginine deiminase) and chemotherapy (cisplatin), offering new insights into development of rational combination therapies.
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Affiliation(s)
- Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Zhijian Duan
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Zhenzhen Liu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Chao Zhang
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Richard J Bold
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Frank J Gonzalez
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Edward J Kim
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine (M.-J.T., Z.D., Z.L., C.Z., A.-M.Y.), Division of Surgical Oncology (R.J.B.), Division of Hematology and Oncology, Department of Internal Medicine (E.J.K.), University of California (UC) Davis School of Medicine, Sacramento, California; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.)
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Wahwah N, Dhar D, Chen H, Zhuang S, Chan A, Casteel DE, Kalyanaraman H, Pilz RB, Boss GR. Metabolic interaction between amino acid deprivation and cisplatin synergistically reduces phosphoribosyl-pyrophosphate and augments cisplatin cytotoxicity. Sci Rep 2020; 10:19907. [PMID: 33199755 PMCID: PMC7670436 DOI: 10.1038/s41598-020-76958-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 11/04/2020] [Indexed: 11/09/2022] Open
Abstract
Cisplatin is a mainstay of cancer chemotherapy. It forms DNA adducts, thereby activating poly(ADP-ribose) polymerases (PARPs) to initiate DNA repair. The PARP substrate NAD+ is synthesized from 5-phosphoribose-1-pyrophosphate (PRPP), and we found that treating cells for 6 h with cisplatin reduced intracellular PRPP availability. The decrease in PRPP was likely from (1) increased PRPP consumption, because cisplatin increased protein PARylation and PARP1 shRNA knock-down returned PRPP towards normal, and (2) decreased intracellular phosphate, which down-regulated PRPP synthetase activity. Depriving cells of a single essential amino acid decreased PRPP synthetase activity with a half-life of ~ 8 h, and combining cisplatin and amino acid deprivation synergistically reduced intracellular PRPP. PRPP is a rate-limiting substrate for purine nucleotide synthesis, and cisplatin inhibited de novo purine synthesis and DNA synthesis, with amino acid deprivation augmenting cisplatin’s effects. Amino acid deprivation enhanced cisplatin’s cytotoxicity, increasing cellular apoptosis and DNA strand breaks in vitro, and intermittent deprivation of lysine combined with a sub-therapeutic dose of cisplatin inhibited growth of ectopic hepatomas in mice. Augmentation of cisplatin’s biochemical and cytotoxic effects by amino acid deprivation suggest that intermittent deprivation of an essential amino acid could allow dose reduction of cisplatin; this could reduce the drug’s side effects, and allow its use in cisplatin-resistant tumors.
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Affiliation(s)
- Nisreen Wahwah
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Debanjan Dhar
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Hui Chen
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Shunhui Zhuang
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Adriano Chan
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Darren E Casteel
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Hema Kalyanaraman
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Renate B Pilz
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA
| | - Gerry R Boss
- Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA.
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Combinatory Treatment of Canavanine and Arginine Deprivation Efficiently Targets Human Glioblastoma Cells via Pleiotropic Mechanisms. Cells 2020; 9:cells9102217. [PMID: 33008000 PMCID: PMC7600648 DOI: 10.3390/cells9102217] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 12/20/2022] Open
Abstract
Glioblastomas are the most frequent and aggressive form of primary brain tumors with no efficient cure. However, they often exhibit specific metabolic shifts that include deficiency in the biosynthesis of and dependence on certain exogenous amino acids. Here, we evaluated, in vitro, a novel combinatory antiglioblastoma approach based on arginine deprivation and canavanine, an arginine analogue of plant origin, using two human glioblastoma cell models, U251MG and U87MG. The combinatory treatment profoundly affected cell viability, morphology, motility and adhesion, destabilizing the cytoskeleton and mitochondrial network, and induced apoptotic cell death. Importantly, the effects were selective toward glioblastoma cells, as they were not pronounced for primary rat glial cells. At the molecular level, canavanine inhibited prosurvival kinases such as FAK, Akt and AMPK. Its effects on protein synthesis and stress response pathways were more complex and dependent on exposure time. We directly observed canavanine incorporation into nascent proteins by using quantitative proteomics. Although canavanine in the absence of arginine readily incorporated into polypeptides, no motif preference for such incorporation was observed. Our findings provide a strong rationale for further developing the proposed modality based on canavanine and arginine deprivation as a potential antiglioblastoma metabolic therapy independent of the blood-brain barrier.
