Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in hepatocellular carcinoma HepG2 cells

Abstract

Despite their strong role in human health, poor bioavailability of flavonoids limits their biological effects in vivo. Enzymatically catalyzed acylation of fatty acids to flavonoids is one of the approaches of increasing cellular permeability and hence, biological activities. In this study, six long chain fatty acid esters of quercetin-3-O-glucoside (Q3G) acylated enzymatically and were used for determining their antiproliferative action in hepatocellular carcinoma cells (HepG2) in comparison to precursor compounds and two chemotherapy drugs (Sorafenib and Cisplatin). Fatty acid esters of Q3G showed significant inhibition of HepG2 cell proliferation by 85 to 90% after 6 h and 24 h of treatment, respectively. The cell death due to these novel compounds was associated with cell-cycle arrest in S-phase and apoptosis observed by DNA fragmentation, fluorescent microscopy and elevated caspase-3 activity and strong DNA topoisomerase II inhibition. Interestingly, Q3G esters showed significantly low toxicity to normal liver cells than Sorafenib (P < 0.05), a chemotherapy drug for hepatocellular carcinoma. Among all, oleic acid ester of Q3G displayed the greatest antiproliferation action and a high potential as an anti-cancer therapeutic. Overall, the results of the study suggest strong antiproliferative action of these novel food-derived compounds in treatment of cancer.

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

“…Natural presence of quercetin in many occurring forms in plant-derived beverages, vegetables and fruits, and its antitumor effects convert quercetin-derived molecules into interesting drugs for cancer treatment. Regardless of this, quercetin derivatives were evaluated in only four of the total articles included in this systematic review, demonstrating an HCC growth inhibitory effectiveness comparable to that of quercetin [57][58][59][60]. The potential of some of these compounds as cancer treatments were also reported in human pancreatic cancer and ovarian cancer with isoquercitrin [79] and 3,4 ,7-O-trimethylquercetin [80], respectively.…”

“…This quercetin-derived compound was able to increase DNA fragmentation in parallel to apoptosis induction mediated by activation of caspase-3 and DNA relaxation activity abrogation [60]. Later, this research group decided to evaluate six long chain fatty acid esters of Q3G (stearic acid ester, oleic acid ester, linoleic acid ester, alpha-linoleic acid ester, eicosapentaenoic acid ester and docosahexanoic acid ester) in the HepG2 HCC cell line, obtaining results with the same trend that those previously published with Q3G [59].…”

“…Quercetin glycosides are one of the main naturally occurring forms of quercetin, which makes them interesting compounds for cancer treatment [60]. This led several researchers to analyze the effects of quercetin derivatives in different tumors, including HCC [57][58][59][60]. Cell growth inhibitory properties of quercetin-3-O-glucoside (Q3G) were reported in an in vitro study with HepG2 cell line, along with S and G2/M phase arrest of cell cycle and morphologic alterations [60].…”

Biocatalytic Synthesis of Flavonoid Esters by Lipases and Their Biological Benefits

“…Acylated isoquercitrin also showed low toxicity for normal liver cells when compared to Sorafenib, a chemotherapy drug for hepatocellular carcinoma. Oleic acid esters of isoquercitrin were considered by the authors to be the best candidates for anticancer therapy [92].…”

Food colorants: their past, present and future

“…This increased stability is a result of intramolecular co‐pigmentation effects resulting from acylation of the glycosides with hydroxycinnamic and hydroxybenzoic acids (Figure ) . Acylation also affords greater heat stability at higher pH values in comparison with non‐acylated anthocyanins . In addition to pH, water in the food system affects degradation – the more water is able to interact with the anthocyanin, the lower the stability .…”