title: Synergistic combination of gemcitabine and dietary molecule induces apoptosis in pancreatic cancer cells and down regulates PKM2 expression.
abstract: 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.
authors.affiliation: School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Pandita
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Bhupender
authors.initials: B
authors.lastname: Kumar
authors.affiliation: School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Manvati
authors.affiliation: School of Biotechnology, Shri Mata Vaishno Devi University, Katra, J&K, India.
authors.forename: Samantha
authors.initials: S
authors.lastname: Vaishnavi
authors.affiliation: Indian Institute of Integrative Medicine, CSIR, Jammu, J&K, India.
authors.forename: Shashank K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rameshwar N K
authors.initials: RN
authors.lastname: Bamezai
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053978:Pentacyclic Triterpenes; D013963:Thyroid Hormones / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000094062:Betulinic Acid; D000093542:Gemcitabine; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D002352:Carrier Proteins; D003841:Deoxycytidine; D008565:Membrane Proteins; D053978:Pentacyclic Triterpenes; D013963:Thyroid Hormones; D014315:Triterpenes; D000094062:Betulinic Acid; D000093542:Gemcitabine; D000097810:Thyroid Hormone-Binding Proteins; C003466:thymoquinone