Development of gallium compounds for treatment of lymphoma: Gallium maltolate, a novel hydroxypyrone gallium compound, induces apoptosis and circumvents lymphoma cell resistance to gallium nitrate
ABSTRACT Clinical studies have shown gallium nitrate to have significant antitumor activity against non-Hodgkin's lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents. In this study, we compared the cytotoxicity of gallium maltolate, a novel gallium compound, with gallium nitrate in lymphoma cell lines, including p53 variant and unique gallium nitrate-resistant cells. We found that gallium maltolate inhibited cell proliferation and induced apoptosis through the mitochondrial pathway at lower concentrations and more rapidly than gallium nitrate. Gallium maltolate produced an increase in intracellular reactive oxygen species (ROS) within 2 h of incubation with cells; this effect could be blocked by mitoquinone, a mitochondria-targeted antioxidant. The role of the transferrin receptor (TfR) in gallium maltolate's action was examined using monoclonal antibody (MoAb) 42/6 to block TfR function. However, although MoAb 42/6 reduced gallium maltolate-induced caspase-3 activity, it had only a minor effect on cell growth inhibition. Importantly, gallium maltolate induced apoptosis in cells resistant to gallium nitrate, and, unlike gallium nitrate, its cytotoxicity was not affected by cellular p53 status. Cellular gallium uptake was greater with gallium maltolate than with gallium nitrate. We conclude that gallium maltolate inhibits cell proliferation and induces apoptosis more efficiently than gallium nitrate. Gallium maltolate is incorporated into lymphoma cells to a greater extent than gallium nitrate via both TfR-independent and -dependent pathways; it has significant activity against gallium nitrate-resistant cells and acts independently of p53. Further studies to evaluate its antineoplastic activity in vivo are warranted.
SourceAvailable from: Amir Hakimi[Show abstract] [Hide abstract]
ABSTRACT: 177 Lu-maltolate (177 Lu-MAL) was successfully developed which can be widely used in bone palliation therapy. At optimized conditions a radiochemical purity of about[99 % was obtained for 177 Lu-MAL shown by ITLC (specific activity, 970–1,000 MBq/mmole). Biodistribution studies of 177 Lu chloride and 177 Lu-MAL were carried out in wild-type rats comparing the critical organ uptakes. Compartmental analysis was used to determine temporal biodistribution model of 177 Lu-MAL in different organs. 177 Lu-MAL is a possible therapeutic agent in human malignancies for the bone palliation therapy so the efficacy of the compound should be tested in various animal models.Journal of Radioanalytical and Nuclear Chemistry 01/2015; 303(1):1-10. DOI:10.1007/s10967-014-3603-2 · 1.42 Impact Factor
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ABSTRACT: Metal-based coordination compounds have been used throughout the history of human medicine to treat various diseases, including cancer. Since the discovery of cisplatin in 1965, a great number of metal coordination complexes, such as platinum, ruthenium, gold or copper have been designed, synthesized and tested in order to develop clinically effective and safe drugs. Currently, many reviews cover applications of cytostatic metal complexes pointing out the most promising examples of platinum- and non-platinum-based compounds in preclinical and clinical trials. However, recent comprehensive reviews covering chemical and biological aspects of metal-based coordination compounds in cancer therapy are still rare. In this review we wish to provide an overview of the coordination chemistry of current and novel cytostatic compounds, including an outline of their design and rationale of synthesis, and summarize bio-chemical reactivity and physicochemical properties of candidate metal complexes.Journal of applied biomedicine 03/2015; 13(2). DOI:10.1016/j.jab.2015.03.003 · 1.78 Impact Factor