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.

中文翻译：

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N-（4-甲基-苯基）-4-甲基邻苯二甲酰亚胺对小鼠骨癌的生物学和毒理学评估。

背景技术最近证明邻苯二甲酰亚胺N-（4-甲基-苯基）-4-甲基邻苯二甲酰亚胺（MPMPH-1）对小鼠的急性和慢性疼痛具有重要作用，其作用机理与抑制腺苷酸环化酶有关。此外，还证明了邻苯二甲酰亚胺衍生物具有抗增殖和抗肿瘤作用。考虑到文献数据，本研究评估了MPMPH-1对乳腺癌骨转移及相关疼痛症状的影响，并提供了有关该化合物及其可能代谢物的其他毒理学信息。方法通过体外和体内实验支持计算机电子毒理学分析，以证明该化合物的抗肿瘤和抗超敏作用。结果通过计算机毒理学分析获得的数据表明，MPMPH-1具有诱变潜力，置信度低至中等。通过微核试验在体内证实了诱变潜力。乳腺癌骨转移模型中的MPMPH-1治疗能够预防骨基质的破骨细胞吸收。关于软骨，唑来膦酸组内的降解显着减少，而在MPMPH-1中，在随机区域观察到软骨细胞增殖，表明骨再生。此外，每天一次用MPMPH-1（10 mg / kg，ip）重复治疗小鼠长达36天，可显着降低患有乳腺癌骨转移的动物的超敏反应。结论总之，本文获得的数据表明MPMPH-1是相对安全的，并显着控制癌症的生长，与减少骨吸收和刺激骨再生有关。MPMPH-1的作用可能至少部分与该化合物干扰腺苷酸环化酶途径激活的能力有关。