Theoretical interaction of muscarinic receptor antagonist with vascular endothelial growth factor receptors (VEGF-R1, R2 and R3) as a therapeutic alternative to treat cancer

Authors

  • Lauro Figueroa-Valverde Laboratory of Pharmaco-Chemistry, Faculty of Chemical Biological Sciences, University Autonomous of Campeche, Av. Agustín Melgar s/n, Col Buenavista C.P. 24039, Campeche, Camp., México https://orcid.org/0000-0001-8056-9069
  • Marcela Rosas-Nexticapa Nutrition Laboratory, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico https://orcid.org/0000-0001-7119-4728
  • Magdalena Alvarez-Ramirez Nutrition Laboratory, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico https://orcid.org/0000-0003-0046-4342
  • Maria Virginia Mateu-Armad Nutrition Laboratory, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico https://orcid.org/0000-0003-3283-0001
  • Regina Cauich-Carrillo Health Sciences, University Autonomous of Quintana Roo State, Campus Chetumal, Av Erik Paolo Martinez s/nesq. Av. Col. Magisteterial, C.P. 77039, Mexico https://orcid.org/0000-0002-7166-5048

DOI:

https://doi.org/10.14295/bjs.v4i5.734

Keywords:

cancer, muscarinic, antagonists, angiogenesis

Abstract

Several biomolecules have been the target of some drugs for the treatment of cancer; however, there is little information on the interaction of muscarinic antagonists with vascular endothelial growth factor receptor (VEGF-R1, R2, R3). The aim of this research was to determine the possible interaction of muscarinic antagonists such as atropine, ML381, af-dx 386, azaprophen, darifenacin, dicyclomine, PD-102807, pirenzepine, telenzepine, Zamifenacin, and cyclohexylamine with VEGF-R1, R2, and R3. The theoretical interaction of muscarinic antagonists with VEGF-R1, R2, and R3 was carried out using the 2ho4, 3hng, and 4bsj proteins as theoretical tools. Besides, cabozantinib, pazopanib, regorafenib, and sorafenib drugs were used as controls. The results showed differences in the number of aminoacid residues and energy levels involved in the interaction of muscarinic antagonists with 2ho4, 3hng, and 4bsj proteins compared with the controls. Besides, the inhibition constants (Ki) values for atropine, ML-381, zaniferacin, and dicyclomine were lower compared with some controls. In conclusion, the results suggest that atropine, ML-381, zaniferacin, and dicyclomine could act as VEGF receptor inhibitors, could result in changes in the biological activity of angiogenesis, and this phenomenon could be translated as a decrease in cancer cell growth. Therefore, these drugs could be a good therapeutic alternative to evaluate their biological activity in some cancer models.

References

Ahmad, A., & Nawaz, M. I. (2022). Molecular mechanism of VEGF and its role in pathological angiogenesis. Journal of cellular biochemistry, 123(12), 1938-1965. https://doi.org/10.1002/jcb.30344

Ali, A., Jadhav, A., Jangid, P., Patil, R., Shelar, A., & Karuppayil, S. M. (2018). The human muscarinic acetylcholine receptor antagonist, Dicyclomine targets signal transduction genes and inhibits the virulence factors in the human pathogen, Candida albicans. The Journal of Antibiotics, 71(4), 456-466.

Ali, A., Jadhav, A., Jangid, P., Patil, R., Shelar, A., & Karuppayil, S. M. (2018). The human muscarinic acetylcholine receptor antagonist, Dicyclomine targets signal transduction genes and inhibits the virulence factors in the human pathogen, Candida albicans. The Journal of Antibiotics, 71(4), 456-466.

Anbarasu, S., & Anbarasu, A. (2023). Cancer-biomarkers associated with sex hormone receptors and recent therapeutic advancements: a comprehensive review. Medical Oncology, 40(6), 171.

Bikadi, Z., & Hazai, E. (2009). Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. Journal of cheminformatics, 1, 1-16.

Bourne, D. W. (1997). Using the Internet as a pharmacokinetic resource. Clinical pharmacokinetics, 33(3), 153-160.

