Chiara Riganti

Sponsor:

MIUR: FIRB2013 RBFR12SOQ1

AIRC 2014

Description:

The limited efficacy of cancer chemotherapy is due to the extremely low therapeutic index of the drugs presently available and to the almost invariable occurrence of "innate" or treatment-induced resistance of tumor cells to anticancer drugs. Multi-drug resistance (MDR), in fact, is a phenomenon by which tumor cells exhibit resistance to a variety of chemically unrelated chemotherapeutic drugs. MDR may originate from several biochemical mechanisms. Classical MDR is due to a lower cell concentration of cytotoxic drugs associated with accelerated efflux of the chemotherapeutic agent as a consequence of the overexpression of proteins such as ABCB1 (Pgp), ABCC1 (MRP1) and BCRP (BCG2). The use of agents which inhibit such pumps is a promising approach to overcome MDR of cancer cells. The co-administration of efflux pump inhibitors and anticancer drugs, in fact, lead to accumulation of the cytotoxic drugs in resistant cells and ensuing reversal of drug resistance.

Among several compounds tested so far by the researchers of the present project some compounds turned out to be promising leads as they potently reverted MDR of various types of cancer cells. This project integrates studies on the pharmacological and toxicological characterization of new derivatives MDR reverters by focusing on the following topics: doxorubicine conjugated with NO-donor groups (NO-DOX) and H2S-donor groups (H2S-DOX). MDRrev-loaded liposomes are also studied in order to increase the specific delivery and efficacy of our compounds against the resistant tumor cells. In vitro assessment of MDR activity will be evaluated on cell lines expressing Pgp and other ABC transporters and the interaction mechanism (substrate, modulator, inhibitor) is studied. The novel compounds will be also studied for their ability to revert MDR by using monolayer (bidimensional model, 2D) and multicellular spheroids (tridimensional model, 3D) of sensitive and doxorubicine-resistant subclones of tumor cells.

In vivo assessment of MDR activity of NO-DOX exhibiting the highest efficacy and pharmacologic safety in the above-mentioned steps will be tested.

Collaboration:

• Institute for Molecular Systems Biology and NCCR Neuro Center for Proteomics,
• ETH (Zurich, Switzerland);
• Neuro-Bio-Oncology Center (Vercelli, Italy)
• Biologic Bank of Mesothelioma (Azienda Nazionale Ospedaliera, Alessandria, Italy)

Keywords:

• multidrug resistance (MDR)
• cancer
• ATP-binding protein

Settori di ricerca ERC (European Research Council) interessati dal Progetto di Ricerca

LS7_3 Pharmacology, pharmacogenomics, drug discovery and design, drug therapy

LS7_5 Toxicology

Settori scientifico-disciplinari interessati dal Progetto di Ricerca

BIO/14 Farmacologia

CHIM/08 Chimica farmaceutica