Back

Anna Maria Caccuri

Anna Maria Caccuri

University of Rome Tor Vergata, Italy

Title: 7-Nitro-2,1,3-benzoxadiazoles, a promising strategy for drug-resistant tumors

Biography

Anna Maria Caccuri graduated with Honors with a degree in Biological Sciences from the University of Rome “Sapienza”. She is Associate Professor of Biochemistry at the Department of Experimental Medicine and Surgery of the University of Rome “Tor Vergata”. She has published 75 papers in reputed peer reviewed journals.

Abstract

A well-established approach for fi ghting cancer is based on signal-transduction inhibitors directed towards protein kinases involved in tumor development,and oft enused in combination with chemotherapy. However, several chemotherapeutic agents require the activation of the c-Jun N-terminal kinase (JNK) and p38 MAP-kinases to cause tumor cell death; therefore, activation of this pathway may enhance the anti-proliferative and pro-apoptotic eff ects of these drugs. Th e glutathione transferase GSTP1-1, an enzyme present at high levels in many solid tumors and overexpressed in drug-resistant ones, is a natural JNK inhibitor. Th e protein–protein interaction involving GSTP1-1 and JNK is an important mechanism for suppressing the response to apoptotic stimuli in tumors. In this regard, we have obtained biochemical evidence for direct interaction between GSTP1-1 and TNF receptor-associated factor 2 (TRAF2) as well, TRAF2 being an upstream adaptor protein responsible for the activation of JNK and p38. Th e TRAF2-GSTP1-1 complex is constitutively present in diff erent tumor types, but can be disrupted by the strong GSTP1-1 inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX); this results in JNK phospho-activation and tumor cell death. Th erefore, agents directed towards GSTP1-1 and able to activate at diff erent levels the MAPK/JNK signaling cascade may represent an alternative strategy for fi ghting cancer. We have synthesized several NBDHEX derivatives, endowed with higher solubility in water, with excellent tolerability and with antitumor activity against poorly responsive tumors. Th ese compounds are very eff ective in vivo against human melanoma models resistant to vemurafenibor to temozolomide. Th ese fi ndings support the potential use of these novel compounds as part of the new therapies for cancer treatment as single agents or in combination regimens.