Interaction of Purine and its Derivatives with A₁, A₂-Adenosine Receptors and Vascular Endothelial Growth Factor Receptor-1 (Vegf-R1) as a Therapeutic Alternative to Treat Cancer

Abstract

Background There are several studies that indicate that cancer development may be conditioned by the activation of some biological systems that involve the interaction of different biomolecules, such as adenosine and vascular endothelial growth factor. These biomolecules have been targeted of some drugs for treat of cancer; however, there is little information on the interaction of purine derivatives with adenosine and vascular endothelial growth factor receptor (VEGF-R1).

Objective The aim of this research was to determine the possible interaction of purine (1) and their derivatives (2–31) with A₁, A₂-adenosine receptors, and VEGF-R1.

Methods Theoretical interaction of purine and their derivatives with A₁, A₂-adenosine receptors and VEGF-R1 was carried out using the 5uen, 5mzj and 3hng proteins as theoretical tools. Besides, adenosine, cgs-15943, rolofylline, cvt-124, wrc-0571, luf-5834, cvt-6883, AZD-4635, cabozantinib, pazopanib, regorafenib, and sorafenib drugs were used as controls.

Results The results showed differences in the number of aminoacid residues involved in the interaction of purine and their derivatives with 5uen, 5mzj and 3hng proteins compared with the controls. Besides, the inhibition constants (Ki) values for purine and their derivatives 5, 9, 10, 14, 15, 16, and 20 were lower compared with the controls

Conclusions Theoretical data suggest that purine and their derivatives 5, 9, 10, 14, 15, 16, and 20 could produce changes in cancer cell growth through inhibition of A₁, A₂-adenosine receptors and VEGFR-1 inhibition. These data indicate that these purine derivatives could be a therapeutic alternative to treat some types of cancer.

