Anti‑proliferative effect of ridaifen‑B on hepatoma cells

Abstract

Abstract. Ridaifens (RIDs), a novel series of tamoxifen derivatives, exhibit a potent growth-inhibitory effect against numerous tumor cells regardless of the expression of estrogen receptors, and are thus promising candidates as novel anti-tumor drugs. RID-B is a first generation RIDs, and inhibits the proliferation of several tumor cell lines. However, the potentially growth inhibitory effect of RID-B against hepatoma cells, and the detailed mechanism underlying RID-B-mediated tumor cell death remain to be elucidated. The purpose of the current study was to evaluate the anti-proliferative effect of RID-B against hepatoma cells. The anti-proliferative effect of RID-B against human hepatoma Huh-7 cells was investigated by cell proliferation assay using WST-1 reagent, and caspase-3 activity was evaluated by using specific fluorescent substrate. In addition, DNA fragmentation in Huh-7 cells induced by RID-B was estimated by terminal deoxynucleotidyl transferase dUTP nick-end labelling assay, and binding of RID-B to double-stranded DNA was confirmed by mass spectrometry. RID-B (0.5, 1 and 2 µM) inhibited the growth of Huh-7 cells, seemingly dose-dependently, but did not inhibit the growth of normal primary rat hepatocytes in the same concentration range. Furthermore, the caspase-3 activity of Huh-7 cells was increased by RID-B (0.5 and 5 µM), and the anti-proliferative effect of RID-B (1 µM) on Huh-7 cells was partially suppressed by the addition of the caspase inhibitor, Z-VAD-FMK. Additionally, RID-B (10 µM) directly bound to double-stranded DNA, and the addition of DNA suppressed RID-B-mediated cell growth inhibition and DNA fragmentation in Huh-7 cells. From these data, it may be concluded that RID-B inhibited cell growth and induced apoptosis via activating caspase-3 and binding to DNA directly, leading to DNA fragmentation in hepatoma cells.

Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER‐positive and Triple‐Negative Breast Cancer Cell Lines

“…The exact amount of tested analogues that could pass the cell membrane, the exact amount of esterases in MCF-7 cell lines are both factors that should be considered on evaluation of compound activities. Compounds bearing propyl ester (14,16,22) or decyl ester (15,23,25) were almost equipotent on MCF-7 cell line; our preliminary assumption was that the difference in ester side chain and therefore its lipophilicity will affect both the compound hydrolysis rate by esterases, its cellular uptake and retention as well. Table 4 Compounds 8-13 bearing bis-aminoalkoxy substituent on rings B and C were selected by NCI for screening.…”

“…[19,20] RID analogues work via noncovalent and nonpeptidic proteasome inhibition, and therefore are promising candidates in TNBC and other cancer types. [20][21][22] Herein we report twenty-five flexible triphenylethylene analogues. Compounds are designed to bypass CYP2D6 metabolism and are alternatively metabolized to the more potent hydroxy metabolite via esterases.…”

“…TNBC lack these three molecular markers, the clinical outcome is affected significantly by the expression of these three markers [19,20] . RID analogues work via noncovalent and nonpeptidic proteasome inhibition, and therefore are promising candidates in TNBC and other cancer types [20–22] …”