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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Biological and Toxicological Evaluation of N-(4methyl-phenyl)-4-methylphthalimide on Bone Cancer in Mice

Author(s): José R. Santin, Gislaine F. da Silva, Maria V.D. Pastor, Milena F. Broering, Roberta Nunes, Rodolpho C. Braga, Iury T.S. de Sousa, Dorimar S. Stiz, Kathryn A.B.S. da Silva, Luis C. Stoeberl, Rogério Corrêa, Valdir C. Filho, Carlos E.M. dos Santos and Nara L.M. Quintão*

Volume 19, Issue 5, 2019

Page: [667 - 676] Pages: 10

DOI: 10.2174/1871520619666190207130732

Price: $65

Abstract

Background: It was recently demonstrated that the phthalimide N-(4-methyl-phenyl)-4- methylphthalimide (MPMPH-1) has important effects against acute and chronic pain in mice, with a mechanism of action correlated to adenylyl cyclase inhibition. Furthermore, it was also demonstrated that phthalimide derivatives presented antiproliferative and anti-tumor effects. Considering the literature data, the present study evaluated the effects of MPMPH-1 on breast cancer bone metastasis and correlated painful symptom, and provided additional toxicological information about the compound and its possible metabolites.

Methods: In silico toxicological analysis was supported by in vitro and in vivo experiments to demonstrate the anti-tumor and anti-hypersensitivity effects of the compound.

Results: The data obtained with the in silico toxicological analysis demonstrated that MPMPH-1 has mutagenic potential, with a low to moderate level of confidence. The mutagenicity potential was in vivo confirmed by micronucleus assay. MPMPH-1 treatments in the breast cancer bone metastasis model were able to prevent the osteoclastic resorption of bone matrix. Regarding cartilage, degradation was considerably reduced within the zoledronic acid group, while in MPMPH-1, chondrocyte multiplication was observed in random areas, suggesting bone regeneration. Additionally, the repeated treatment of mice with MPMPH-1 (10 mg/kg, i.p.), once a day for up to 36 days, significantly reduces the hypersensitivity in animals with breast cancer bone metastasis.

Conclusion: Together, the data herein obtained show that MPMPH-1 is relatively safe, and significantly control the cancer growth, allied to the reduction in bone reabsorption and stimulation of bone and cartilage regeneration. MPMPH-1 effects may be linked, at least in part, to the ability of the compound to interfere with adenylylcyclase pathway activation.

Keywords: Phthalimide, breast cancer, pain, toxicity, mutagenicity, in silico.

