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.

Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells

“…Consistent with our recent report [32], 100 µM gallium nitrate produced only a minor increase in caspase-3 activity when compared with control cells incubated without gallium nitrate. With the addition of NAC to the incubation there was an approximately 3-fold increase in caspase-3 activity ( Figure 4B).…”

Cellular uptake and anticancer activity of carboxylated gallium corroles

“…The uptake, intracellular accumulation, and potency (IC 50 ) varied by compound: carboxylated derivatives 3 and 4 augmented cell permeability, as revealed by enhanced uptake rates, and increased intracellular accumulation, resulting in higher potency compared with 1 and 2. The carboxylated corroles exhibited strong cytotoxic effects in prostate, melanoma, breast, and ovarian cancer cells; the effective cytotoxic dose (<20 μM) was lower than that of a widely used chemotherapeutic agent, cisplatin (45,46), as well as those of other gallium compounds under study as therapeutic agents (54)(55)(56). Compound 4 was exceptionally active as a cytotoxic agent against melanoma SK-MEL-28 cells (IC 50 = 4.8 μM); notably, >99% of cells exhibited intracellular corrole accumulation within 15 min.…”

Comparative solution equilibrium studies of anticancer gallium(III) complexes of 8-hydroxyquinoline and hydroxy(thio)pyrone ligands

“…Promising compounds are found to be the six-coordinate [1,2]. Both complexes can be administered orally, exhibit moderate side effects and can overcome Ga(III) nitrate resistance [3,7,8].…”