4--7-8-trihydroxyisoflavone and Colonic-Neoplasms

Isoflavones are a class of polyphenols that contain various substituents such as hydroxy, methoxy, and glycosyl groups. Methoxy groups are known to increase cell permeability and stability, but small structural changes can result in large differences in biological activity. In this study, the anticancer activities of several methoxy isoflavones were tested using a clonogenic survival assay. The relationship between structural properties of methoxy isoflavones and their anticancer activities on HCT116 colon cancer cell lines were studied quantitatively using comparative molecular field analysis and comparative molecular similarity indices analysis. The purpose of this study was to identify structural changes in isoflavones that increase the inhibitory effect on HCT116 colon cancer cell clonogenicity.

Topics: Antineoplastic Agents; Biological Assay; Cell Line, Tumor; Cell Proliferation; Cell Survival; Clone Cells; Colonic Neoplasms; Flavonoids; HCT116 Cells; Humans; Isoflavones; Models, Molecular; Molecular Structure

In this study, we evaluated the effects of 8-hydroxydaidzein (8HD), an isoflavone isolated from fermented soy germ koji, and epirubicin (Epi), an antineoplastic agent, on the production of reactive oxygen species (ROS). We subsequently correlated the ROS levels to the anticancer mechanisms of Epi and 8HD in human colon adenocarcinoma Caco-2 cells. 8HD enhanced cytotoxicity of Epi and generated a synergistic effect. Epi and/or 8HD treatments increased the hydrogen peroxide( )and( )superoxide levels. Combined treatment markedly decreased mRNA expression levels of multidrug resistance protein 1 (MDR1), MDR-associated protein (MRP) 1, and MRP2. 8HD significantly intensified Epi intracellular accumulation in Caco-2 cells. 8HD and/or Epi-induced apoptosis, as indicated by the reduced mitochondrial membrane potential and increased sub-G1 phase in cell cycle. Moreover, 8HD and Epi significantly enhanced the mRNA expressions of Bax, p53, caspases-3, -8, and -9. To our best knowledge, this study verifies for the first time that 8HD effectively circumvents MDR in Caco-2 cells through the ROS-dependent inhibition of efflux transporters and p53-mediated activation of both death receptor and mitochondrial pathways of apoptosis. Our findings of 8HD shed light on the future search for potential biotransformed isoflavones to intensify the cytotoxicity of anticancer drugs through simultaneous reversal of pump and nonpump resistance.

Topics: Adenocarcinoma; Caco-2 Cells; Caspases; Cell Death; Cell Proliferation; Colonic Neoplasms; DNA Fragmentation; Drug Synergism; Epirubicin; G1 Phase; Gene Expression Regulation, Neoplastic; Humans; Intracellular Space; Isoflavones; Membrane Potential, Mitochondrial; Models, Biological; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; RNA, Messenger