Synergistic combination of gemcitabine and dietary molecule induces apoptosis in pancreatic cancer cells and down regulates PKM2 expression
Gemcitabine, an effective agent in treatment of cancer of pancreas, has undergone failures in many instances after multiple cycles of therapy due to emergence of drug resistance. Combination of dietary compounds with clinically validated drugs has emerged as an effective therapeutic approach to trea...
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| description | Gemcitabine, an effective agent in treatment of cancer of pancreas, has undergone failures in many instances after multiple cycles of therapy due to emergence of drug resistance. Combination of dietary compounds with clinically validated drugs has emerged as an effective therapeutic approach to treat pancreatic tumors, refractory to gemcitabine therapy. In order to optimize a possible synergistic combination of Gemcitabine (GCB) with dietary molecules, Betuilnic acid (BA) and Thymoquinone (TQ), stand-alone IC50 dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC50 dose ratio of the dietary molecules in combination with reduced IC50 dose of GCB was tested on GCB resistant PANC-1 and sensitive MIA PaCa-2 cells for synergism, additive response and antagonism, using calcusyn. Combination index (CI) revealed that pre-treatment of BA and TQ along with GCB synergistically inhibited the cancer cell proliferation in in-vitro experiments. Pyruvate kinase (PK) M2 isoform, a promising target involved in cancer cell metabolism, showed down-regulation in presence of TQ or BA in combination with GCB. GCB with BA acted preferentially on tumor mitochondria and triggered mitochondrial permeability transition. Pre-exposure of the cell lines, MIA PaCa-2 and PANC-1, to TQ in combination with GCB induced apoptosis. Thus, the effectiveness of BA or TQ in combination with GCB to inhibit cell proliferation, induce apoptosis and down-regulate the expression of PKM2, reflects promise in pancreatic cancer treatment. |
| doi_str_mv | 10.1371/journal.pone.0107154 |
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Combination of dietary compounds with clinically validated drugs has emerged as an effective therapeutic approach to treat pancreatic tumors, refractory to gemcitabine therapy. In order to optimize a possible synergistic combination of Gemcitabine (GCB) with dietary molecules, Betuilnic acid (BA) and Thymoquinone (TQ), stand-alone IC50 dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC50 dose ratio of the dietary molecules in combination with reduced IC50 dose of GCB was tested on GCB resistant PANC-1 and sensitive MIA PaCa-2 cells for synergism, additive response and antagonism, using calcusyn. Combination index (CI) revealed that pre-treatment of BA and TQ along with GCB synergistically inhibited the cancer cell proliferation in in-vitro experiments. Pyruvate kinase (PK) M2 isoform, a promising target involved in cancer cell metabolism, showed down-regulation in presence of TQ or BA in combination with GCB. GCB with BA acted preferentially on tumor mitochondria and triggered mitochondrial permeability transition. Pre-exposure of the cell lines, MIA PaCa-2 and PANC-1, to TQ in combination with GCB induced apoptosis. Thus, the effectiveness of BA or TQ in combination with GCB to inhibit cell proliferation, induce apoptosis and down-regulate the expression of PKM2, reflects promise in pancreatic cancer treatment.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0107154</identifier><identifier>PMID: 25197966</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Antagonism ; Antimetabolites, Antineoplastic - pharmacology ; Antineoplastic Agents, Phytogenic - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Benzoquinones - pharmacology ; Betulinic Acid ; Biotechnology ; Cancer ; Cancer therapies ; Carrier Proteins - antagonists & inhibitors ; Carrier Proteins - metabolism ; Cell division ; Cell proliferation ; Cell Proliferation - drug effects ; Colorectal cancer ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - pharmacology ; Diet ; Drug dosages ; Drug resistance ; Drug Synergism ; Enzymes ; Flow Cytometry ; Gemcitabine ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Immunoblotting ; Kinases ; Leukemia ; Life sciences ; Medicine and Health Sciences ; Membrane Potential, Mitochondrial - drug effects ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - metabolism ; Metabolism ; Mitochondria ; Nigella sativa ; Oils & fats ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Pentacyclic Triterpenes ; Permeability ; Pyruvate kinase ; Pyruvic acid ; Synergism ; Therapy ; Thyroid Hormone-Binding Proteins ; Thyroid Hormones - metabolism ; Triterpenes - pharmacology ; Tumor cell lines ; Tumor Cells, Cultured ; Tumors</subject><ispartof>PloS one, 2014-09, Vol.9 (9), p.e107154</ispartof><rights>2014 Pandita et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Combination of dietary compounds with clinically validated drugs has emerged as an effective therapeutic approach to treat pancreatic tumors, refractory to gemcitabine therapy. In order to optimize a possible synergistic combination of Gemcitabine (GCB) with dietary molecules, Betuilnic acid (BA) and Thymoquinone (TQ), stand-alone IC50 dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC50 