Boronic acid-based arginase inhibitors in cancer immunotherapy (original) (raw)
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Evaluation of the Anti-cancer and Biological Effects of Boric Acid on Colon Cancer Cell Line
Meandros Medical and Dental Journal, 2020
Öz Amaç: Borun biyolojideki rolü, gen ekspresyonunun koordineli düzenlenmesini ve tüm canlı organizmaların büyümesini ve çoğalmasını içerir. Borik asidin kanser hücrelerinin çoğalmasını düzenlediği bilinmektedir. Kolon kanseri, erkeklerde ve kadınlarda yüksek mortaliteye sahip kanser türleri arasındadır. Bu çalışmanın amacı, borik asidin plazmada formu olan borik asidin Caco-2 kolorektal kanser hücreleri üzerindeki etkilerini değerlendirmektir. Gereç ve Yöntemler: İlk olarak, Caco-2 insan kolon kanseri hücrelerinde borik asidin (0 ila 1 mM) hücre proliferasyonuna aktivitesini belirlenmiş daha sonra ve Western Blot ve SDS PAGE analizi kullanılarak Caspase-3 ve BCL-2 protein düzeyleri değerlendirilmiştir. Bulgular: Sonuçlarımız, borik asidin Caco-2 kanser hücrelerinin çoğalmasını doza bağımlı bir şekilde inhibe ettiğini göstermiştir. Ayrıca, borik asit konsantrasyonu arttıkça BCL-2 protein ekspresyonunun azalttığı saptanmıştır. Sonuç: Bu araştırma borik asidin Caco-2 kanser hücrelerine karşı anti-kanser etkilerini gösteren ilk çalışmadır. Borik asidin anti-kanser mekanizmasını açıklamak için ileri moleküler teknikleri kullanan çalışmalara ihtiyaç vardır. Objective: The role of boron in biology includes the coordinated regulation of gene expression as well as the growth and proliferation of all living organisms. Boric acid is known to regulate the proliferation of cancer cells. Colon cancer is among the types of cancer with a high rate of mortality in both men and women. The aim of this study is to evaluate the effects of boric acid (the dominant of boron in plasma) on Caco-2 colorectal cancer cell line. Materials and Methods: Firstly, the cytotoxic effect of boric acid (0 to 1 mM) on Caco-2 human colon cancer cells was determined and the expressions of Caspase-3 and BCL-2 were evaluated using Western Blot and sodium dodecyl sulphatepolyacrylamide gel electrophoresis analysis. Results: Our results showed that boric acid inhibits the proliferation Caco-2 cancer cells in a dose dependent manner. We also demonstrated that BCL-2 protein expression decreased with increasing concentrations of boric acid. Conclusion: This is the first study that demonstrates the anti-cancer effects of boric acid against Caco-2 cancer cell line. Further studies using advanced molecular techniques are needed to precisely explain the anti-cancer mechanisms of boric acid.
An in Vitro Study in Which New Boron Derivatives Maybe an Option for Breast Cancer Treatment
Eurasian Journal of Medicine and Oncology, 2019
B reast cancer is the most common cancer among women and is the second leading cause of cancer deaths in women. [1] The agents against breast cancer, the effects of the molecular mechanisms related to the cell proliferation, and survival are tried for the treatment. [2] Boron compounds are now subject to study due to their possible beneficial effects on human health. [3] There is increasing evidence that leads to the hypothesis that boron has anticarcinogenic properties. In recent studies, it has also been reported that the use of boron-based compounds as anticancer agents has increased, especially in inoperable cancers, and those with high malignancy. [4] However, the mechanisms that underlie the observed antitumorigenic effects of boron are not clearly known. There are previous studies that promote boron as a chemopreventative agent for prostate cancer, [5] but its effect on MDA-MB-231 human breast cancer cells remains obscure. The boron-soluble forms include boric acid (BA-H 3 BO 3), borax pentahydrate or boron penta (BP-Na 2 B 4 O 7 .5H 2 O), and disodium pentaborate decahydrate or T-Boron (DPD-Na 2 O.5B 2 O 3 .10H 2 O, BOREN; National Boron Research Institute, Ankara, Turkey). On the other hand, the effect of BA, BP, and T-Boron on angiogenesis and oxidative stress is not known. Angiogenesis, one of the major hallmarks of cancer, is in-Objectives: We aimed to investigate the distribution of immunoreactivities of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and inducible NOS (iNOS) on breast cancer cells in response to treatment with boron derivatives. Methods: We initially analyzed the cytotoxic effect and IC50 value of boron by MTT assay. For the evaluation of the angiogenesis, expression level of antibodies was detected to following boron derivatives such as boric acid, boron penta (BP), and T-Boron (DPD) in the absence of boron treatment using the indirect immunohistochemical method. The evaluation of these staining was done using the H-scoring system. Results: It was found that immunoreactivities of VEGF, eNOS, and iNOS increased on control compared to those of the cells of MDA-MB231 human breast cancer cell line. Following boron derivatives treatment, it was observed that they were inhibited the VEGF/NOS labeling in MDA-MB-231 breast cancer cells. Conclusion: The present data suggest that BP, especially DPD, inhibits the angiogenesis of breast cancer cells through VEGF pathway. From this point, these boron derivatives may provide a novel therapeutic approach for breast cancer treatment.
