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.

Highlights

  • Hepatocellular carcinoma (HCC), the most common form of liver cancer, represent the fifth worldwide malignancy and third cause of mortality among cancer related death [1]

  • The potential cytotoxic effects of fatty acid esters of phloridzin, phloridzin, free fatty acids and phloretin as well as standard commercial cancer drugs were investigated on human hepatocarcinoma (HepG2), breast adenocarcinoma (MDA-MB-231) and acute monocytic leukemia (THP-1) cell lines, primary normal human hepatocytes and rat hepatocytes by using MTS assay

  • The cytotoxic effect was drawn on the basis of lower EC50 values (,40 mM) and higher selective index (SI) values (.3) that were obtained for the fatty acid esters of phloridzin

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Summary

Introduction

Hepatocellular carcinoma (HCC), the most common form of liver cancer, represent the fifth worldwide malignancy and third cause of mortality among cancer related death [1]. In Canada, the incidence of HCC has been increasing over the past several decades [2]. HCC accounts for 71.9% of liver cancers in males and females in Canada. According to Canadian Cancer Statistics in 2013, the incidence rate of liver cancer in Canada has increased by 3.6% per year, and the mortality rate increased by 2.2% per year. The contributing factors of HCC include contact with hepatocarcinogens especially aflatoxin [3], hepatic viral infection and liver cirrhosis [4]. The potential curative treatment options are surgical resection, liver transplantation, and ablation or transarterial embolization [1]. Many phytochemicals have been explored as potential chemopreventive agents that can reverse or suppress hepatocarcinogenic progression

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