7-(O)-Carboxymethyl daidzein conjugated to N-t-Boc-hexylenediamine: a novel compound capable of inducing cell death in epithelial ovarian cancer stem cells.
One of the major difficulties in the treatment of epithelial ovarian cancer (EOC) is the high rate of recurrent disease. This is thought to be due to the survival of a population of chemo-resistant cells within the tumor, the ovarian cancer stem cells (OCSCs), that are able to regenerate the tumor following chemotherapy. Therefore, the identification of a compund that can target the OCSCs is one of the main steps in improving overall survival of ovarian cancer patients. The objective of this study was to determine the effect of N-t-boc-Daidzein, a novel daidzain derivative, on OCSCs. The efficacy of this compound was evaluated in OCSC and mature ovarian cancer cell (mOCC) lines isolated from malignant ovarian cancer asicites. Cells were treated with increasing concentrations of N-t-boc-Daidzein (0.003-10 microM) and cell growth was monitored by "real time in vitro micro-imaging" using the IncuCyte system. Cell viability was measured using the CellTiter 96 Assay. Apoptosis was determined by Caspase-Glo 3/7, 8 and 9 assays. The components of the apoptotic cascade were characterized by western blot analysis. N-t-boc-Daidzein was able to significantly inhibit cell growth and decrease cell viability of OCSC as well as mOCC cells in a dose and time dependent maner. This effect was due to the induction of apoptosis, which is characterized by caspase activation, XIAP and AKT degradation, and mitochondrial depolarization. This study describes a novel compound that can target the OCSCs. These findings may provide vital aide in improving overall survival in patients with EOC.
Green
Jamie M
JM
Department of Obstetrics and Gynecology and Reproductive Science, Yale University School of Medicine, New Haven, CT 06520, USA.
Alvero
Ayesha B
AB
Kohen
Fortune
F
Mor
Gil
G
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
C527125:5-(2-(3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yloxy)acetylamino)hexylcarbamic acid tert-butyl ester; D002219:Carbamates; D002867:Chromones; D007529:Isoflavones; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C004742:daidzein; D051058:Oncogene Protein v-akt; D020169:Caspases