Fatty acid esters of phloridzin induce apoptosis of human liver cancer cells through altered gene expression

• Published in: PloS one 2014-09, Vol.9 (9), p.e107149
• Main Authors: Nair, Sandhya V G, Ziaullah, Rupasinghe, H P Vasantha
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute monocytic leukemia; Acylation; Adenocarcinoma; Adenosine Triphosphate - metabolism; AKT protein; Animals; Annexin A5 - metabolism; Antigens, Neoplasm; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biology and Life Sciences; Cancer; Cancer therapies; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Caspase; Caspase 3 - metabolism; Caspase-3; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cytotoxicity; Daunorubicin; Deoxyribonucleic acid; Derivatives; DNA; DNA Fragmentation; DNA topoisomerase; DNA Topoisomerases, Type II; DNA-Binding Proteins - antagonists & inhibitors; Doxorubicin; Drugs; Environmental science; Epigenetics; Esters; Fatty acids; Fatty Acids - metabolism; Flavonoids; G1 phase; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Growth factor receptors; Hepatocellular carcinoma; Hepatocytes; Humans; Intestine; Kinases; L-Lactate Dehydrogenase - metabolism; Laboratories; Leukemia; Lipase; Lipid peroxidation; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Medicine and Health Sciences; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Monocytic leukemia; Penicillin; Phlorhizin - pharmacology; Poly-ADP-Ribose Binding Proteins; Polyphenols; Proteins; Rats; Receptors; Regulators; Research and Analysis Methods; Signaling; Telomerase; Tumor cell lines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0107149

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.