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.
RupasingheHPVNairSRobinsonRChemopreventive properties of fruit phenolics and their possible mode of actions. In: Atta-Ur-Rahman (ed.). Studies in natural products chemistry2014; Vol 42.Amsterdam: Elsevier Science Publishers, pp. 229–66.
2.
ArtsICHollmanPCDe MesquitaHBFeskensEJKromhoutD. Dietary catechins and epithelial cancer incidence: the Zutphen elderly study. Int J Cancer2001; 92: 298–302.
3.
KnektPKumpulainenJJärvinenRRissanenHHeliövaaraMReunanenAHakulinenTAromaaA. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr2002; 76: 560–8.
4.
Le MarchandLMurphySPHankinJHWilkensLRKolonelLN. Intake of flavonoids and lung cancer. J Natl Cancer Inst2000; 92: 154–60.
5.
ShenSCChenYCHsuFLLeeWR. Differential apoptosis-inducing effect of quercetin and its glycosides in human promyeloleukemic HL-60 cells by alternative activation of the caspase 3 cascade. J Cell Biochem2003; 89: 1044–55.
6.
SinghalRYehYAPrajaNOlahESlegeGWWeberG. Quercetin down-regulates signal transduction in human breast carcinoma cells. Biochem Biophys Res Commun1995; 208: 425–31.
7.
NguyenTTranENguyenTDoPTHuynhTHHuynhH. The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis2004; 25: 647–59.
8.
AgulloGGamet-PayrastreLManentiSVialaCRemesyCChapHPayrastreB. Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem Pharmacol1997; 53: 1649–57.
9.
Granado-SerranoABMartínMABravoLGoyaLRamosS. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J Nutr2006; 136: 2715–21.
10.
LanoueLGreenKKwik-UribeCKeenCL. Dietary factors and the risk for acute infant leukemia: evaluating the effects of cocoa-derived flavanols on DNA topoisomerase activity. Exp Biol Med2010; 235: 77–89.
11.
RazaviSMZahriSZarriniGNazemiyehHMohammadiS. Biological activity of quercetin-3-O-glucoside, a known plant flavonoid. Bioorg Khim2009; 35: 414–6.
12.
SudanSRupasingheHPV. Quercetin-3-O-glucoside induces human DNA topoisomerase II inhibition, cell cycle arrest and apoptosis in hepatocellular carcinoma cells. Anti-cancer Res2014; 34: 1691–9.
13.
PassamontiSTerdoslavichMFrancaRVanzoATramerFBraidotEPetrussaEVianelloA. Bioavailability of flavonoids: a review of their membrane transport and the function of bilitranslocase in animal and plant organisms. Curr Drug Metabol2009; 10: 369–94.
14.
LinYTHsiuSLHouYCChenHYLeeCP. Degradation of flavonoid aglycones by rabbit, rat and human fecal flora. Biol Pharm Bull2003; 26: 747–51.
15.
SalemJChevalotISchiavoCHParisCFickMHumeauC. Biological activities of flavonoids from Nitraria retusa (Forssk.) Asch. and their acylated derivatives. Food Chem2011; 124: 486–94.
16.
Mainou-FowlerTProctorSJDickinsonAM. Gamma-linolenic acid induces apoptosis in B-chronic lymphocytic leukaemia cells in vitro. Leuk Lymph2001; 40: 393–403.
17.
HardmanWE. Omega-3 fatty acids to augment cancer therapy. J Nutr2002; 132: 3508–12.
18.
ZiaullahBhullarKSWarnakulasuriyaSNRupasingheHPV. Biocatalytic synthesis structural elucidation, antioxidant capacity and tyrosinase inhibition activity of long chain fatty acid acylated derivatives of phloridzin and isoquercitrin. Bioorg Med Chem2013; 21: 684–92.
19.
TalibWMahasnehA. Antiproliferative activity of plant extracts used against cancer in traditional medicine. Sci Pharm2010; 78: 33–45.
20.
ShanBWangMLiR. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/β-catenin signaling pathway. Cancer Invest2009; 27: 604–12.
21.
PatraNDeUKangJAKimJMAhnMYLeeJ. A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells. Eur J Pharmacol2011; 658: 98–107.
22.
Van de LoosdrechtAABeelenRHJOssenkoppeleGJBroekhovenMGLangenhuijsenMM. A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. J Immunol Methods1994; 174: 311–20.
23.
Lisa KM. Handbook of assay development in drug discovery. 2004: Series 5. 385–406.
24.
RissTLMoravecRA. Use of multiple assay endpoints to investigate the effects of incubation time, dose of toxin, and plating density in cell-based cytotoxicity assays. Assay Drug Dev Technol2004; 2: 51–62.
25.
RiedlSJShiY. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol2004; 5: 897–907.
26.
GibelliniLPintiMNasiM. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med2011, pp. 1–15.
27.
KitagawaSTanakaYTanakaMEndoKYoshiiA. Enhanced skin delivery of quercetin by microemulsion. J Pharm2009; 61: 855–60.
28.
BrökerLEKruytFAEGiacconeG. Cell death independent of caspases: a review. Clin Cancer Res2005; 11: 3155–62.
29.
PoonIKHHulettMDParishCR. Molecular mechanisms of late apoptotic/necrotic cell clearance. Cell Death Differ2010; 17: 381–97.
30.
SarasteAPulkkiK. Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res2000; 45: 528–37.
31.
CheongEIvoryKDolemanJParkerMLRhodesA. Synthetic and naturally occurring COX-2 inhibitors suppress proliferation in a human oesophageal adenocarcinoma cell line (OE33) by inducing apoptosis and cell cycle arrest. Carcinogenesis2004; 25: 1945–52.
32.
HosokawaNHosokawaYSakaiTYoshidaMMaruiN. Inhibitory effect of quercetin on the synthesis of a possibly cell-cycle-related 17-kDa protein, in human colon cancer cells. Int J Cancer1990; 45: 1119–24.
33.
ChoiJ-AKimJYLeeJYKangCMKwonHJ. Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol2001; 19: 837–44.
34.
CossATosettoMFoxEJSapetto-RebowBGormanSKennedyBNLloydATHylandJMO'DonoghueDPSheahanKLeahyDTMulcahyHEO'SullivanJN. Increased topoisomerase IIα expression in colorectal cancer is associated with advanced disease and chemotherapeutic resistance via inhibition of apoptosis. Cancer Lett2009; 276: 228–38.
35.
El-AwadyAAliMMSalehEMGhalebFM. Apoptosis is the most efficient death-pathway in tumor cells after topoisomerase II inhibition. Saudi Med J2008; 29: 558–64.
36.
NiidaHNakanishiM. DNA damage checkpoints in mammals. Mutagenesis2006; 21: 3–9.
37.
NairSVGZiaullahRupasingheHPV. Fatty acid esters of phloridzin induce apoptosis of human liver cancer cells through altered gene expression. PLoS ONE2014; 9: e107149.
