Abstract
Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy, characterized by a monoclonal proliferation of malignant cells in the bone marrow. Despite recent advances in treatment strategies, MM remains incurable and new therapeutical targets are needed. Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels. We therefore tested whether forodesine was able to inhibit proliferation and/or induce apoptosis in both murine and human MM cells through a similar pathway. We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis. When investigating the pathways leading to cell cycle arrest and apoptosis, we observed an upregulation of p27, caspase 3, and BIM. We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells. Forodesine might be however potentiating towards other established cytotoxic drugs in MM.
Highlights
Multiple myeloma (MM) is the second most prevalent hematological malignancy, accounting for 1% of all cancers
We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis
We examined the effects of forodesine on the dGTP levels as well as proliferation and apoptosis of the MM cells, compared to a T-cell acute lymphoblastic leukemia (T-ALL) line, the MOLT-4 line
Summary
Multiple myeloma (MM) is the second most prevalent hematological malignancy, accounting for 1% of all cancers. Forodesine has been shown to induce apoptosis in vitro in several malignant T-cell lines, such as T-cell acute lymphoblastic leukemia (T-ALL) [5], and B-cell lines, such as B-cell acute lymphoblastic leukemia [9] and B-cell chronic lymphocytic leukemia (B-CLL) [6, 7] It is Advances in Hematology currently being tested in phase I/II clinical trials for patients with these malignancies [10,11,12,13,14,15]. As forodesine is more potent than the first-line PNAs and blocks proliferation through a different pathway, we tested its activity in MM cells in vitro For this we used both the murine 5T33MM cells as well as the human RPMI-8226 cells. We investigated the signaling pathways which lead to apoptosis and cell cycle arrest
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