Synthesis of dinitrosyl iron complexes (DNIC) and activity against head and neck squamous cell carcinoma

• Grant number: 13/02981-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2013
• End date: January 31, 2014
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: José Carlos Toledo Junior
• Grantee: José Clayston Melo Pereira
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 10/00550-2 - Mechanisms of cellular s-nitrosation from free nitric oxide. Involviment of transition metals and reactive species, AP.JP

Abstract

Head and neck squamous cell carcinoma is the sixth most common cancer with more than 500 thousand patients worldwide each year. The combination of the two well known drugs, Cisplatin and fluorouracil, has been used for treatment of this type of cancer. However, recently, it has been reported that the enzyme system glutathione/glutathione s-transferases (GSH/GSTs) causes neck squamous cell carcinoma cell lines and primary tumors in the head increasingly resistant to the treatment. This project proposes to use in situ or synthetic DNIC as alternative and helping drug to cysplatin. DNIC are formed inside cells upon cellular exposure to nitric oxide (NO) and are known to bind strongly to and inhibit the GST enzyme family. Thus, the effect of NO donors and cysplatin combination will be tested in tumor cell lines. In addition, we propose to synthesize and characterize new DNIC of the type [Fe(NO)2(L)2] and [Fe(NO)2L1L2] where L, L1 and L2 are anticancer drugs with distinct mechanisms of action (6-mercaptopurine, 5-fluorouracil and methotrexate and L2 = 5-fluorouracil). According to the literature, the DNIC ligands other than NO are readily replaced by GSTs aminoacid side chain groups, leading to a possible synergism of inhibiting GST and releasing anticancer agents in the same cell and simultaneously. The citotoxicity effects of these new DNIC compounds will be tested individually and in combination with cisplatin in assays using human tumor cell lines (HN13, HN12, HN6 and CAL27). (AU)