The Effects of Forodesine in Murine and Human Multiple Myeloma Cells

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.

559 Preferential Allocation and Inducible Calcium Sinks in Leaf Primordia of Dracaena sanderiana Hort. Sander ex M.T. Mast (Dracaenaceae)

We induced preferential allocation of Ca to two calcium oxalate (CO) sinks in immature leaf tissues of D. sanderiana: subepidermal extracellular deposits and intracellular raphides. Allocation was affected by exogenous Ca levels. Two groups of rooted cuttings were termed Ca-deficient and non-deficient. The first group consisted of cuttings that had been deprived of Ca for 18 months, and, the second, cuttings rooted under standard horticultural conditions. All plants were grown in liquid medium supplemented with 100 ppm of potassium nitrate and subjected to 0, 3, or 7mm Ca from calcium acetate. The most striking feature of Ca-deficient plants grown in 0 mm Ca was the absence of intracellular raphides in the leaf primordia. The largest number of intracellular raphides developed in Ca-deficient plants grown in 7 mm Ca. The number of extracellular crystals in Ca-deficient plants grown in Ca-supplemented solutions versus non-supplemented were similar, but crystals were considerably smaller in non-supplemented plants. Total number of extracellular crystals per epidermal cell did not differ significantly between plants in all treatments. This implies that nucleation sites are pre-determined and finite in number. In contrast, the number of intracellular raphides was highly variable. In terms of Ca prioritization, the extracellular crystals took precedence over intracellular raphides, and this was most obvious in Ca-deficient plants. The significance of this research is that the extracellular crystals represent Ca sinks with limited induction capacity compared to intracellular Ca sinks. Plants with genetic predisposition for intracellular CO crystal formation may be able to respond favorably to root environments with low Ca levels compared to species with limited capacity for intracellular CO deposition. Intracellular CO crystals, therefore, play an integral role in plant nutrition as Ca storage sinks.