Study of the effect of FKBP12 inhibitors on cancer cell apoptosis

A growing number of evidence support the view that FK506 binding proteins (FKBPs) play a role in cancer survival and chemoresistance. A hyper-expression of FKBP12 was found associated with aggressive phenotype of childhood astrocytoma and FKBP51 has been found involved in proliferation of normal megakaryoblasts independent of growth factors, in idiopathic myelofibrosis. Previous studies from our laboratory showed that rapamycin can either overcome resistance to doxorubicin in human melanoma and increase anthracycline-induced apoptosis of primary acute lymphoblastic leukemia cells, by specifically inhibiting FKBP51. Among the multiple biological functions of FKBPs, the control of transforming growth factor (TGF)-beta signaling exerted by FKBP12 appears of particular interest in anticancer research. Indeed, a failure in transduction of TGF-beta signal has been extensively found involved in tumorigenesis, cancer aggressiveness and low response to the treatment. In most solid tumours molecular alterations of components of TGF-beta signal transduction pathway have been found, whereas in the majority of leukemias and lymphomas components of TGF-beta signaling pathway are generally intact, therefore an alteration of regulatory steps of this pathway is likely to occur. An over-activation of TGF-beta signaling was found in fibroblasts from FKBP12 deficient mice. This finding prompted us to investigate if a rescue of TGF-beta apoptotic response can be obtained by inhibiting or downmodulating FKBP12 in tumor cells. As cancer model we choose B Cell Chronic Lymphocytic Leukemia (BCLL) as it is a disorder characterized by progressive loss of response to TGF-beta and defective apoptosis. Actually the treatment is not curative, therefore new therapeutic strategies deserve examination. Preliminary results from our laboratory indicate that FK506 can induce apoptosis of BCLL cells whereas another immunosuppressant, cyclosporin A, a specific inhibitor of cyclophilin A, did not display the same effect. Moreover, we found that FK506 increased apoptosis induced by vincristine in BCLL samples. This data is encouraging in that envisions that TGF-beta resistance can be overcome, in certain tumours, by inactivating FKBP12.