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*   Pages 667 - 676 ( 10 )

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.

Affiliation:

Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Biomedicine Course, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, ALTOX – Alternative toxicology, Sao Paulo, SP, ALTOX – Alternative toxicology, Sao Paulo, SP, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901, ALTOX – Alternative toxicology, Sao Paulo, SP, Postgraduate Program in Pharmaceutical Science, Universidade do Vale do Itajaí, Rua Uruguai, 458, Itajaí/SC, CEP 88302-901

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