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[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics 2016. CA Cancer J. Clin., 2017, 66, 7-30.
[2]
Choudhury, B.; Kandimalla, R.; Elancheran, R.; Bharali, R.; Kotoky, J. Garcinia morella fruit, a promising source of antioxidant and anti-inflammatory agents induces breast cancer cell death via triggering apoptotic pathway. Biomed. Pharmacother., 2018, 103, 562-573.
[3]
Instituto Nacional do Cancer-INCA. Available at: http://www. inca.gov.br/estimativa/2018/ (Accessed on October 29, 2018).
[4]
Marino, S.; Bishop, R.T.; Capulli, M.; Sophocleous, A.; Logan, J.G.; Mollat, P.; Mognetti, B.; Ventura, L.; Sims, A.H.; Rucci, N.; Ralston, S.H.; Idris, A.I. Regulation of breast cancer induced bone disease by cancer-specific IKKβ. Oncotarget, 2018, 9, 16134-16148.
[5]
Mundy, G.R. Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer, 2002, 2, 584-593.
[6]
Shupp, A.B.; Kolb, A.D.; Mukhopadhyay, D.; Bussard, K.M. Cancer Metastases to bone: Concepts, mechanisms, and interactions with bone osteoblasts. Cancers (Basel), 2019, 10, 1-37.
[7]
Tulotta, C.; Ottewell, P. The role of IL-1B in breast cancer bone metastasis. Endocr. Relat. Cancer, 2018, 25, R421-R434.
[8]
Macedo, F.; Ladeira, K.; Pinho, F.; Saraiva, N.; Bonito, N.; Pinto, L.; Goncalves, F. Bone metastases: An overview. Oncol. Rev., 2017, 11, 321.
[9]
Roodman, G.D. Mechanism of bone metastasis. N. Engl. J. Med., 2004, 350, 1655-1664.
[10]
Remeniuk, B.; King, T.; Sukhtankar, D.; Nippert, A.; Li, N.; Li, F.; Cheng, K.; Rice, K.C.; Porrec, F. Porrec. Disease modifying actions of interleukin-6 blockade in a rat model of bone cancer pain. Pain, 2018, 159, 684-698.
[11]
Paice, J.A.; Ferrell, B. The management of cancer pain. CA: A Cancer J. Clin., 2011, 61, 157-182.
[12]
O’Carrigan, B.; Wong, M.H.; Willson, M.L.; Stockler, M.R.; Pavlakis, N.; Goodwin, A. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst. Rev., 2017, 10CD003474
[13]
Cechinel-Filho, V.; Campos-Buzzi, F.; Corrêa, R.; Yunes, R.A.; Nunes, R.J. Aspectos químicos e potencial terapêutico de imidas cíclicas: Uma revisão da literature. Quim. Nova, 2003, 26, 230-241.
[14]
da Silva, G.F.; Dos Anjos, M.F.; Rocha, L.W.; Ferreira, L.F.G.R.; Stiz, D.S.; Corrêa, R.; Santin, J.R.; Cechinel Filho, V.; Hernandes, M.Z.; Quintão, N.L.M. Anti-hypersensitivity effects of the phthalimide derivative N-(4methyl-phenyl)-4-methylphthalimide in different pain models in mice. Biomed. Pharmacother., 2017, 96, 503-512.
[15]
Cardoso, M.V.; Moreira, D.R.; Oliveira Filho, G.B.; Cavalcanti, S.M.; Coelho, L.C.; Espíndola, J.W.; Gonzalez, L.R.; Rabello, M.M.; Hernandes, M.Z.; Ferreira, P.M.; Pessoa, C.; Alberto de Simone, C.; Guimarães, E.T.; Soares, M.B.; Leite, A.C. Design, synthesis and structure activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities. Eur. J. Med. Chem., 2015, 96, 491-503.
[16]
Kudva, G.C.; Collins, B.T.; Dunphy, F.R. Thalidomide for malignant melanoma. N. Engl. J. Med., 2001, 345, 1214-1215.
[17]
ANVISA 2015. Resolução de Diretoria Colegiada-RDC n. 53, de 4 dezembro de 2015.
[18]
OECD,Test No. 487. In Vitro Mammalian Cell Micronucleus Test; OECD Publishing: Paris, 2010.
[19]
Zimmermann, M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain, 1983, 16, 109-110.
[20]
Campbell, J.P.; Merkel, A.R.; Masood-Campbell, S.K.; Elefteriou, F.; Sterling, J.A. Models of bone metastasis. J. Vis. Exp., 2012, 67e4260
[21]
Zhang, Z.; Hu, Z.; Gupta, J.; Krimmel, J.D.; Gerseny, H.M.; Berg, A.F.; Robbins, J.S.; Du, H.; Prabhakar, B.; Seth, P. Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host. Cancer Gene Ther., 2012, 19, 630-636.