Brave, S. R., Ratcliffe, K., Wilson, Z., James, N. H., Ashton, S., Wainwright, A., ... & Barry, S. T. (2011). Assessing the activity of cediranib, a VEGFR-2/3 tyrosine kinase inhibitor, against VEGFR-1 and members of the structurally related PDGFR family. Molecular cancer therapeutics, 10(5), 861-873. https://doi.org/10.1158/1535-7163.MCT-10-0976

Carroll, F. I., Abraham, P., Mascarella, S. W., Singh, P., Moreland, C. G., Sankar, S. S., & Triggle, D. J. (1991). Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen. Journal of medicinal chemistry, 34(4), 1436-1440. https://doi.org/10.1021/jm00108a030

Carroll, F. I., Abraham, P., Mascarella, S. W., Singh, P., Moreland, C. G., Sankar, S. S., ... & Triggle, D. J. (1991). Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen. Journal of medicinal chemistry, 34(4), 1436-1440. https://doi.org/10.1021/jm00108a030

Cazzola, M., Matera, M. G., Liccardi, G., Sacerdoti, G., D'Amato, G., & Rossi, F. (1994). Effect of telenzepine, an M1-selective muscarinic receptor antagonist, in patients with nocturnal asthma. Pulmonary Pharmacology, 7(2), 91-97. https://doi.org/10.1006/pulp.1994.1010

Chen, J., Shin, V. Y., Cheuk, W. Y. I., Siu, J. M. T., & Kwong, A. (2020). Cholinergic receptor muscarinic 3 (CHRM3) contributes to breast cancer tumorigenesis through angiogenesis regulation. In San Antonio Breast Cancer Symposium (SABCS). American Association Cancer Research, 80(4), 1-7. http://dx.doi.org/10.1158%2F1538-

SABCS19-P1-07-01

Chhikara, B. S., & Parang, K. (2023). Global Cancer Statistics 2022: the trends projection analysis. Chemical Biology Letters, 10(1), 451-451.

Cossy, J., Dumas, C., & Pardo, D. G. (1997). A short and efficient synthesis of zamifenacin a muscarinic M3 receptor antagonist. Bioorganic & Medicinal Chemistry Letters, 7(10), 1343-1344. https://doi.org/10.1016/S0960-894X(97)00221-7

Costa, M. F. F. D., Bilobran, M. A., de Oliveira, L. C., Muniz, A. H. R., Chelles, P. A., & Sampaio, S. G. D. S. M. (2024). Correlation between cancer pain and quality of life in patients with advanced cancer admitted to a palliative care unit. American Journal of Hospice and Palliative Medicine®, 41(8), 882-888. https://doi.org/10.1177/10499091231195318

Eguchi, R., Kawabe, J. I., & Wakabayashi, I. (2022). VEGF-independent angiogenic factors: beyond VEGF/VEGFR2 signaling. Journal of Vascular Research, 59(2), 78-89. https://doi.org/10.1159/000521584

El‐Helby, A. G. A., Ayyad, R. R., Sakr, H., El‐Adl, K., Ali, M. M., & Khedr, F. (2017). Design, synthesis, molecular docking, and anticancer activity of phthalazine derivatives as VEGFR‐2 inhibitors. Archiv der Pharmazie, 350(12), 1700240. https://doi.org/10.1002/ardp.201700240

Eşkazan, E., Aker, R., Onat, F., Köseoğlu, S., Gören, M. Z., & Hasanoğlu, A. (1999). Effect of pirenzepine, a muscarinic M1 receptor antagonist, on amygdala kindling in rat. Epilepsy research, 37(2), 133-140. https://doi.org/10.1016/S0920-1211(99)00040-6

Español, A. J., & Sales, M. E. (2004). Different muscarinc receptors are involved in the proliferation of murine mammary adenocarcinoma cell lines. International journal of molecular medicine, 13(2), 311-317.

Feurino, L. W., Zhang, Y., Bharadwaj, U., Zhang, R., Li, F., Fisher, W. E., & Li, M. (2007). IL-6 stimulates Th2 type cytokine secretion and upregulates VEGF and NRP-1 expression in pancreatic cancer cells. Cancer biology & therapy, 6(7), 1096-1100. https://doi.org/10.4161/cbt.6.7.4328

Figueroa-Valverde, L., Diaz-Cedillo, F., Lopez-Ramos, M., Garcia-Cervera, E., Pool-Gomez, E., Cardena-Arredondo, C., & Ancona-Leon, G. (2012). Glibenclamide-pregnenolone derivative has greater hypoglycemic effects and biodistribution than glibenclamide-OH in alloxan-rats. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 156(2), 122-127.

Figueroa-Valverde, L., Rosas-Nexticapa, M., Alvarez-Ramirez, M., Lopez-Ramos, M., & Mateu-Armand, V. (2022). Theoretical evaluation of interaction of some dibenzo derivatives on both androgen receptor and 5α-reductase enzyme. Clinical Cancer Investigation Journal, 11(5-2022), 11-16.

