Tyrosine protein kinase inhibition and cancer

Boutin, Jean A.

doi:10.1016/0020-711x(94)90091-4

Cited by 64 publications

(30 citation statements)

References 165 publications

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“…Some isoflavones and flavones inhibit protein tyrosine kinases (26,27), which play important roles in cell signal transduction and the regulation of the cell cycle (Table 3). GEN is the most potent inhibitor.…”

Section: Postreceptor Activationmentioning

confidence: 99%

Cross-species and interassay comparisons of phytoestrogen action.

Whitten

Patisaul

2001

Environ Health Perspect

174

105

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This paper compiles animal and human data on the biologic effects and exposure levels of phytoestrogens in order to identify areas of research in which direct species comparisons can be made. In vitro and in vivo assays of phytoestrogen action and potency are reviewed and compared to actions, dose-response relationships, and estimates of exposure in human subjects. Binding studies show that the isoflavonoid phytoestrogens are high-affinity ligands for estrogen receptors (ERs), especially ER beta, but have lower potency in whole-cell assays, perhaps because of interactions with binding proteins. Many other enzymatic actions require concentrations higher than those normally seen in plasma. In vivo data show that phytoestrogens have a wide range of biologic effects at doses and plasma concentrations seen with normal human diets. Significant in vivoresponses have been observed in animal and human tests for bone, breast, ovary, pituitary, vasculature, prostate, and serum lipids. The doses reported to be biologically active in humans (0.4--10 mg/kg body weight/day) are lower than the doses generally reported to be active in rodents (10--100 mg/kg body weight/day), although some studies have reported rodent responses at lower doses. However, available estimates of bioavailability and peak plasma levels in rodents and humans are more similar. Steroidogenesis and the hypothalamic-pituitary-gonadal axis appear to be important loci of phytoestrogen actions, but these inferences must be tentative because good dose-response data are not available for many end points. The similarity of reported proliferative and antiproliferative doses illustrates the need for fuller examination of dose-response relationships and multiple end points in assessing phytoestrogen actions.

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Section: Postreceptor Activationmentioning

confidence: 99%

Cross-species and interassay comparisons of phytoestrogen action.

Whitten

Patisaul

2001

Environ Health Perspect

174

105

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“…They are believed to possess properties capable of potential protection against carcinogenesis [57] and have long been known to interact with various kinases at the ATP-binding site [58]. Flavone acetic acid, genistein, and quercetin, whose structures are presented in Fig. The isolation from the stem bark of Dysoxylum binectariferum and the total synthesis of a compound [60] previously described as rohitukine [61,62], enabled the synthesis of flavopiridol and its analogues [38], summarised in Fig.…”

Section: Flavonoidsmentioning

confidence: 99%

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Fischer

Lane²

2000

CMC

141

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Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell growth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anticancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cystostatic drugs. Numerous active-site inhibitors of CDKs have been studied; the main limitation with these ATP antagonists is kinase specificity for CDKs. However, screening of compound collections, as well as rational design based on enzyme-ligand complex crystal structures, are now yielding pre-clinical candidates, particularly certain purine and flavonoid analogues, with impressive potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour suppressor gene products p16 INK4 , p21 WAF1 , and p27 KIP1 , form the starting point for the design of mechanism-based CDK inhibitors. A number of these small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these peptides into pharmaceutically useful molecules is greatly aided by the recent elucidation of CKI/CDK crystal and solution structures. Additional interaction sites on CDKs being exploited for the purposes of inhibitor design include: phosphorylation/dephosphorylation sites, macromolecular substrate binding site, CKS regulatory subunit binding sites, cyclin-binding site, cellular localisation domain, and destruction box. Finally, progress has recently been made in the application of antisense technology in order to target CDK activity.

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“…These compounds include the flavinoid, quercetin, the isoflavinoid, genistein, the antibiotic herbimycin A, and erbstatin (Boutin, 1994;Casnellie, 1991;Chang and Geahlen, 1992). Although these compounds can revert cells transformed by tyrosine kinase oncogenes to a nontransformed phenotype, none of these compounds have demonstrated specificity among tyrosine kinases.…”

Section: Development Of Imatinib (Sti571)mentioning

confidence: 99%