dose ratio of the dietary molecules in combination with reduced IC50 dose of GCB was tested on GCB resistant PANC-1 and sensitive MIA PaCa-2 cells for synergism, additive response and antagonism, using calcusyn. Combination index (CI) revealed that pre-treatment of BA and TQ along with GCB synergistically inhibited the cancer cell proliferation in in-vitro experiments. Pyruvate kinase (PK) M2 isoform, a promising target involved in cancer cell metabolism, showed down-regulation in presence of TQ or BA in combination with GCB. GCB with BA acted preferentially on tumor mitochondria and triggered mitochondrial permeability transition. Pre-exposure of the cell lines, MIA PaCa-2 and PANC-1, to TQ in combination with GCB induced apoptosis. Thus, the effectiveness of BA or TQ in combination with GCB to inhibit cell proliferation, induce apoptosis and down-regulate the expression of PKM2, reflects promise in pancreatic cancer treatment.</description><subject>Acids</subject><subject>Antagonism</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Benzoquinones - pharmacology</subject><subject>Betulinic Acid</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Carrier Proteins - antagonists & inhibitors</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell division</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Colorectal cancer</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - pharmacology</subject><subject>Diet</subject><subject>Drug dosages</subject><subject>Drug resistance</subject><subject>Drug Synergism</subject><subject>Enzymes</subject><subject>Flow Cytometry</subject><subject>Gemcitabine</subject><subject>Gene Expression Regulation, Neoplastic - 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Combination of dietary compounds with clinically validated drugs has emerged as an effective therapeutic approach to treat pancreatic tumors, refractory to gemcitabine therapy. In order to optimize a possible synergistic combination of Gemcitabine (GCB) with dietary molecules, Betuilnic acid (BA) and Thymoquinone (TQ), stand-alone IC50 dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC50 dose ratio of the dietary molecules in combination with reduced IC50 dose of GCB was tested on GCB resistant PANC-1 and sensitive MIA PaCa-2 cells for synergism, additive response and antagonism, using calcusyn. Combination index (CI) revealed that pre-treatment of BA and TQ along with GCB synergistically inhibited the cancer cell proliferation in in-vitro experiments. Pyruvate kinase (PK) M2 isoform, a promising target involved in cancer cell metabolism, showed down-regulation in presence of TQ or BA in combination with GCB. GCB with BA acted preferentially on tumor mitochondria and triggered mitochondrial permeability transition. Pre-exposure of the cell lines, MIA PaCa-2 and PANC-1, to TQ in combination with GCB induced apoptosis. Thus, the effectiveness of BA or TQ in combination with GCB to inhibit cell proliferation, induce apoptosis and down-regulate the expression of PKM2, reflects promise in pancreatic cancer treatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25197966</pmid><doi>10.1371/journal.pone.0107154</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-09, Vol.9 (9), p.e107154 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1560821270 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acids Antagonism Antimetabolites, Antineoplastic - pharmacology Antineoplastic Agents, Phytogenic - pharmacology Apoptosis Apoptosis - drug effects Benzoquinones - pharmacology Betulinic Acid Biotechnology Cancer Cancer therapies Carrier Proteins - antagonists & inhibitors Carrier Proteins - metabolism Cell division Cell proliferation Cell Proliferation - drug effects Colorectal cancer Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology Diet Drug dosages Drug resistance Drug Synergism Enzymes Flow Cytometry Gemcitabine Gene Expression Regulation, Neoplastic - drug effects Humans Immunoblotting Kinases Leukemia Life sciences Medicine and Health Sciences Membrane Potential, Mitochondrial - drug effects Membrane Proteins - antagonists & inhibitors Membrane Proteins - metabolism Metabolism Mitochondria Nigella sativa Oils & fats Pancreas Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Pentacyclic Triterpenes Permeability Pyruvate kinase Pyruvic acid Synergism Therapy Thyroid Hormone-Binding Proteins Thyroid Hormones - metabolism Triterpenes - pharmacology Tumor cell lines Tumor Cells, Cultured Tumors |
| title | Synergistic combination of gemcitabine and dietary molecule induces apoptosis in pancreatic cancer cells and down regulates PKM2 expression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T12%3A31%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Synergistic%20combination%20of%20gemcitabine%20and%20dietary%20molecule%20induces%20apoptosis%20in%20pancreatic%20cancer%20cells%20and%20down%20regulates%20PKM2%20expression&rft.jtitle=PloS%20one&rft.au=Pandita,%20Archana&rft.date=2014-09-08&rft.volume=9&rft.issue=9&rft.spage=e107154&rft.pages=e107154-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0107154&rft_dat=%3Cproquest_plos_%3E3426352711%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1560821270&rft_id=info:pmid/25197966&rft_doaj_id=oai_doaj_org_article_bbf90befb6bb42d285b44fa897b2da82&rfr_iscdi=true |