Intermediate Biomarkers

Kosmeder, Jerome W.; Pezzuto, John M.

doi:10.1007/978-1-4615-1657-6_2

“…As distinct cell types, by definition, have homeostatic regulatory processes, this finding is not surprising. These points should be carefully considered in the interpretation of molecular biomarkers of efficacy, typically used in the conduct of human cancer chemoprevention trials (46). A failure to consider this possibility may wrongly lead one to conclude that a given chemopreventive agent is inducing an ''undesirable'' molecular phenotype, when in fact it is actually inhibiting the process being targeted.…”

Section: Discussionmentioning

confidence: 99%

Dietary Genistein Inhibits Metastasis of Human Prostate Cancer in Mice

Lakshman¹,

Xu²,

Ananthanarayanan

³

et al. 2008

View full text Add to dashboard Cite

Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in >80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 MAPK, and HSP27 ''promotility'' proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way.

show abstract

“…The panels of in vitro bioassays used for the discovery of potential cancer chemopreventive drugs include screening assays that are usually enzyme-or cell-based assays [25], [28]. These assays are adapted to high-throughput measurement techniques performed relatively rapidly in order to uncover the biological properties of a large number of candidate substances [25], [28].…”

Section: Overview Of Cancer Chemoprevention Trials Involving Phytochementioning

confidence: 99%

Natural Inhibitors of Carcinogenesis

Kinghorn

¹

,

Su

²

,

Dae

³

et al. 2004

Self Cite

View full text Add to dashboard Cite

Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4¢-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of previously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structureactivity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay, when used as a secondary discriminator in our work. The-2,4,2¢,4¢-tetrahydroxychalcone 11¢-O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents.

show abstract

“…The panels of in vitro bioassays used for the discovery of potential cancer chemopreventive drugs include screening assays that are usually enzyme-or cell-based assays [25], [28]. These assays are adapted to high-throughput measurement techniques performed relatively rapidly in order to uncover the biological properties of a large number of candidate substances [25], [28].…”

Section: Overview Of Cancer Chemoprevention Trials Involving Phytochementioning

confidence: 99%

“…These assays are adapted to high-throughput measurement techniques performed relatively rapidly in order to uncover the biological properties of a large number of candidate substances [25], [28]. The initial bioassays afford a strategic framework for the evaluation of agents according to defined criteria, and to provide evidence of agent efficacy, and serve to generate valuable dose-response, toxicity, and pharmacokinetic data required prior to phase I clinical safety testing [25], [28], [29].…”

Section: Overview Of Cancer Chemoprevention Trials Involving Phytochementioning

confidence: 99%

Untitled

2004

Planta Med

0

View full text Add to dashboard Cite

Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4¢-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of previously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structureactivity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay, when used as a secondary discriminator in our work. The-2,4,2¢,4¢-tetrahydroxychalcone 11¢-O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents.

show abstract

Intermediate Biomarkers

Cited by 5 publications

References 214 publications

Dietary Genistein Inhibits Metastasis of Human Prostate Cancer in Mice

Dietary Genistein Inhibits Metastasis of Human Prostate Cancer in Mice

Natural Inhibitors of Carcinogenesis

Untitled

Contact Info

Product

Resources

About