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Chow AKM, Yau SWL, Ng L. Novel molecular targets in hepatocellular carcinoma. World J Clin Oncol 2020; 11:589-605. [PMID: 32879846 PMCID: PMC7443834 DOI: 10.5306/wjco.v11.i8.589] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/04/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.
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Affiliation(s)
- Ariel Ka-Man Chow
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Simon Wing-Lung Yau
- School of Nursing and Health Studies, The Open University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Phase II Study of Arginine Deprivation Therapy With Pegargiminase in Patients With Relapsed Sensitive or Refractory Small-cell Lung Cancer. Clin Lung Cancer 2020; 21:527-533. [PMID: 32859536 DOI: 10.1016/j.cllc.2020.07.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 07/02/2020] [Accepted: 07/25/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC). PATIENTS AND METHODS Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or < 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/m2 (36.8 mg/m2), until unacceptable toxicity or disease progression. The primary endpoint was tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with secondary endpoints including tolerability, pharmacodynamics, and immunogenicity. RESULTS Between January 2011 and January 2014, 22 patients were enrolled: 9 in the sensitive disease cohort and 13 in the refractory disease cohort. At a pre-planned interim analysis, the best overall response observed was stable disease in 2 patients in each cohort (18.2%). Owing to the lack of response and slow accrual in the sensitive disease cohort, the study was terminated early. Pegargiminase treatment was well-tolerated with no unexpected adverse events or discontinuations. CONCLUSION Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward.
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Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res 2020; 30:507-519. [PMID: 32467593 PMCID: PMC7264181 DOI: 10.1038/s41422-020-0337-2] [Citation(s) in RCA: 486] [Impact Index Per Article: 97.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/29/2020] [Indexed: 02/08/2023] Open
Abstract
Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies of primary and secondary resistance to immunotherapy are multifaceted, deriving not only from tumor intrinsic factors, but also from the complex interplay between cancer and its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories of approaches to the design of novel drugs and combination therapies: the first involves direct modification of the tumor, while the second indirectly enhances immunogenicity through alteration of the microenvironment. By systematically addressing the factors that mediate resistance, we are able to identify mechanistically-driven novel approaches to improve immunotherapy outcomes.
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Affiliation(s)
| | - Allison Betof Warner
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- Weill Cornell Medicine, New York, NY, 10065, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
| | - Jedd D Wolchok
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
- Weill Cornell Medicine, New York, NY, 10065, USA.
- Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
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Garcia-Bermudez J, Williams RT, Guarecuco R, Birsoy K. Targeting extracellular nutrient dependencies of cancer cells. Mol Metab 2020; 33:67-82. [PMID: 31926876 PMCID: PMC7056928 DOI: 10.1016/j.molmet.2019.11.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 11/11/2019] [Accepted: 11/13/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Cancer cells rewire their metabolism to meet the energetic and biosynthetic demands of their high proliferation rates and environment. Metabolic reprogramming of cancer cells may result in strong dependencies on nutrients that could be exploited for therapy. While these dependencies may be in part due to the nutrient environment of tumors, mutations or expression changes in metabolic genes also reprogram metabolic pathways and create addictions to extracellular nutrients. SCOPE OF REVIEW This review summarizes the major nutrient dependencies of cancer cells focusing on their discovery and potential mechanisms by which metabolites become limiting for tumor growth. We further detail available therapeutic interventions based on these metabolic features and highlight opportunities for restricting nutrient availability as an anti-cancer strategy. MAJOR CONCLUSIONS Strategies to limit nutrients required for tumor growth using dietary interventions or nutrient degrading enzymes have previously been suggested for cancer therapy. The best clinical example of exploiting cancer nutrient dependencies is the treatment of leukemia with l-asparaginase, a first-line chemotherapeutic that depletes serum asparagine. Despite the success of nutrient starvation in blood cancers, it remains unclear whether this approach could be extended to other solid tumors. Systematic studies to identify nutrient dependencies unique to individual tumor types have the potential to discover targets for therapy.
