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.

Codelivery of doxorubicin and triptolide with reduction-sensitive lipid–polymer hybrid nanoparticles for in vitro and in vivo synergistic cancer treatment

“…The CI values of all DOX/TPL combinations (1/0.05, 1/0.1, 1/0.2, 1/0.5, and 1/1) were simulated with a reported method. 37,38 Most of the DOX/TPL combinations showed synergistic effect (CI ,1) for all treatment concentrations ( Figure 2B). Moreover, when the weight ratio of TPL/DOX decreased from 1/1 to 0.2/1, the CI decreased from 0.433 to 0.114 (Figure 3).…”

Sorafenib in Combination with Betulinic Acid Synergistically Induces Cell Cycle Arrest and Inhibits Clonogenic Activity in Pancreatic Ductal Adenocarcinoma Cells

“…Importantly, some reports showed that BA induced cell death by downregulating the expression of the P13K/Akt signaling pathway [ 19 ]. BA exhibits significant antitumor activities in various cancer cells, including pancreatic cancer [ 20 ].…”

The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma

“…The same research team also reported that Rauwolfia vomitoria extract can potentiate gemcitabine's anti-tumor effects, via reduction in tumor burden and prevented metastatic potential in an orthotopic pancreatic cancer mouse model [49]. Alternative study by Archana Pandita and coworkers suggested that gemcitabine may synergise with betulinic acid and thymoquinone, both of which are common dietary compounds, by inhibiting the proliferation of pancreatic cancer cells, inducing apoptosis and down-regulating pyruvate kinase M2 isoforms [50]. Irofulven (a compound from sesquiterpene mushroom metabolites) [51], cucurbitaicin B (Cucurbitacae family) were some of the pure compounds isolated from plants that can enhance the anti-tumor effects of gemcitabine [52].…”

“…Abbreviations ANOVA: One-way analysis of variance; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; BID: Bcl-2 homology 3 interacting domain death agonist; CI: Combination index; cIAP-2: Cellular inhibitor of apoptosis 2; DMSO: Dimethylsulfoxide; DRI: Drug reduction index; ELISA: Enzyme-linked immunosorbent assay; EOHSA: Excess Over Highest Single Agent; Gem: Gemcitabine; HSA: Highest Single Agent; IC 50…”