Fiszman, G. L., Middonno, M. C., de la Torre, E., Farina, M., Español, A. J., & Sales, M. E. (2007). Activation of muscarinic cholinergic receptors induces MCF-7 cells proliferation and angiogenesis by stimulating nitric oxide synthase activity. Cancer biology & therapy, 6(7), 1106-1113. https://doi.org/10.4161/cbt.6.7.4330

Gentry P, Kokubo M, Bridges T. (2014). Discovery, Synthesis and Characterization of a Highly Muscarinic Acetylcholine Receptor (mAChR)‐Selective M5‐Orthosteric Antagonist, VU0488130 (ML381): A Novel Molecular Probe. ChemMedChem, 9(8): 1677-1682. https://doi.org/10.1002/cmdc.201402051

Gentry, P. R., Kokubo, M., Bridges, T. M., Cho, H. P., Smith, E., Chase, P., ... & Lindsley, C. W. (2014). Discovery, Synthesis and Characterization of a Highly Muscarinic Acetylcholine Receptor (mAChR)‐Selective M5‐Orthosteric Antagonist, VU0488130 (ML381): A Novel Molecular Probe. ChemMedChem, 9(8), 1677-1682. https://doi.org/10.1002/cmdc.201402051

Haab, F., Stewart, L., & Dwyer, P. (2004). Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. European urology, 45(4), 420-429.

Halgren, T. A. (1996). Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. Journal of computational chemistry, 17(5‐6), 490-519.

Hazan, S., Tauber, M., & Ben-Chaim, Y. (2024). Voltage dependence of M2 muscarinic receptor antagonists and allosteric modulators. Biochemical Pharmacology, 227, 116421. https://doi.org/10.1016/j.bcp.2024.116421

Holzgrabe U, Heller E. (2003) A new synthetic route to compounds of the AFDX-type with affinity to muscarinic M2-receptor. Tetrahedron, 59(6): 781-787. https://doi.org/10.1016/S0040-4020(02)01623-X

Hoshi N, Ehlert F. (2024). Muscarinic Antagonists and Their Clinical Uses. Brody's Human Pharmacology-E-Book: Brody's Human Pharmacology-E-Book, 79.

Houghton, L. A., Rogers, J., Whorwell, P. J., Campbell, F. C., Williams, N. S., & Goka, J. (1997). Zamifenacin (UK‐76, 654), a potent gut M3 selective muscarinic antagonist, reduces colonic motor activity in patients with irritable bowel syndrome. Alimentary pharmacology & therapeutics, 11(3), 561-568. https://doi.org/10.1046/j.1365-2036.1997.00189.x

Hwang, J. E., Lee, J. H., Park, M. R., Kim, D. E., Bae, W. K., Shim, H. J., & Chung, I. J. (2013). Blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in gastric cancer cells. Yonsei Medical Journal, 54(2), 374-380. https://doi.org/10.3349/ymj.2013.54.2.374

Klasa-Mazurkiewicz, D., Jarząb, M., Milczek, T., Lipińska, B., & Emerich, J. (2011). Clinical significance of VEGFR-2 and VEGFR-3 expression in ovarian cancer patients. Polish Journal of Pathology, 62(1), 31-40.

Kohn, E. C., Alessandro, R., Probst, J., Jacobs, W., Brilley, E., & Felder, C. C. (1996). Identification and molecular characterization of a m5 muscarinic receptor in A2058 human melanoma cells: Coupling to inhibition of adenylyl cyclase and stimulation of phospholipase A2. Journal of Biological Chemistry, 271(29), 17476-17484. https://doi.org/10.1074/jbc.271.29.17476.

Kopparapu, P. K., Boorjian, S. A., Robinson, B. D., Downes, M., Gudas, L. J., Mongan, N. P., & Persson, J. L. (2013). Expression of VEGF and its receptors VEGFR1/VEGFR2 is associated with invasiveness of bladder cancer. Anticancer research, 33(6), 2381-2390.

Kwon, M. J., Kang, H. S., Choi, H. G., Kim, J. H., Kim, J. H., Bang, W. J., & Lee, H. K. (2023). Risk for esophageal cancer based on lifestyle factors–smoking, alcohol consumption, and body mass index: insight from a South Korean population study in a low-incidence area. Journal of Clinical Medicine, 12(22), 7086. https://www.mdpi.com/2077- 0383/12/22/7086#

Levitt, D. G. (2002). PKQuest: a general physiologically based pharmacokinetic model. Introduction and application to propranolol. BMC clinical pharmacology, 2, 1-21.

