ABSTRACT
Thieno analogues of kenpaullone have been synthesized using an established method. We investigated the effect of five structural analogues of kenpaullone on vincristine sensitive and resistant MCF7 (human mammary adenocarcinoma) cells. One analogue, 8-Bromo-6,11-dihydro-thieno-[3',2':2,3]azepino[4,5-b]indol-5(4H)-one (3a), showed an antiproliferative activity in the drug sensitive cell line that led to cell accumulation in G2/M phase. In addition, repression of cdk1, a G2/M transition key regulator, as well as induction of p21 were observed at the mRNA level. Programmed cell death (apoptosis) was induced in early time treatments and was accompanied by p53 mRNA induction. The antiproliferative and proapoptotic properties of 3a make this CDK inhibitor an interesting candidate for further investigations.
Subject(s)
Benzazepines/chemistry , Benzazepines/therapeutic use , Breast Neoplasms/drug therapy , Indoles/chemistry , Indoles/therapeutic use , Thiophenes/chemistry , Thiophenes/therapeutic use , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , HumansABSTRACT
There is increasing evidence that bisphosphonates have direct antitumor effects in vivo in addition to their therapeutic antiresorptive properties. Bisphosphonates inhibit proliferation and induce apoptosis of many cancer cell lines. They also exhibit anti-invasive properties in vitro and in vivo. We have previously shown that a novel non-nitrogen-containing bisphosphonate inhibited tumor growth of A431 human epidermoid carcinoma cells. In the present study, we investigated the antitumor properties of three nitrogen-containing bisphosphonates on A431 cells in vitro. We first compared the antiproliferative effects of pamidronate, alendronate and neridronate. Then, by matrigel invasion assay, the effect of alendronate on A431 cell invasiveness was studied. All three bisphosphonates were found to inhibit cell proliferation dose- and time-dependently. The most potent molecule was alendronate. The invasion test demonstrated that alendronate also inhibited cell invasion in a Boyden chamber. These data suggest that alendronate may have beneficial effects in the treatment of carcinomas exhibiting important angiogenesis.
Subject(s)
Alendronate/pharmacology , Carcinoma, Squamous Cell/drug therapy , Vulvar Neoplasms/drug therapy , Carcinoma, Squamous Cell/pathology , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Diphosphonates/pharmacology , Dose-Response Relationship, Drug , Female , Growth Inhibitors/pharmacology , Humans , Neoplasm Invasiveness , Pamidronate , Vulvar Neoplasms/pathologyABSTRACT
An efficient synthetic method of nucleoside-5'-(1-hydroxymethylene-1,1-bisphosphonates) is reported here. The procedure was optimized with 3'-protected thymidine and then applied to synthesis of new AZT analogues.
