Efficacy Of Conventional Chemotherapeutic Agents Research Articles

Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1: MAPPING THE SITE OF BINDING

In brain and tumor cells, the hexokinase isoforms HK-I and HK-II bind to the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. We have previously shown that HK-I decreases murine VDAC1 (mVDAC1) channel conductance, inhibits cytochrome c release, and protects against apoptotic cell death. Now, we define mVDAC1 residues, found in two cytoplasmic domains, involved in the interaction with HK-I. Protection against cell death by HK-I, as induced by overexpression of native or mutated mVDAC1, served to identify the mVDAC1 amino acids required for interaction with HK-I. HK-I binding to mVDAC1 either in isolated mitochondria or reconstituted in a bilayer was inhibited upon mutation of specific VDAC1 residues. HK-I anti-apoptotic activity was also diminished upon mutation of these amino acids. HK-I-mediated inhibition of cytochrome c release induced by staurosporine was also diminished in cells expressing VDAC1 mutants. Our results thus offer new insights into the mechanism by which HK-I promotes tumor cell survival via inhibition of cytochrome c release through HK-I binding to VDAC1. These results, moreover, point to VDAC1 as a key player in mitochondrially mediated apoptosis and implicate an HK-I-VDAC1 interaction in the regulation of apoptosis. Finally, these findings suggest that interference with the binding of HK-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents.

The Therapeutic Potential of Gallium-Based Complexes in Anti-Tumor Drug Design

The investigation of metal-containing drugs over several decades has set out to improve upon the toxicity and efficacy of conventional chemotherapeutic agents. Promising pre-clinical and clinical data have fostered the broadening for the search of metal compounds in cancer treatment and combination therapy. Gallium is only second to platinum in terms of anti-tumor activity. Its subsequent investigation has been ongoing for nearly three decades, primarily in the form of salts, and more recently coordinated to organic ligands as coordination complexes. From its early investigation as a diagnostic agent to its anti-tumor potential, promising clinical results have shown a renewed interest in exploring gallium in a host of malignancies, especially lymphoma and bladder cancer. However, the detailed mechanisms of action of gallium compounds are not completely defined. Further understanding the underlying mechanisms along with optimizing the structural components of gallium complexes will further improve the therapeutic index of gallium. Keywords: Gallium, Gallium Complexes, Drug design, Drug discovery, Metal complexes, Ligands

Activation of Glycogen Synthase Kinase 3β Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity

Transformed cells are highly glycolytic and overexpress hexokinase II (HXK II). HXK II is capable of binding to the mitochondria through an interaction with the voltage-dependent anion channel (VDAC), an abundant outer mitochondrial membrane protein. The binding of HXK II to mitochondria has been shown to protect against loss of cell viability. Akt activation inhibits apoptosis partly by promoting the binding of HXK II to the mitochondria, but the mechanism through which Akt accomplishes this has not been characterized. The present report shows that Akt mediates the binding of HXK II to the mitochondria by negatively regulating the activity of glycogen synthase kinase 3beta (GSK3beta). On inhibition of Akt, GSK3beta is activated and phosphorylates VDAC. HXK II is unable to bind VDAC phosphorylated by GSK3beta and dissociates from the mitochondria. Inhibition of Akt potentiates chemotherapy-induced cytotoxicity, an effect that is dependent on GSK3beta activation and its attendant ability to disrupt the binding of HXK II to the mitochondria. Moreover, agents that can force the detachment of HXK II from mitochondria in the absence of Akt inhibition or GSK3beta activation promoted a synergistic increase in cell killing when used in conjunction with chemotherapeutic drugs. Such findings indicate that interference with the binding of HXK II to mitochondria may be a practicable modality by which to potentiate the efficacy of conventional chemotherapeutic agents.