Cytotoxic and toxicological effects of phthalimide derivatives on tumor and normal murine cells.

Paulo Michel Pinheiro Ferreira,Cláudia Pessoa,Patricia Marçal Da Costa,Diogo Rodrigo De Magalhães Moreira,Arinice De Menezes Costa,Gevânio Bezerra De Oliveira Filho,Daisy Jereissati Barbosa Lima,Maria Goretti Rodrigues De Queiroz,Renata Rosado Drumond,Ana Cristina Lima Leite,Jurandy Do Nascimento Silva,Jamile Magalhães Ferreira

doi:10.1590/0001-3765201520130345

Abstract

Eleven phthalimide derivatives were evaluated with regards to their antiproliferative activity on tumor and normal cells and possible toxic effects. Cytotoxic analyses were performed against murine tumors (Sarcoma 180 and B-16/F-10 cells) and peripheral blood mononuclear cells (PBMC) using MTT and Alamar Blue assays. Following, the investigation of cytotoxicity was executed by flow cytometry analysis and antitumoral and toxicological potential by in vivo techniques. The molecules 3b, 3c, 4 and 5 revealed in vitro cytotoxicity against Sarcoma 180, B-16/F-10 and PBMC. Since compound 4 was the most effective derivative, it was chosen to detail the mechanism of action after 24, 48 and 72 h exposure (22.5 and 45 µM). Sarcoma 180 cells treated with compound 4 showed membrane disruption, DNA fragmentation and mitochondrial depolarization in a time- and dose-dependent way. Compounds 3c, 4 and 5 (50 mg/kg/day) did not inhibit in vivo tumor growth. Compound 4-treated animals exhibited an increase in total leukocytes, lymphocytes and spleen relative weight, a decreasing in neutrophils and hyperplasia of spleen white pulp. Treated animals presented reversible histological changes. Molecule 4 had in vitro antiproliferative action possibly triggered by apoptosis, reversible toxic effects on kidneys, spleen and livers and exhibited immunostimulant properties that can be explored to attack neoplasic cells.

Highlights

Cancer is an extremely common disease, being the second leading cause of death, surpassed by cardiovascular disorders only (Jemal et al 2005)
One of the most known phthalimide derivatives is thalidomide (Thl) and its analogues, multi-target compounds that can acts as immunomodulators (Pessoa et al 2010), angiogenesis inhibitors (D’Amato et al 1994, Dredge et al 2005, Badamtseren et al 2011) and against human multiple myeloma (Kagoya et al 2012), oral squamous cell carcinoma (Yang et al 2011) and prostate cancer (Nabhan and Petrylak 2012)
In this work, we evaluated some N-phthaloyl amino acid derivatives with regards to in vitro and in vivo antiproliferative activity on tumor and normal cells in order to investigate their mechanism of action and their toxic effects

Summary

Introduction

Cancer is an extremely common disease, being the second leading cause of death, surpassed by cardiovascular disorders only (Jemal et al 2005). Conjugated amino acids in such compounds can serve as substrate for enzymes that are produced by tumor and stroma cells (Leite et al 2007). Findings have demonstrated that specific sequences of amino acids would act on tumor molecules (Arap et al 2001). These enzymatic cascade activations such as aminopeptidases are important for cancer progression (angiogenesis and metastasis) and present a functional interplay between malignant and nonmalignant cells in the tumor microenvironment (Guzman-Rojas et al 2011)

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Results

Conclusion