[22]
Quintão, N.L.; Medeiros, R.; Santos, A.R.; Campos, M.M.; Calixto, J.B. The effects of diacerhein on mechanical allodynia in inflammatory and neuropathic models of nociception in mice. Anesth. Analg., 2005, 10, 1763-1769.
[23]
OECD, Guidance Document on the Validation of (Quantitative) Structure Activity Relationship [(Q)SAR] Models, OECD Series on Testing and Assessment, No. 69, OECD Publishing; ,Paris,. , 2014.
[24]
Fenech, M. The in vitro micronucleus technique. Mutat. Res., 2000, 20, 81-95.
[25]
Szikriszt, B.; Póti, Á.; Pipek, O.; Krzystanek, M.; Kanu, N.; Molnár, J.; Ribli, D.; Szeltner, Z.; Tusnády, G.E.; Csabai, I.; Szallasi, Z.; Swanton, C.; Szüts, D. A comprehensive survey of the mutagenic impact of common cancer cytotoxics. Genome Biol., 2016, 17, 99.
[26]
Drugs. Available at: https://www.drugs.com/ (oxaliplatin; zoledronic acid) (Accessed on: October 29, 2018).
[27]
Reinecke, P.; Corvin, J.; Gabbert, H.E.; Gerharz, C.D. Antiproliferative effects of paclitaxel (Taxol) on human renal clear cell carcinomas in vitro. Eur. J. Cancer, 1997, 33, 1122-1129.
[28]
Kondo, Y.; Honda, S.; Nakajima, M.; Miyahana, K.; Hayashi, M.; Shinagawa, Y.; Sato, S.; Inoue, K.; Nito, S.; Ariyuki, F. Micronucleus test with vincristine sulfate and colchicine in peripheral blood reticulocytes of mice using acridine orange supravital staining. Mutat. Res., 1992, 278, 187-191.
[29]
Jagetia, G.C.; Jacob, P.S. Vinblastine treatment induces dose-dependent increases in the frequency of micronuclei in mouse bone marrow. Mutat. Res., 1992, 280, 87-92.
[30]
Siddik, Z.H.; Newman, R.A. Metabolism of new anticancer agents. Pharmacol. Ther., 1989, 41, 163-194.
[31]
Henesey, C.M.; Harvison, P.J. Potential metabolism and cytotoxicity of IV-(3,Sdichlorophenyl) succinimide and its hepatic metabolites in isolated rat renal cortical tubule cells. Toxicology, 1995, 104, 9-16.
[32]
Baklaushev, V.P.; Grinenko, N.F.; Yusubalieva, G.M.; Gubskii, I.L.; Burenkov, M.S.; Rabinovich, E.Z.; Ivanova, N.V.; Chekhonin, V.P. Mono- and combined therapy of metastasizing breast carcinoma 4T1 with zoledronic acid and doxorubicin. Bull. Exp. Biol. Med., 2016, 161, 580-586.
[33]
Cheng, X.; Ji, Z.; Tsalkova, T.; Mei, F. Epac and PKA: A tale of two intracellular cAMP receptors. Acta Biochim. Biophys. Sin. (Shanghai), 2008, 40, 651-662.
[34]
Almahariq, M.; Mei, F.C.; Cheng, X. The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: Implications for therapeutic intervention. Acta Biochim. Biophys. Sin. (Shanghai), 2016, 48, 75-81.
[35]
Hussain, M.; Tang, F.; Liu, J.; Zhang, J.; Javeed, A. Dichotomous role of protein kinase A type I (PKAI) in the tumor microenvironment: A potential target for ‘two-in-one’ cancer chemo immunotherapeutic. Cancer Lett., 2015, 369, 9-19.
[36]
Kumar, N.; Prasad, P.; Jash, E.; Saini, M.; Husain, A.; Goldman, A.; Sehrawat, S. Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment. Mol. Cell. Biochem., 2018, 447, 77-92.
[37]
Kumar, N.; Gupta, S.; Dabral, S.; Singh, S.; Sehrawat, S. Role of exchange protein directly activated by cAMP (EPAC1) in breast cancer cell migration and apoptosis. Mol. Cell. Biochem., 2017, 430, 115-125.
[38]
Onodera, Y.; Nam, J.M.; Bissell, M.J. Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J. Clin. Invest., 2014, 124, 367-384.
[39]
Stiz, D.; Corrêa, R.; D’Auria, F.D.; Simonetti, G.; Cechinel-Filho, V. Synthesis of cyclic imides (methylphtalimides, carboxylic acid phtalimides and itaconimides) and evaluation of their antifungal potential. Med. Chem., 2016, 12, 647-654.

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