Li, M., Huang, C., Wu, X., Ding, F., Hu, Z., Zhu, Y., & Tang, D. (2020). The optimization of a novel selective antagonist for human M2 muscarinic acetylcholine receptor. Bioorganic & Medicinal Chemistry Letters, 30(24), 127632. https://doi.org/10.1016/j.bmcl.2020.127632

Liu, H., Xia, J., Wang, T., Li, W., Song, Y., & Tan, G. (2019). Differentiation of human glioblastoma U87 cells into cholinergic neuron. Neuroscience Letters, 704, 1-7. https://doi.org/10.1016/j.neulet.2019.03.049.

Liu, Y., Lu, L., Yang, H., Wu, X., Luo, X., Shen, J., & Li, M. (2023). Dysregulation of immunity by cigarette smoking promotes inflammation and cancer: a review. Environmental Pollution, 339, 122730. https://doi.org/10.1016/j.envpol.2023.122730

Liu, Z., Zhang, Y., Lagergren, J., Li, S., Li, J., Zhou, Z., & Xie, S. H. (2023). Circulating sex hormone levels and risk of gastrointestinal cancer: systematic review and meta-analysis of prospective studies. Cancer Epidemiology, Biomarkers & Prevention, 32(7), 936-946. https://doi.org/10.1158/1055-9965.EPI-23-00396

Lombardi, M. G., Negroni, M. P., Pelegrina, L. T., Castro, M. E., Fiszman, G. L., Azar, M. E., & Sales, M. E. (2013). Autoantibodies against muscarinic receptors in breast cancer: their role in tumor angiogenesis. PloS one, 8(2), e57572. https://doi.org/10.1371/journal.pone.0057572

Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., & Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of computational chemistry, 19(14), 1639-1662.

Movahedi, N., Zendehdel, M., Vazir, B., & Hassanpour, S. (2024). Sericin-induced hypophagia mediates via M1 muscarinic, NMDA glutamate and glycine receptors in neonatal chicken. Archives of Razi Institute, 79(5), 1109-1116. https://doi.org/10.32592/ARI.2024.79.5.1109

Myslivecek J, Farar V. (2024). Autoradiography Assessment of Muscarinic Receptors in the Central Nervous System with a Special Focus on Specific the Selectivity Protocol for M1 M2. Muscarinic Receptor: From Structure to Animal Models. New York, NY: Springer US. 213-227.

Nagano, H., Tomida, C., Yamagishi, N., & Teshima-Kondo, S. (2019). VEGFR-1 regulates EGF-R to promote proliferation in colon cancer cells. International Journal of Molecular Sciences, 20(22), 1-22. https://doi.org/10.3390/ijms20225608

Nakajima, Y., Tsujimura, T., Tsutsui, Y., Chotirungsan, T., Kawada, S., Dewa, N., & Inoue, M. (2023). Atropine facilitates water-evoked swallows via central muscarinic receptors in anesthetized rats. American Journal of Physiology-Gastrointestinal and Liver Physiology, 325(2), G109-G121.

Olianas, M. C., & Onali, P. (1999). PD 102807, a novel muscarinic M4 receptor antagonist, discriminates between striatal and cortical muscarinic receptors coupled to cyclic AMP. Life sciences, 65(21), 2233-2240. https://doi.org/10.1016/S0024-3205(99)00488-9

Pauling P, Petcher T. (1970). Interaction of atropine with the muscarinic receptor. Nature, 228(5272): 673-674.

Poland, A., & Glover, E. (1973). Studies on the mechanism of toxicity of the chlorinated dibenzo-p-dioxins. Environmental health perspectives, 5, 245-251.

Rimmaudo, L. E., de la Torre, E., de Lustig, E. S., & Sales, M. E. (2005). Muscarinic receptors are involved in LMM3 tumor cells proliferation and angiogenesis. Biochemical and biophysical research communications, 334(4), 1359-1364. https://doi.org/10.1016/j.bbrc.2005.07.031

Rössler, J., Monnet, Y., Farace, F., Opolon, P., Daudigeos‐Dubus, E., Bourredjem, A., & Geoerger, B. (2011). The selective VEGFR1‐3 inhibitor axitinib (AG‐013736) shows antitumor activity in human neuroblastoma xenografts. International journal of cancer, 128(11), 2748-2758. https://doi.org/10.1002/ijc.25611

Salem, A, Pulido P., Sanchez F et al. Effect of low dose metronomic therapy on MCF-7 tumor cells growth and angiogenesis. Role of muscarinic acetylcholine receptors. Int Immunopharm 2020; 84, 106514. https://doi.org/10.1016/j.intimp.2020.106514

