Superior efficacy of the antifungal agent ciclopirox olamine over gemcitabine in pancreatic cancer models
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Chrysovalantou Mihailidou1, Pavlos Papakotoulas1,2, Athanasios G. Papavassiliou1 and Michalis V. Karamouzis1,3
1Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
22nd Department of Medical Oncology, Theagenion Hospital, 54007 Thessaloniki, Greece
3First Department of Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
Keywords: pancreatic cancer; ciclopirox olamine; pharmacodynamic activity; gemcitabine; human pancreatic tumor xenograft models
Received: August 21, 2017 Accepted: November 17, 2017 Published: December 08, 2017
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.
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