The relationship between the physicochemical properties and the biological effects of alloxan and several N-alkyl substituted alloxan derivatives

Munday, Rex; Ludwig, Kurt S.; Lenzen, Sigurd

doi:10.1677/joe.0.1390153

Cited by 27 publications

(21 citation statements)

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“…It causes b-cell destruction by a mechanism involving free radical formation (Munday 1988, Munday et al 1993, Lenzen 2008. We observed significant reductions in tumor growth following alloxan exposure or with insulin/IGF1R family kinase inhibition, but not by metformin.…”

Section: Introductionmentioning

confidence: 67%

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer

Dool¹,

Mashhedi²,

Zakikhani³

et al. 2011

Endocrine-Related Cancer

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Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IR family tyrosine kinase activity and insulin deficiency have antineoplastic activity in a model of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers insulin levels only in settings of hyperinsulinemia, had minimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical.

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Section: Introductionmentioning

confidence: 67%

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer

Dool¹,

Mashhedi²,

Zakikhani³

et al. 2011

Endocrine-Related Cancer

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“…GK inhibition was specific to glucosensing neurons because the inhibitors had no effect on NG neurons, which presumably utilize hexokinase I to mediate glycolysis (40). Although alloxan is probably the most selective GK inhibitor (24,25), it can also produce toxicity by generation of free radicals (48). However, the doses and exposure times used here produced no toxicity.…”

Section: Diabetes Vol 51 July 2002mentioning

confidence: 85%

Glucokinase Is the Likely Mediator of Glucosensing in Both Glucose-Excited and Glucose-Inhibited Central Neurons

et al. 2002

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Specialized neurons utilize glucose as a signaling molecule to alter their firing rate. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons reduce activity as ambient glucose levels rise. Glucoseinduced changes in the ATP-to-ADP ratio in GE neurons modulate the activity of the ATP-sensitive K ؉ channel, which determines the rate of cell firing. The GI glucosensing mechanism is unknown. We postulated that glucokinase (GK), a high-Michaelis constant (K m ) hexokinase expressed in brain areas containing populations of GE and GI neurons, is the controlling step in glucosensing. Double-label in situ hybridization demonstrated neuron-specific GK mRNA expression in locus ceruleus norepinephrine and in hypothalamic neuropeptide Y, pro-opiomelanocortin, and ␥-aminobutyric acid neurons, but it did not demonstrate this expression in orexin neurons. GK mRNA was also found in the area postrema/nucleus tractus solitarius region by RT-PCR. Intracarotid glucose infusions stimulated c-fos expression in the same areas that expressed GK. At 2.5 mmol/l glucose, fura-2 Ca 2؉ imaging of dissociated ventromedial hypothalamic nucleus neurons demonstrated GE neurons whose intracellular Ca 2؉ oscillations were inhibited and GI neurons whose Ca 2؉ oscillations were stimulated by four selective GK inhibitors. Finally, GK expression was increased in rats with impaired central glucosensing (posthypoglycemia and diet-induced obesity) but was unaffected by a 48-h fast. These data suggest a critical role for GK as a regulator of glucosensing in both GE and GI neurons in the brain. S pecialized neurons utilize glucose as a signaling molecule rather than as an energy substrate. Glucose-excited (GE) neurons increase, whereas glucose-inhibited (GI) neurons decrease, their firing rate as ambient glucose levels rise (1-3). It is unclear how GI neurons sense glucose, but GE neurons function much like the pancreatic ␤-cell, which utilizes the ATPsensitive K ϩ (K ATP ) channel to sense glucose and regulate insulin secretion (2-7). Although many neurons contain K ATP channels, few exhibit glucosensing properties (8,9). This makes control of glycolysis a major candidate as a regulator of ATP production and K ATP channel activity (6). The pancreatic form of glucokinase (GK; hexokinase IV, ATP:D-glucose 6-phosphotransferase) is selectively expressed in brain areas where glucosensing neurons reside (5,10 -12). GK has the physiological properties that would make it an ideal regulator of glucosensing in neurons (6,13). Previous studies examined a role for GK in hypothalamic glucosensing neurons in brain slice preparations, where presynaptic inputs could not be excluded, and under conditions outside the physiological range of brain glucose (4,5). The current studies provide new data on the neurotransmitter and peptide phenotype of neurons expressing GK, the regulatory role of GK in isolated hypothalamic GE and GI neuron activity, and the in vivo conditions associated with altered brain GK expression. RESEARCH DESIGN AND METHODSAnimals. All ...

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“…N-substituted alloxan derivatives with a long carbon side chain, such as butylalloxan ( Fig. 2), differ chemically from alloxan in that they are lipophilic [36]. Butylalloxan acts in a similar manner to alloxan and preferentially damages beta cells [6,11].…”

Section: Beta Cell Selectivity Of Alloxanmentioning

confidence: 99%

The mechanisms of alloxan- and streptozotocin-induced diabetes

2007

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Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive oxygen species (ROS) in a cyclic redox reaction with its reduction product, dialuric acid. Autoxidation of dialuric acid generates superoxide radicals, hydrogen peroxide and, in a final iron-catalysed reaction step, hydroxyl radicals. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent 'alloxan diabetes'. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Following its uptake into the beta cells, streptozotocin is split into its glucose and methylnitrosourea moiety. Owing to its alkylating properties, the latter modifies biological macromolecules, fragments DNA and destroys the beta cells, causing a state of insulin-dependent diabetes. The targeting of mitochondrial DNA, thereby impairing the signalling function of beta cell mitochondrial metabolism, also explains how streptozotocin is able to inhibit glucose-induced insulin secretion.

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The relationship between the physicochemical properties and the biological effects of alloxan and several N-alkyl substituted alloxan derivatives

Cited by 27 publications

References 0 publications

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer

Glucokinase Is the Likely Mediator of Glucosensing in Both Glucose-Excited and Glucose-Inhibited Central Neurons

The mechanisms of alloxan- and streptozotocin-induced diabetes

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