The role of the intrinsic FAS pathway in Titanocene Y apoptosis: The mechanism of overcoming multiple drug resistance in malignant leukemia cells

Despite the advantages in the outcome of patients with acute lymphoblastic leukemia, 25% of the affected children suffer relapses. As the response to chemotherapy is essentially determined by the development of cellular drug resistance, new drugs that are capable to overcome resistance to conventional chemotherapeutics are urgently needed. With regard to this demand, we investigated the titanium-based anticancer drug Titanocene Y. Treatment with Titanocene Y leads to inhibition of tumour cell proliferation and induces apoptosis in established cell lines of leukemia, lymphoma and melanoma. The extrinsic pathway appears to be responsible, at least in part, for the effect: cell death is partly inhibited in BJAB cells overexpressing a dominant negative Fas-associated death domain (FADD) mutant and via real time PCR we found a significant up-regulation of Fan ligand in the affected cells. Apoptosis is triggered regardless of the expression of anti-apoptotic Bcl-2 and pro-apoptotic smac and the agent is also effective on cells that are multidrug resistant due to overexpression of P-gp. In combination with vincristine impressive synergistic effects could be observed, exposing Titanocene Y as a possible component for polychemotherapy. Taken together, Titanocene Y turns out to be a promising candidate for anti-tumour therapy, especially for the treatment of multidrug resistant malignancies. (C) 2011 Elsevier Ltd. All rights reserved.