Abstract
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.
Highlights
Pancreatic cancer is the third most frequent cause of cancer-related death in both women and men, with a rather low five-year survival rate [1]
To investigate the improvement of gemcitabine antitumor effect by Ciclopirox olamine (CPX) combination strategy, cells were exposed to gemcitabine co-cultured with CPX (Figure 1C)
CPX has recently been repositioned as a potential therapeutic agent to treat patients suffering from human acute myelogenous leukemia [27, 26], breast cancer, rhabdomyosarcoma and colon carcinomas [23]
Summary
Pancreatic cancer is the third most frequent cause of cancer-related death in both women and men, with a rather low five-year survival rate [1]. Pancreatectomy is the only curative treatment option for localized pancreatic cancer [3]. This disease is usually diagnosed at an advanced stage and most available treatments render ineffective, portending to dismal survival [4, 5]. KRAS is mutated in approximately 95% of advanced and/or metastatic pancreatic carcinomas and is a well-confirmed driver of pancreatic tumor growth and progression. Pancreatic cancer is characterized by a desmoplastic stroma that can encompass 70%–80% of the tumor volume. The delivery of drugs to the pancreatic tissue is low and the tumor pancreatic tissue is characterized by low bioavailability [6]. More research is required with novel therapeutic strategies that may overcome the pathophysiological obstacles of this life-threatening malignancy
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