TY - JOUR
TI - Superior efficacy of the antifungal agent ciclopirox olamine over gemcitabine in pancreatic cancer models
AU - Mihailidou, C.
AU - Papakotoulas, P.
AU - Papavassiliou, A.G.
AU - Karamouzis, M.V.
JO - OncoTargets and therapy
PY - 2018
VL - 9
TODO - 12
SP - 10360-10374
PB - Impact Journals, LLC
SN - null
TODO - 10.18632/oncotarget.23164
TODO - antifungal agent;  antineoplastic agent;  BxPc3 protein;  caspase;  caspase 3;  ciclopiroxolamine;  epidermal growth factor receptor;  gemcitabine;  nucleotide binding protein;  Panc1 protein;  protein bcl xl;  reactive oxygen metabolite;  serine 473;  survivin;  unclassified drug, animal experiment;  animal model;  animal tissue;  antineoplastic activity;  apoptosis;  Article;  autophagy;  cancer growth;  cancer mortality;  cancer patient;  cell proliferation;  clonogenesis;  controlled study;  drug efficacy;  drug mechanism;  enzyme linked immunosorbent assay;  female;  human;  monotherapy;  mouse;  MTT assay;  nonhuman;  pancreas cancer;  pancreas tissue;  pharmacodynamics;  protein cleavage;  survival rate;  tumor growth;  tumor regression;  tumor volume;  tumor xenograft;  Western blotting
TODO - Ciclopirox olamine (CPX) is an antifungal agent that has recently demonstrated promising anti-neoplastic activity against hematologic and solid tumors. Here, we evaluated CPX compared with gemcitabine alone as well as their combination in human pancreatic cancer cell lines; BxPC-3, Panc-1, and MIA PaCa-2 and in humanized xenograft mouse models. We also examined the preclinical pharmacodynamic activity of CPX. CPX caused a pronounced decrease in cell proliferation and clonogenic growth potential. These inhibitory effects were accompanied by induction of reactive oxygen species (ROS), which were strongly associated with reduced Bcl-xL and survivin levels and activation of a panel of caspases, especially caspase-3, and finally resulted in apoptotic death. CPX-induced apoptosis was associated with reduced pEGFR (Y1068) and pAkt (Ser473) protein levels. Additionally, decreased proliferation was observed in CPX-treated xenografts tumors, demonstrating unique tumor regression and a profound survival benefit. Finally, we showed that CPX significantly abrogated gemcitabine-induced ROS levels in pancreatic tissues. These pre-clinical results have verified the superior antitumor efficacy of CPX over gemcitabine alone, while their combination is even more effective, providing the rationale for further clinical testing of CPX plus gemcitabine in pancreatic cancer patients. © Mihailidou et al.
ER -