Science et thérapie du cancer

Role of Leptomycin in p53 Induced Apoptosis

Abstract

Siva Chandran Ramakrishna

Purpose: Leptomycin B [LMB] is an anti fungal metabolite which was tested for anti cancer activity, but failed in clinical trials due to non specific killing at higher concentrations. Leptomycin B acts on CRM1, a nuclear export protein that exports p53 out of the nucleus. Leptomycin B blocks CRM1, hence leading to sequestration of p53 in the nucleus, which in turn leads to apoptosis. DR5 antibody is one of the most successful compounds being used in the market for cancer therapy. In this project, Leptomycin B is combined with DR5 [dual treatment] and tested on PC3, LNCAP and MCF7 cells to find out whether leptomycin B increases the percentage of apoptotic cells. This project aims at testing leptomycin B on PC3 cells which are p53 null mutants, and to find out the expression levels of p53 related genes using RT-PCR. Nutlin 3a, a MDM2 antagonist is also combined with dual treatment to check whether there is increased apoptosis.

Results: Leptomycin induced apoptosis in PC3 cells [p53 null mutants] even at lower concentrations. Dual treatment showed an increased percentage in apoptotic cells when compared to DR5 alone treatment. Nutlin was also found to induce apoptosis in PC3 cells.

Conclusion: Leptomycin B and Nutlin 3a induce p53 independent apoptosis. Dual treatment can be considered for further trials for better killing of cancer cells