ABSTRACT
BACKGROUND: Rapidly dividing tumor cells have an increased demand for nutrients to support their characteristic unabated growth; this demand is met by an increased availability of nutrients such as amino acids through vasculogenesis and by the enhanced cellular entry of nutrients through the upregulation of specific transporters. Deprivation of intracellular amino acids or block of amino acid uptake has been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft models. RESULTS: In this paper, we provide evidence that the two small molecule oxyphenisatine analogs TOP001 and TOP216 exert their anti-cancer effect by affecting tumor cell metabolism and inducing intracellular amino acid deprivation, leading to a block of cell proliferation. GCN2-mediated phosphorylation of eIF2α as well as mTOR pathway inhibition supports the above notion. In addition, these novel anti-cancer compounds inhibit DNA and protein synthesis and induce apoptosis in a broad spectrum of cancer cell lines. In vivo, the compounds induce tumor stasis and regression in mouse xenograft models of human breast, prostate, ovarian and pancreatic cancer, both when administered intravenously and orally. CONCLUSION: In conclusion, these small molecules, built on a 1,3-dihydroindole-2-one scaffold, elicit strong anti-proliferative and cytotoxic activity, and importantly, a strong anti-tumorigenicity is observed in in vivo xenograft models of human breast, ovary, prostate and pancreatic cancers encouraging the translation of this class of compounds into the clinic.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Neoplasms/drug therapy , Oxyphenisatin Acetate/analogs & derivatives , AMP-Activated Protein Kinase Kinases , Amino Acids/metabolism , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Caspases/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Energy Metabolism/drug effects , Female , Humans , Male , Mice , Mice, Nude , Neoplasms/metabolism , Oxyphenisatin Acetate/chemistry , Oxyphenisatin Acetate/pharmacology , Protein Kinases/metabolism , TOR Serine-Threonine Kinases/metabolism , Tumor Stem Cell Assay , Xenograft Model Antitumor AssaysABSTRACT
Syntheses and structure-antiproliferative relationship for oxyphenisatin analogues are described. The cell proliferation data showed that the presence of substituents (especially F, Cl, Me, CF(3), and OMe) in the 6- and 7-position of oxyphenisatin markedly enhanced the potency in the MDA-468 cell line without affecting the MDA-231 cell line. The best compounds from this series showed low nanomolar antiproliferative activity towards the MDA-468 cell line and a 1000-fold selectivity over the MDA-231 cell line.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Oxyphenisatin Acetate/analogs & derivatives , Oxyphenisatin Acetate/chemical synthesis , Oxyphenisatin Acetate/pharmacology , Humans , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Phenlaxine and bisacodyl were shown to inhibit gastric emptying and motility by activating a reflex arising from the small intestine. This effect produced by the cathartics could not be prevented either by alpha or beta sympatholytic, or by parasympatholytic agents; further it was antagonized by quinine and quinidine, as well as by chloroquine and mepacrine in doses found to suppress gastric motility in untreated animals. The inhibition of gastric motility through cathartics does not appear to be due to an effect on adrenergic or cholinergic pathways but rather to involve a purinergic mechanism.
Subject(s)
Cathartics/pharmacology , Purines/metabolism , Reflex/drug effects , Animals , Bisacodyl/pharmacology , Female , Gastrointestinal Motility/drug effects , Oxyphenisatin Acetate/analogs & derivatives , Oxyphenisatin Acetate/pharmacology , RatsSubject(s)
Cathartics/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Indoles/adverse effects , Oxyphenisatin Acetate/adverse effects , Chemical and Drug Induced Liver Injury/pathology , Female , Humans , Liver/drug effects , Liver/pathology , Male , Middle Aged , Oxyphenisatin Acetate/analogs & derivativesSubject(s)
Indoles/analogs & derivatives , Indoles/pharmacology , Intestinal Absorption/drug effects , Oxyphenisatin Acetate/analogs & derivatives , Oxyphenisatin Acetate/pharmacology , Animals , Bile/analysis , Colon/metabolism , Ileum/metabolism , Liver/metabolism , Oxyphenisatin Acetate/metabolism , RatsABSTRACT
The effectiveness of five laxatives - Dulcolax, Normacen, Laxadine, Dorbanex and Senokot in the bowel preparation of adult patients for radiological examinations has been compared. The value of using suppositories in addition to the tablets in those preparations that have tablet and suppository forms has also been assessed. The use of Dulcolax tablets plus suppository was most effective. Dulcolax, especially its suppository, was however very expensive and more frequently attended by side effects when compared with the other preparations. Normacen tablet was the second most effective and it is cheap and quite free of side effects. It is therefore given the position of first choice. Laxadine tablet plus its suppository was third best. It is cheap and free of side effects. Dorbanex was fourth best but it is rather expensive. Senokot tablet was the least effective but it is cheap and relatively free from side effects. In those laxatives with tablet and suppository forms, the use of both tablet and suppository is much more effective than the use of the tablet form alone.
