Co-treatment with gemcitabine and nab-paclitaxel exerts additive effects on pancreatic cancer cell death

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer and current treatments exert small effects on life expectancy. The most common adjuvant treatment for PDAC is gemcitabine. However, relapse almost invariably occurs and most patients develop metastatic, incurable disease. The aim of the present study was to assess the activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) alone or in combination with gemcitabine in PDAC cell lines displaying different degrees of sensitivity to gemcitabine treatment. We evaluated the effects of gemcitabine and nab-paclitaxel and their combination on cell proliferation, death, apoptosis and cell cycle distribution in PDAC cell lines either sensitive to gemcitabine, or with primary or secondary resistance to gemcitabine. Our results indicated that the dose‑response of PDAC cell lines to nab-paclitaxel was similar, regardless of their sensitivity to gemcitabine. In addition, nab-paclitaxel elicited similar cytotoxic effects on a PDAC cell line highly resistant to gemcitabine that was selected after prolonged exposure to the drug. Notably, we found that combined treatment with gemcitabine and nab-paclitaxel exerted additive effects on cell death, even at lower doses of the drugs. The combined treatment caused an increase in cell death by apoptosis and in cell cycle blockage in S phase, as assessed by flow cytometry and western blot analysis of the PARP-1 cleavage. These results revealed that a combined treatment with nab-paclitaxel may overcome resistance to gemcitabine and may represent a valuable therapeutic approach for PDAC.

Synergistic Pharmacodynamic Effects of Gemcitabine and Fibroblast Growth Factor Receptor Inhibitors on Pancreatic Cancer Cell Cycle Kinetics and Proliferation

“…Although neither agent alone elicited statistically significant responses, despite the 3-fold range of concentrations administered, the combination regimen suppressed addition of BGJ398 to the standard-of-care Gem+nab-paclitaxel combination mediates a significant increase in efficacy (Lin, et al, unpublished). These results are consistent with recent reports that paclitaxel prolongs Gem-mediated inhibition of S phase progression (Passacantilli et al, 2018), and suggest that BGJ398 may cooperate mechanistically to increase efficacy of Gem+nab-paclitaxel. Studies investigating in vitro interactions in the four-drug FOLFIRINOX regimen (Zoetemelk et al, 2020) report both additivity and antagonism in promoting cell death, with which our in vitro studies are consistent (Garner, et al, unpublished).…”

Paclitaxel Restores Sensitivity to Chemotherapy in Preclinical Models of Multidrug-Resistant Intrahepatic Cholangiocarcinoma

“…In MT-CHC01R1.5 cells, instead, this same treatment caused a mild decrease in the G0/G1 phase and a proportional increase in the S phase. Although not common, a block in the S phase has already been observed in pancreatic tumor cell lines resistant to GEM after PTX exposure ( 33 ). In our opinion, this outcome may indicate a marginal cytostatic effect due to the poor efficacy of single-agent PTX in this cell model.…”

MYC Upregulation Confers Resistance to Everolimus and Establishes Vulnerability to Cyclin-Dependent Kinase Inhibitors in Pancreatic Neuroendocrine Neoplasm Cells

“…ER-BON-1 were plated and treated at the desired concentrations, as previously described. The cells were then stained as previously described [17]. Samples were processed using BD FACSCanto (BD Biosciences) and analyzed using FlowJo-10 software.…”