Sertoglu, E., Yücel, Ç., Omma, A., Hayran, Y., Colak, S., Sandıkçı, S. C., & Ozgurtas, T. (2022). Determination of serum vascular endothelial growth factor (VEGF) and VEGF receptor levels with VEGF gene polymorphisms in patients with Behçet’s uveitis. Advances in Clinical and Experimental Medicine, 31(3), 231-240. https://doi.org/10.17219/acem/143586

Shah, N., Khurana, S., Cheng, K., & Raufman, J. P. (2009). Muscarinic receptors and ligands in cancer. American Journal of Physiology-Cell Physiology, 296(2), C221-C232. https://doi.org/10.1152/ajpcell.00514.2008

Shang, H. X., Ning, W. T., Sun, J. F., Guo, N., Guo, X., Zhang, J. N., & Wu, S. H. (2024). Investigation of the quality of life, mental status in patients with gynecological cancer and its influencing factors. World Journal of Psychiatry, 14(7), 1053. https://doi.org/10.5498%2Fwjp.v14.i7.1053

Sicak, Y. (2021). Design and antiproliferative and antioxidant activities of furan-based thiosemicarbazides and 1, 2, 4-triazoles: their structure-activity relationship and SwissADME predictions. Medicinal Chemistry Research, 30(8), 1557-1568.

Siegel, R. L., Miller, K. D., Wagle, N. S., & Jemal, A. (2023). Cancer statistics, 2023. CA: Cancer Journal for Clinicians, 73(1), 17-48. https://doi.org/10.3322/caac.21820

Sloan, B., & Scheinfeld, N. S. (2008). Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Current opinion in investigational drugs (London, England: 2000), 9(12), 1324-1335.

Solis, F. J., & Wets, R. J. B. (1981). Minimization by random search techniques. Mathematics of operations research, 6(1), 19-30.

Tolaymat, M., Larabee, S. M., Hu, S., Xie, G., & Raufman, J. P. The Role of M3 Muscarinic Receptor Ligand-Induced Kinase Signaling in Colon Cancer Progression. Cancers (Basel). 2019; 11 (3). https://doi.org/10.3390/cancers11030308

Tompkins, E., Mimic, B., Penn, R. B., & Pera, T. (2023). The biased M3 mAChR ligand PD 102807 mediates qualitatively distinct signaling to regulate airway smooth muscle phenotype. Journal of Biological Chemistry, 299(10), 1-12.

Wang, J., Krysiak, P. S., Laurier, L. G., Sims, S. M., & Preiksaitis, H. G. (2000). Human esophageal smooth muscle cells express muscarinic receptor subtypes M1 through M5. American Journal of Physiology-Gastrointestinal and Liver Physiology, 279(5), G1059-G1069. https://doi.org/10.1152/ajpgi.2000.279.5.G1059.

Wang, Z., Wang, N., Han, S., Wang, D., Mo, S., Yu, L., ... & Chen, J. (2013). Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PloS one, 8(7), e68566. https://doi.org/10.1371/journal.pone.0068566

Wilhelm, S. M., Dumas, J., Adnane, L., Lynch, M., Carter, C. A., Schütz, G., ... & Zopf, D. (2011). Regorafenib (BAY 73‐4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. International journal of cancer, 129(1), 245-255. https://doi.org/10.1002/ijc.25864

Yakes, F. M., Chen, J., Tan, J., Yamaguchi, K., Shi, Y., Yu, P., & Joly, A. H. (2011). Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular cancer therapeutics, 10(12), 2298-2308. https://doi.org/10.1158/1535-7163.MCT-11-0264

Yu, H., Xia, H., Tang, Q., Xu, H., Wei, G., Chen, Y., & Bi, F. Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation. Sci Rep., 2017, 7, 40802.

Zhao, Q., Yue, J., Zhang, C., Gu, X., Chen, H., & Xu, L. (2015). Inactivation of M2 AChR/NF-κB signaling axis reverses epithelial-mesenchymal transition (EMT) and suppresses migration and invasion in non-small cell lung cancer (NSCLC). Oncotarget, 6(30), 29335. https://doi.org/10.18632/oncotarget.5004

Downloads

Published

2025-04-17

How to Cite

Figueroa-Valverde, L., Rosas-Nexticapa, M., Alvarez-Ramirez, M., Mateu-Armad, M. V., & Cauich-Carrillo, R. (2025). Theoretical interaction of muscarinic receptor antagonist with vascular endothelial growth factor receptors (VEGF-R1, R2 and R3) as a therapeutic alternative to treat cancer. Brazilian Journal of Science, 4(5), 1–14. https://doi.org/10.14295/bjs.v4i5.734