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.