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New MDR1 inhibitor for overcoming multidrug Resistance

lung cancerMDR1multi drug resistance

Introduction

The patent relates to a new synthetic molecule (AIF1) capable of inhibiting the MDR1 cellular receptor responsible for drug resistance by promoting its extrusion from the target cell. In particular, its increased expression on the plasma membrane of tumor cells determines the outflow of chemotherapy from the cell, reducing its concentration and its toxic effect and ultimately its therapeutic efficacy. AIF1, highly active and selective in inhibiting MDR1, is able to increase the cellular concentration of the anti-cancer agent doxorubicin and potentiate its efficacy in a model of non small cell lung cancer (NSCLC).

Technical features

The patent relates to a new molecule (AIF1) capable of blocking the MDR1 activity in cancer cells. MDR1 is one of the most important efflux pumps belonging to the ATP-binding cassette transporters family involved in the Multi Drug Resistance phenomenon. The anthracycline antibiotic adriamycin (Doxorubicin; DOXO) is an effective anti-cancer agent. Therefore, inhibition of ABCB1 would lead to increased accumulation of DOX within the cell enhancing its cytotoxicity and restoring its clinical efficacy. Our molecule AIF-1 in a cellular model of non small cell lung cancer (NSCLC), markedly increased the amount of DOXO within the tumor cells leading to a significant inhibition of cell proliferation by enhancing the cytotoxicity of DOXO. We also provided in vivo evidence in a murine model of xenograft for a significant increase in the antitumor effect of DOX administered in combination with AIF-1. In fact, the % increase of tumor volume was 267% in control mice treated with vehicle and 148% after treatment with DOXO alone. The combination of DOX+AIF-1 led to only a slight increase of tumor volume (+13.4%, ns). This result clearly indicate that the antitumor activity of DOX is significantly potentiated by co-administration with AIF-1. In addition, our data show that treatment with DOX in combination with AIF-1 did not induce further toxicity compared to DOX alone.

Possible Applications

  • Our new molecule AIF-1 is therefore a potential drug that given in combination with DOXO would preserve the effectiveness of cancer therapy over time and reduce the dosage of chemotherapeutic and therefore its toxicity;
  • AIF-1 may be marketed as single drug or its fixed association in a medicinal product would allow to extend the patent for the chemotherapeutic already marketed.

Advantages

  • The activity of the anti-cancer agent DOXO results significantly enhanced when co-administred with AIF-1 in an in vivo model of non small cell lung cancer (NSCLC);
  • The new compound AIF1 results highly specific for MDR1 transporter;
  • The association of AIF1 with doxorubicin does not result to be further toxic as compared to doxorubicin alone in an in vivo model of non small cell lung (NSCLC).