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.
Small molecule nAS-E targeting cAMP response element binding protein (CREB) and CREB-binding protein interaction inhibits breast cancer bone metastasis
