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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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Autores principales: Pandita, Archana, Kumar, Bhupender, Manvati, Siddharth, Vaishnavi, Samantha, Singh, Shashank K., Bamezai, Rameshwar N. K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157832/
https://www.ncbi.nlm.nih.gov/pubmed/25197966
http://dx.doi.org/10.1371/journal.pone.0107154
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author Pandita, Archana
Kumar, Bhupender
Manvati, Siddharth
Vaishnavi, Samantha
Singh, Shashank K.
Bamezai, Rameshwar N. K.
author_facet Pandita, Archana
Kumar, Bhupender
Manvati, Siddharth
Vaishnavi, Samantha
Singh, Shashank K.
Bamezai, Rameshwar N. K.
author_sort Pandita, Archana
collection PubMed
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 IC(50) dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC(50) dose ratio of the dietary molecules in combination with reduced IC(50) 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.
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spelling pubmed-41578322014-09-09 Synergistic Combination of Gemcitabine and Dietary Molecule Induces Apoptosis in Pancreatic Cancer Cells and Down Regulates PKM2 Expression Pandita, Archana Kumar, Bhupender Manvati, Siddharth Vaishnavi, Samantha Singh, Shashank K. Bamezai, Rameshwar N. K. PLoS One Research Article 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 IC(50) dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC(50) dose ratio of the dietary molecules in combination with reduced IC(50) 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. Public Library of Science 2014-09-08 /pmc/articles/PMC4157832/ /pubmed/25197966 http://dx.doi.org/10.1371/journal.pone.0107154 Text en © 2014 Pandita et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pandita, Archana
Kumar, Bhupender
Manvati, Siddharth
Vaishnavi, Samantha
Singh, Shashank K.
Bamezai, Rameshwar N. K.
Synergistic Combination of Gemcitabine and Dietary Molecule Induces Apoptosis in Pancreatic Cancer Cells and Down Regulates PKM2 Expression
title Synergistic Combination of Gemcitabine and Dietary Molecule Induces Apoptosis in Pancreatic Cancer Cells and Down Regulates PKM2 Expression
title_full Synergistic Combination of Gemcitabine and Dietary Molecule Induces Apoptosis in Pancreatic Cancer Cells and Down Regulates PKM2 Expression
title_fullStr Synergistic Combination of Gemcitabine and Dietary Molecule Induces Apoptosis in Pancreatic Cancer Cells and Down Regulates PKM2 Expression
title_full_unstemmed Synergistic Combination of Gemcitabine and Dietary Molecule Induces Apoptosis in Pancreatic Cancer Cells and Down Regulates PKM2 Expression
title_short Synergistic Combination of Gemcitabine and Dietary Molecule Induces Apoptosis in Pancreatic Cancer Cells and Down Regulates PKM2 Expression
title_sort synergistic combination of gemcitabine and dietary molecule induces apoptosis in pancreatic cancer cells and down regulates pkm2 expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157832/
https://www.ncbi.nlm.nih.gov/pubmed/25197966
http://dx.doi.org/10.1371/journal.pone.0107154
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