Small-molecule arginase inhibitors
Pharmaceutical patent analyst, 2014
Arginase is an enzyme that metabolizes L-arginine to L-ornithine and urea. In addition to its fundamental role in the hepatic ornithine cycle, it also influences the immune systems in humans and mice. Arginase participates in many inflammatory disorders by decreasing the synthesis of nitric oxide and inducing fibrosis and tissue regeneration. L-arginine deficiency, which is modulated by myeloid cell arginase, suppresses T-cell immune response. This mechanism plays a fundamental role in inflammation-associated immunosuppression. Pathogens can synthesize their own arginase to elude immune reaction. Small-molecule arginase inhibitors are currently described as promising therapeutics for the treatment of several diseases, including allergic asthma, inflammatory bowel disease, ulcerative colitis, cardiovascular diseases (atherosclerosis and hypertension), diseases associated with pathogens (e.g., Helicobacter pylori, Trypanosoma cruzi, Leishmania, Mycobacterium tuberculosis and Salmonell...
Inhibition of human arginase I by substrate and product analogues
Archives of Biochemistry and Biophysics, 2010
Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to generate L-ornithine and urea. We demonstrate that N-hydroxy-L-arginine (NOHA) binds to this enzyme with K d = 3.6 μM, and nor-N-hydroxy-L-arginine (nor-NOHA) binds with K d = 517 nM (surface plasmon resonance) or K d ≈ 50 nM (isothermal titration calorimetry). Crystals of human arginase I complexed with NOHA and nor-NOHA afford 2.04 Å and 1.55 Å resolution structures, respectively, which are significantly improved in comparison with previously determined structures of the corresponding complexes with rat arginase I. Higher resolution structures clarify the binding interactions of the inhibitors. Finally, the crystal structure of the complex with L-lysine (K d = 13 μM) is reported at 1.90 Å resolution. This structure confirms the importance of hydrogen bond interactions with inhibitor α-carboxylate and α-amino groups as key specificity determinants of amino acid recognition in the arginase active site. Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of Larginine to generate L-ornithine and urea. This reaction is the key step of the urea cycle in the liver that allows for the excretion of nitrogenous waste resulting from protein catabolism; healthy adults excrete approximately 10 kg urea per year [1-4]. In extrahepatic tissues arginase serves to regulate L-arginine concentrations for other metabolic pathways. For example, arginase activity can decrease L-arginine concentrations utilized by nitric oxide synthase to generate NO; arginase inhibitors can increase L-arginine concentrations and thereby enhance NO biosynthesis and NO-dependent physiological processes such as smooth muscle relaxation [5]. Accordingly, arginase is a pharmaceutical target for the treatment of diseases associated with aberrant smooth muscle physiology such as erectile dysfunction [6,7] and asthma [8,9]. Among substrate analogue inhibitors of arginase, boronic acid and N-hydroxyguanidinium derivatives exhibit the highest affinity (selected inhibitors are shown in Table 1) [7,10-19]. The crystal structures of rat arginase I complexed with 2(S)-amino-6-boronohexanoic acid (ABH) [6], dehydro-ABH [17], and S-(2-boronoethyl)-L-cysteine (BEC) [7], human arginase I complexed with ABH and BEC [18], and human arginase II complexed with BEC [20] reveal that the planar boronic acid moiety of the inhibitor undergoes nucleophilic attack by the metalbridging hydroxide ion to yield a tetrahedral boronate anion that mimics the tetrahedral
International Journal of Molecular Sciences, 2018
Human arginase I (hARGI) is an important enzyme involved in the urea cycle; its overexpression has been associated to cardiovascular and cerebrovascular diseases. In the last years, several congeneric sets of hARGI inhibitors have been reported with possible beneficial roles for the cardiovascular system. At the same time, crystallographic data have been reported including hARGI–inhibitor complexes, which can be considered for the design of novel inhibitors. In this work, the structure–activity relationship (SAR) of Cα substituted 2(S)-amino-6-boronohexanoic acid (ABH) derivatives as hARGI inhibitors was studied by using a three-dimensional quantitative structure–activity relationships (3D-QSAR) method. The predictivity of the obtained 3D-QSAR model was demonstrated by using internal and external validation experiments. The best model revealed that the differential hARGI inhibitory activities of the ABH derivatives can be described by using steric and electrostatic fields; the local...