Keywords

cancer - angiogenesis - purine - adenosine - receptors

Publikationsverlauf

Eingereicht: 10. Juli 2024

Angenommen: 29. Juli 2024

Artikel online veröffentlicht:
22. August 2024

• References

• 1 Leclerc B, Charlebois R, Chouinard G. et al. CD73 expression is an independent prognostic factor in prostate cancer. Clin Cancer Res 2016; 22: 158-166
• 2 Supernat A, Markiewicz A, Welnicka-Jaskiewicz M. et al. CD73 expression as a potential marker of good prognosis in breast carcinoma. Appl Immunohistochem Mol Morphol 2012; 20: 103-107
• 3 Jiang T, Xu X, Qiao M. et al. Comprehensive evaluation of NT5E/CD73 expression and its prognostic significance in distinct types of cancers. BMC cancer 2018; 18: 1-10
• 4 Mostafa G, Matthews B, Norton H. et al. Influence of demographics on colorectal cancer. Am Surg 2004; 70: 259-264
• 5 Thomas D, Jimenez L, McTieman A. et al. Breast cancer in men: risk factors with hormonal implications. Am J Epidemiol 1992; 135: 734-748
• 6 O’Keeffe L, Taylor G, Huxley R. et al. Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open 2018; 8: e021611
• 7 Benusiglio P, Fallet V, Sanchis-Borja M. et al. Lung cancer is also a hereditary disease. Eur Respir Rev. 2021 30. 210045
• 8 Katzke V, Kaaks R, Kühn T. Lifestyle and cancer risk. Cancer J 2015; 21: 104-110
• 9 King R, Shukla S, He C. et al. CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis. Oncogene 2022; 41: 971-982
• 10 García-Rocha R, Monroy-García A, Carrera-Martínez M. et al. Evidence that cervical cancer cells cultured as tumorspheres maintain high CD73 expression and increase their protumor characteristics through TGF-β production. Cell Biochem Funct 2022; 40: 760-772
• 11 Gao Z, Dong K, Zhang H. The roles of CD73 in cancer. BioMed Res Int 2014; 2014: 460654
• 12 Regateiro F, Cobbold S, Waldmann H. CD73 and adenosine generation in the creation of regulatory microenvironments. Clin Exp Immunol 2013; 171: 1-7
• 13 Flores-Santibáñez F, Fernández D, Meza D. et al. 73-mediated adenosine production promotes stem cell-like properties in mouse Tc17 cells. Immunology 2015; 146: 582-594
• 14 Gessi S, Merighi S, Sacchetto V. et al. Adenosine receptors and cancer. Biochim Biophys Acta (BBA)-Biomembr 2011; 1808: 1400-1412
• 15 Kazemi M, Raoofi-Mohseni S, Hojjat-Farsangi M. et al. Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer. J Cell Physiol 2018; 233: 2032-2057
• 16 Hajizadeh F, Masjedi A, Asl S. et al. Adenosine and adenosine receptors in colorectal cancer. Int Immunopharmacol 2020; 87: 106853
• 17 Khoo H, Ho C, Chhatwal V. et al. Differential expression of adenosine A1 receptors in colorectal cancer and related mucosa. Cancer Lett 1996; 106: 17-21
• 18 Saito M, Yaguchi T, Yasuda Y. et al. Adenosine suppresses CW2 human colonic cancer growth by inducing apoptosis via A1 adenosine receptors. Cancer Lett 2010; 290: 211-215
• 19 Clark A, Youkey R, Liu X. et al. A1 adenosine receptor activation promotes angiogenesis and release of VEGF from monocytes. Circ Res 2007; 101: 1130-1138
• 20 Zeynali P, Jazi M, Asadi J. et al. A1 adenosine receptor antagonist induces cell apoptosis in KYSE-30 and YM-1 esophageal cancer cell lines. BioMedicine 2023; 13: 54
• 21 Sorrentino C, Morello S. Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target. J Cancer Metastasis Treat 2017; 3: 127-138
• 22 Ludwig N, Yerneni S, Azambuja J. et al. Tumor-derived exosomes promote angiogenesis via adenosine A 2B receptor signaling. Angiogenesis 2020; 23: 599-610
• 23 Ryzhov S, Novitskiy S, Carbone D. et al. Host A2B adenosine receptors promote carcinoma growth. Neoplasia 2008; 10: 987-995
• 24 Kasama H, Sakamoto Y, Kasamatsu A. et al. Adenosine A2b receptor promotes progression of human oral cancer. BMC cancer 2015; 15: 1-12
• 25 Cekic C, Sag D, Li Y. et al. Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J Immunol 2012; 188: 198-205
• 26 Beavis P, Divisekera U, Paget C. et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci 2013; 110: 14711-14716
