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

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.

• Authors: Paulo Michel Pinheiro Ferreira, Patricia Marçal Da Costa, Arinice de Menezes Costa, Daisy Jereissati Barbosa Lima, Renata Rosado Drumond, Jurandy do Nascimento Silva, Diogo Rodrigo de Magalhães Moreira, Gevânio Bezerra De Oliveira Filho, Jamile Magalhães Ferreira, Maria Goretti Rodrigues De Queiroz, Ana Cristina Lima Leite, Cláudia Pessoa
• Journal: Anais da Academia Brasileira de Ciencias (An Acad Bras Cienc) Vol. 87 Issue 1 Pg. 313-30 (Mar 2015) ISSN: 1678-2690 [Electronic] Brazil
• PMID: 25651156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phthalimides
• phthalimide

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Leukocytes, Mononuclear (drug effects)
• Mice
• Phthalimides (pharmacology, toxicity)