Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression
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 differ...
Published in: | PLoS ONE |
---|---|
Main Authors: | , , |
Format: | Text |
Language: | English |
Published: |
Public Library of Science
2014
|
Subjects: | |
Online Access: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167698 http://www.ncbi.nlm.nih.gov/pubmed/25229655 https://doi.org/10.1371/journal.pone.0107149 |
id |
ftpubmed:oai:pubmedcentral.nih.gov:4167698 |
---|---|
record_format |
openpolar |
spelling |
ftpubmed:oai:pubmedcentral.nih.gov:4167698 2023-05-15T13:32:18+02:00 Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression Nair, Sandhya V. G. Ziaullah, Rupasinghe, H. P. Vasantha 2014-09-17 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167698 http://www.ncbi.nlm.nih.gov/pubmed/25229655 https://doi.org/10.1371/journal.pone.0107149 en eng Public Library of Science http://www.ncbi.nlm.nih.gov/pmc/articles/PMC http://www.ncbi.nlm.nih.gov/pubmed/25229655 http://dx.doi.org/10.1371/journal.pone.0107149 This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. CC-BY Research Article Text 2014 ftpubmed https://doi.org/10.1371/journal.pone.0107149 2014-10-05T01:37:43Z 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 ... Text Antarc* Antarctica PubMed Central (PMC) PLoS ONE 9 9 e107149 |
institution |
Open Polar |
collection |
PubMed Central (PMC) |
op_collection_id |
ftpubmed |
language |
English |
topic |
Research Article |
spellingShingle |
Research Article Nair, Sandhya V. G. Ziaullah, Rupasinghe, H. P. Vasantha Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression |
topic_facet |
Research Article |
description |
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 ... |
format |
Text |
author |
Nair, Sandhya V. G. Ziaullah, Rupasinghe, H. P. Vasantha |
author_facet |
Nair, Sandhya V. G. Ziaullah, Rupasinghe, H. P. Vasantha |
author_sort |
Nair, Sandhya V. G. |
title |
Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression |
title_short |
Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression |
title_full |
Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression |
title_fullStr |
Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression |
title_full_unstemmed |
Fatty Acid Esters of Phloridzin Induce Apoptosis of Human Liver Cancer Cells through Altered Gene Expression |
title_sort |
fatty acid esters of phloridzin induce apoptosis of human liver cancer cells through altered gene expression |
publisher |
Public Library of Science |
publishDate |
2014 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167698 http://www.ncbi.nlm.nih.gov/pubmed/25229655 https://doi.org/10.1371/journal.pone.0107149 |
genre |
Antarc* Antarctica |
genre_facet |
Antarc* Antarctica |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC http://www.ncbi.nlm.nih.gov/pubmed/25229655 http://dx.doi.org/10.1371/journal.pone.0107149 |
op_rights |
This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1371/journal.pone.0107149 |
container_title |
PLoS ONE |
container_volume |
9 |
container_issue |
9 |
container_start_page |
e107149 |
_version_ |
1766025747955187712 |