• 27 Pulaski B, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol 2000; 39: 20-22
• 28 Ma S, Deng W, Liu J. et al. Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma. Mol Cancer 2017; 16: 99
• 29 Fishman P, Bar-Yehuda S, Barer F. et al. The A3 adenosine receptor as a new target for cancer therapy and chemoprotection. Exp Cell Res 2001; 269: 230-236
• 30 Fishman P, Bar-Yehuda S, Liang B. et al. Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 2012; 17: 359-366
• 31 Madi L, Ochaion A, Rath-Wolfson L. et al. The A3 adenosine receptor is highly expressed in tumor versus normal cells: potential target for tumor growth inhibition. Clin Cancer Res 2004; 10: 4472-4479
• 32 Merighi S, Battistello E, Giacomelli L. et al. Targeting A3 and A2A adenosine receptors in the fight against cancer. Expert Opin Ther Targets 2019; 23: 669-678
• 33 Harish A, Hohana G, Fishman P. et al. A3 adenosine receptor agonist potentiates natural killer cell activity. Int J Oncol 2003; 23: 1245-1249
• 34 Yuan G, Jankins T, Patrick C. et al. Fluorinated adenosine A2A receptor antagonists inspired by preladenant as potential cancer immunotherapeutics. Int J Med Chem 2017; 2017: 4852537
• 35 Fong P, Ao C, Tou K. et al. Experimental and in silico analysis of cordycepin and its derivatives as endometrial cancer treatment. Oncol Res 2019; 27: 237
• 36 Jhuo C, Hsu Y, Chen W. et al. Attenuation of tumor development in mammary carcinoma rats by theacrine, an antagonist of adenosine 2A receptor. Molecules 2021; 26: 7455
• 37 Bikadi Z, Hazai E. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDockJ. Cheminf 2009; 1: 15
• 38 Halgren T. Merck molecular force field. I. Basis, form, scope, parametrization, and performance of MMFF94. J Comput Chem 1998; 17: 490-519
• 39 Morris G, Goodsell D, Halliday R. et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19: 1639-1662
• 40 Solis F, Roger J. WetsMinimization by Random Search Techniques. Math Oper Res 1981; 6: 19-30
• 41 Figueroa-Valverde L, Diaz-Cedillo F, Nexticapa M. et al. Biochemical interaction of twenty steroid derivatives with ribosomal protein kinase 4 S6 (RSK-4) surface using a theoretical model. Braz J Sci 2024; 3: 66-81
• 42 Figueroa-Valverde L, López-Ramos M, Rosas-Nexticapa M. et al. Interaction of twenty-two carbazole derivatives with M1-muscarinic receptor using a theoretical model. Braz J Sci 2024; 3: 26-37
• 43 Borodovsky A, Barbon C, Wang Y. et al. Small molecule AZD4635 inhibitor of A2AR signaling rescues immune cell function including CD103+ dendritic cells enhancing anti-tumor immunity. J Immunother Cancer 2020; 8
• 44 Mediavilla-Varela M, Castro J, Chiappori A. et al. A novel antagonist of the immune checkpoint protein adenosine A2a receptor restores tumor-infiltrating lymphocyte activity in the context of the tumor microenvironment. Neoplasia 2017; 19: 530-536
• 45 Zeynali P, Jazi M, Asadi J. et al. A1 adenosine receptor antagonist induces cell apoptosis in KYSE-30 and YM-1 esophageal cancer cell lines. BioMedicine 2023; 13: 54
• 46 Edling C, Selvaggi F, Ghonaim R. et al. Caffeine and the analog CGS 15943 inhibit cancer cell growth by targeting the phosphoinositide 3-kinase/Akt pathway. Cancer Biol Ther 2014; 15: 524-532
• 47 Liu R, Duan W, Yan W. et al. (Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A2A adenosine receptors and histone deacetylases. Chin Chem Lett 2024; 35: 108136
• 48 Yu F, Zhu C, Ze S. et al. Design, Synthesis, and Bioevaluation of 2-Aminopteridin-7 (8 H)-one Derivatives as Novel Potent Adenosine A2A Receptor Antagonists for Cancer Immunotherapy. J Med Chem 2022; 65: 4367-4386
• 49 Kim S, Gao Z, Jeong L. et al. Docking studies of agonists and antagonists suggest an activation pathway of the A3 adenosine receptor. J Mol Graph Model 2006; 25: 562-577
• 50 Kim S, Jacobson K. Computational prediction of homodimerization of the A3 adenosine receptor. J Mol Graph Model 2006; 25: 549-561
• 51 Wei J, Li H, Qu W. et al. Molecular docking study of A3 adenosine receptor antagonists and pharmacophore-based drug design. Neurochem Int 2009; 55: 637-642