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Affiliation(s)
- Javier Garcia-Bermudez
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
| | - Robert T Williams
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Rohiverth Guarecuco
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
| | - Kıvanç Birsoy
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
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Agnello G, Alters SE, Rowlinson SW. Preclinical safety and antitumor activity of the arginine-degrading therapeutic enzyme pegzilarginase, a PEGylated, cobalt-substituted recombinant human arginase 1. Transl Res 2020; 217:11-22. [PMID: 31954097 DOI: 10.1016/j.trsl.2019.12.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 12/19/2019] [Accepted: 12/23/2019] [Indexed: 11/24/2022]
Abstract
Metabolic remodeling contributes to the development and progression of some cancers and exposes them to vulnerabilities, including specific nutrient dependencies that can be targeted therapeutically. Arginine is a semiessential amino acid, and several cancers are unable to endogenously synthesize sufficient levels of arginine for survival and proliferation, most commonly due to reduced expression of argininosuccinate synthase (ASS1). Such cancers are dependent on arginine and they can be targeted via enzyme-mediated depletion of systemic arginine. We report the preclinical safety, antitumor efficacy, and immune-potentiating effects of pegzilarginase, a highly potent human arginine-degrading enzyme. Toxicology studies showed that pegzilarginase-mediated arginine depletion is well tolerated at therapeutic levels that elicit an antitumor growth effect. To determine which tumor types are best suited for clinical development, we profiled clinical tumor samples for ASS1 expression, which correlated with pegzilarginase sensitivity in vivo in patient-derived xenograft (PDx) models. Among the histologies tested, malignant melanoma, small cell lung cancer and Merkel cell carcinoma had the highest prevalence of low ASS1 expression, the highest proportion of PDx models responding to pegzilarginase, and the strongest correlation between low or no ASS1 expression and sensitivity to pegzilarginase. In an immune-competent syngeneic mouse model, pegzilarginase slowed tumor growth and promoted the recruitment of CD8+ tumor infiltrating lymphocytes. This is consistent with the known autophagy-inducing effects of arginine depletion, and the link between autophagy and major histocompatibility complex antigen presentation to T cells. Our work supports the ongoing clinical investigations of pegzilarginase in solid tumors and clinical combination of pegzilarginase with immune checkpoint inhibitors.
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Jariyal H, Weinberg F, Achreja A, Nagarath D, Srivastava A. Synthetic lethality: a step forward for personalized medicine in cancer. Drug Discov Today 2020; 25:305-320. [DOI: 10.1016/j.drudis.2019.11.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 11/06/2019] [Accepted: 11/27/2019] [Indexed: 12/15/2022]
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Zarei M, Rahbar MR, Negahdaripour M, Morowvat MH, Nezafat N, Ghasemi Y. Cell Penetrating Peptide: Sequence-Based Computational Prediction for Intercellular Delivery of Arginine Deiminase. CURR PROTEOMICS 2020. [DOI: 10.2174/1570164616666190701120351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:Cell-Penetrating Peptides (CPPs), a family of short peptides, are broadly used as the carrier in the delivery of drugs and different therapeutic agents. Thanks to the existence of valuable databases, computational screening of the experimentally validated CPPs can help the researchers to select more effective CPPs for the intercellular delivery of therapeutic proteins. Arginine deiminase of Mycoplasma hominis, an arginine-degrading enzyme, is currently in the clinical trial for treating several arginine auxotrophic cancers. However, some tumor cells have developed resistance to ADI treatment. The ADI resistance arises from the over-expression of argininosuccinate synthetase 1 enzyme, which is involved in arginine synthesis. Intracellular delivery of ADI into tumor cells is suggested as an efficient approach to overcome the aforesaid drawback.Objective:In this study, in-silico tools were used for evaluating the experimentally validated CPPs to select the best CPP candidates for the intracellular delivery of ADI.Results:In this regard, 150 CPPs of protein cargo available at CPPsite were retrieved and evaluated by the CellPPD server. The best CPP candidates for the intracellular delivery of ADI were selected based on stability and antigenicity of the ADI-CPP fusion form. The conjugated forms of ADI with each of the three CPPs including EGFP-hcT (9-32), EGFP-ppTG20, and F(SG)4TP10 were stable and nonantigenic; thus, these sequences were introduced as the best CPP candidates for the intracellular delivery of ADI. In addition, the proposed CPPs had appropriate positive charge and lengths for an efficient cellular uptake.Conclusion:These three introduced CPPs not only are appropriate for the intracellular delivery of ADI, but also can overcome the limitation of its therapeutic application, including short half-life and antigenicity.
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Affiliation(s)
- Mahboubeh Zarei
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Reza Rahbar
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Manica Negahdaripour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Navid Nezafat
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Younes Ghasemi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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