Journal for immunotherapy of cancer, 2017
Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small-molecule inhibitor of arginase, to investigate the role of Arg1 in regulating anti-tumor immunity. CB-1158 was tested for the ability to block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for tumor growth inhibition in syngeneic mouse models of cancer as a single agent and in combination with other therapies. Tumors from animals treated with CB-1158 were profiled for changes in immune cell subsets, expression of immune-related genes, and cytokines. Human tumor tissue microarrays were probed for Arg1 expression by immunohistochemistry and immunofluorescence. Cancer patient plasma samples were a...
Arginase, a Possible Therapeutic Target in Prostate Cancer
Journal of Pharmaceutical Research International
With increasing populations, the prevalence of prostate cancer increases. In the future, a significant public health crisis can be recognized in the present incidence of prostate cancer. In order to counter this, markers should be established for the advanced diagnosis and treatment of the illness prognosis. The cells dominate our immune system and grow into a detectable tumour, causing cancer. At this stage in the body, several processes are dominated, governed and deregulated by the tumour. In most cases, immune response undertakes measures by limiting the availability of Arginine. In this context it is fascinating to examine how the levels of Arginine fluctuate with the severity of the disease and the levels of Arginase and NO. Substances and methods: In 25 beginning phases and 25 advanced stage of the prostate cancer patients and compared to 25 healthy controls, 5 ml of the blood were taken and tested for serum levels of Arginina, and nitric oxide. A substantial reduction in arg...
Boronic acid compounds as potential pharmaceutical agents
Medicinal Research Reviews, 2003
Boronic acid compounds have been used, because of their unique structural features, for the development of potent enzyme inhibitors, boron neutron capture agents for cancer therapy, and as antibody mimics that recognize biologically important saccharides. Consequently, there has been a surge of interests in boronic acid compounds. This study reviews the recent development in this area during the last six years. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 3, 346–368, 2003
BNCT induced immunomodulatory effects contribute to mammary tumor inhibition
PLOS ONE, 2019
In the United States, breast cancer is one of the most common and the second leading cause of cancer-related death in women. Treatment modalities for mammary tumor are surgical removal of the tumor tissue followed by either chemotherapy or radiotherapy or both. Radiation therapy is a whole body irradiation regimen that suppresses the immune system leaving hosts susceptible to infection or secondary tumors. Boron neutron capture therapy (BNCT) in that regard is more selective, the cells that are mostly affected are those that are loaded with 109 or more 10B atoms. Previously, we have described that liposomal encapsulation of boron-rich compounds such as TAC and MAC deliver a high payload to the tumor tissue when injected intravenously. Here we report that liposome-mediated boron delivery to the tumor is inversely proportional to the size of the murine mammary (EMT-6) tumors. The plausible reason for the inverse ratio of boron and EMT-6 tumor size is the necrosis in these tumors, which is more prominent in the large tumors. The large tumors also have receding blood vessels contributing further to poor boron delivery to these tumors. We next report that the presence of boron in blood is essential for the effects of BNCT on EMT-6 tumor inhibition as direct injection of boron-rich liposomes did not provide any added advantage in inhibition of EMT-6 tumor in BALB/c mice following irradiation despite having a significantly higher amount of boron in the tumor tissue. BNCT reaction in PBMCs resulted in the modification of these cells to anti-tumor phenotype. In this study, we report the immunomodulatory effects of BNCT when boron-rich compounds are delivered systemically.