• 52 Spinaci A, Lambertucci C, Buccioni M. et al. A2A adenosine receptor antagonists: are triazolotriazine and purine scaffolds interchangeable?. Molecules 2022; 27: 2386
• 53 Tintori C, Manetti F, Botta M. Pharmacophoric models and 3D QSAR studies of the adenosine receptor ligands. Curr Top Med Chem 2010; 10: 1019-1035
• 54 Cotter G, Dittrich H, Weatherley B. et al. The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Cardiac Failure 2008; 14: 631-640
• 55 Hess S. Recent advances in adenosine receptor antagonist research. Expert Opin Ther Pat 2001; 11: 1533-1561
• 56 Martin P, Wysocki R, Barrett R. et al. Characterization of 8-(N-methylisopropyl) amino-N6-(5’-endohydroxy-endonorbornyl)-9-methyladenine (WRC-0571), a highly potent and selective, non-xanthine antagonist of A1 adenosine receptors. J Pharmacol Exp Ther 1996; 276: 490-499
• 57 Gottlieb S, Brater D, Thomas I. et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 2002; 105: 1348-1353
• 58 Lane J, Klaasse E, Lin J. et al. Characterization of [3H] LUF5834: a novel non-ribose high-affinity agonist radioligand for the adenosine A1 receptor. Biochem Pharmacol 2010; 80: 1180-1189
• 59 Kalla R, Zablocki J. Progress in the discovery of selective, high affinity A 2B adenosine receptor antagonists as clinical candidates. Purinergic signal 2009; 5: 21-29
• 60 Borodovsky A, Wang Y, Ye M. et al. Preclinical pharmacodynamics and antitumor activity of AZD4635, a novel adenosine 2A receptor inhibitor that reverses adenosine mediated T cell suppression. Cancer Res 2017; 77: 5580-5580
• 61 Nishida N, Yano H, Nishida T. et al. Angiogenesis in cancer. Vasc Health Risk Manag 2006; 2: 213-219
• 62 Rajabi M, Mousa S. The role of angiogenesis in cancer treatment. Biomedicines 2017; 5: 34
• 63 Hoff P, Machado K. Role of angiogenesis in the pathogenesis of cancer. Cancer Treat Rev 2012; 38: 825-833
• 64 Barcz E, Sommer E, Janik P. et al. Adenosine receptor antagonism causes inhibition of angiogenic activity of human ovarian cancer cells. Oncol Rep 2000; 7: 1285-1376
• 65 Webb R, Sills M, Chovan J. et al. CGS 21680: A potent selective adenosine A2 receptor agonist. Cardiovasc Drug Rev 1992; 10: 26-53
• 66 Montesinos M, Shaw J, Yee H. et al. Adenosine A2A receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. Am J Pathol 2004; 164: 1887-1892
• 67 Vailhé B, Vittet D, Feige J. In vitro models of vasculogenesis and angiogenesis. Lab Invest 2001; 81: 439-452
• 68 Mehnert J, McCarthy M, Jilaveanu L. et al. Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays. Hum Pathol 2010; 41: 375-384
• 69 Gray R, O'Donnell M, Maxwell P. et al. Long-term follow-up of immunocytochemical analysis of vascular endothelial growth factor (VEGF), and its two receptors, VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1/KDR), in oesophagogastric cancer. Int J Biol Markers 2013; 28: 63-70
• 70 Zhang Y, Huo M, Zhou J. et al. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 2010; 99: 306-314
• 71 Shumaker R. PKCALC: a basic interactive computer program for statistical and pharmacokinetic analysis of data. Drug Metab Rev 1986; 17: 331-348
• 72 Fagerholm U, Hellberg S, Alvarsson J. et al. ANDROMEDA by Prosilico software successfully predicts human clinical pharmacokinetics of 300 drugs out of reach for in vitro methods. bioRxiv 2022; 10
• 73 Drwal M, Banerjee P, Dunkel M. et al. ProTox: a web server for the in silico prediction of rodent oral toxicity. Nucleic Acids Rese 2014; 42: 53-58
• 74 Borba J, Alves V, Braga R. et al. STopTox: An in silico alternative to animal testing for acute systemic and topical toxicity. Environ Health Perspect 2022; 130: 027012
• 75 La-Farré M, García M, Tirapu L. et al. Wastewater toxicity screening of non-ionic surfactants by Toxalert® and Microtox® bioluminescence inhibition assays. Anal Chim Acta 2001; 427: 181-189
• 76 Utaganovich F, Ismatovich B. in silico and in vivo study of acute toxicity of the substance of the mee series. J Med Pract Nurs 2023; 1: 46-48