title: Fatty acid esters of phloridzin induce apoptosis of human liver cancer cells through altered gene expression.
abstract: Phloridzin (phlorizin or phloretin 2'-O-glucoside) is known for blocking intestinal glucose absorption. We have investigated the anticarcinogenic effect of phloridzin and its novel derivatives using human cancer cell lines. We have synthesised novel acylated derivatives of phloridzin with six different long chain fatty acids by regioselective enzymatic acylation using Candida Antarctica lipase B. The antiproliferative effects of the new compounds were investigated in comparison with the parent compounds, phloridzin, aglycone phloretin, the six free fatty acids and chemotherapeutic drugs (sorafenib, doxorubicin and daunorubicin) using human hepatocellular carcinoma HepG2 cells, human breast adenocarcinoma MDA-MB-231 cells and acute monocytic leukemia THP-1 cells along with normal human and rat hepatocytes. The fatty acid esters of phloridzin inhibited significantly the growth of the two carcinoma and leukemia cells while similar treatment doses were not toxic to normal human or rat hepatocytes. The antiproliferative potency of fatty esters of phloridzin was comparable to the potency of the chemotherapeutic drugs. The fatty acid esters of phloridzin inhibited DNA topoisomerases IIα activity that might induce G0/G1 phase arrest, induced apoptosis via activation of caspase-3, and decreased ATP level and mitochondrial membrane potential in HepG2 cells. Based on the high selectivity on cancer cells, decosahexaenoic acid (DHA) ester of phloridzin was selected for gene expression analysis using RT2PCR human cancer drug target array. Antiproliferative effect of DHA ester of phloridzin could be related to the down regulation of anti-apoptotic gene (BCL2), growth factor receptors (EBFR family, IGF1R/IGF2, PDGFR) and its downstream signalling partners (PI3k/AKT/mTOR, Ras/Raf/MAPK), cell cycle machinery (CDKs, TERT, TOP2A, TOP2B) as well as epigenetics regulators (HDACs). These results suggest that fatty esters of phloridzin have potential chemotherapeutic effects mediated through the attenuated expression of several key proteins involved in cell cycle regulation, DNA topoisomerases IIα activity and epigenetic mechanisms followed by cell cycle arrest and apoptosis.
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, Canada.
authors.forename: Sandhya V G
authors.initials: SV
authors.lastname: Nair
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, Canada.
authors.lastname: Ziaullah
authors.affiliation: Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, Canada.
authors.forename: H P Vasantha
authors.initials: HP
authors.lastname: Rupasinghe
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004952:Esters; D005227:Fatty Acids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010695:Phlorhizin / Q000494:pharmacology*; D000075223:Poly-ADP-Ribose Binding Proteins; D051381:Rats
chemical_list: D017304:Annexin A5; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004952:Esters; D005227:Fatty Acids; D000075223:Poly-ADP-Ribose Binding Proteins; D000255:Adenosine Triphosphate; D010695:Phlorhizin; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618813:Top2a protein, rat