Abstract

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers, in part because it is insensitive to many chemotherapeutic drugs. Gemcitabine still remains the best chemotherapeutic agent available for the treatment of advanced pancreatic cancer. However, gemcitabine treatment results in only a marginal survival advantage. Thus, there is a strong need for the continuous development of novel therapeutic agents to improve pancreatic cancer therapy. The compound C-1748 is the most active derivative of 1-nitroacridine antitumor agents developed in our laboratory. Strong cytotoxic activity against colon cancer cell lines (HCT8 and HT29) and high antitumor activity against xenografts in nude mice of prostate (LnCaP) and colon carcinoma (HCT8), along with low mutagenic potential and slight myelosuppressive properties allowed the selection of C-1748 for phase I clinical trials. The aim of the current study was to investigate and characterize the cellular response of human pancreatic cancer cell line BxPC-3 to C-1748 treatment. Cell cycle analysis revealed that between 96 h and 192 h of C-1748 treatment, BxPC-3 cells underwent accumulation in the G2/M phase which was preceded by prolonged arrest in the G1 phase. The cell cycle perturbations were accompanied by the appearance of sub-G1 fraction, which can be considered as the apoptotic cells population. C-1748 induced apoptosis was more significant in dose- than time-dependent manner and was confirmed by morphological changes like condensed chromatin and apoptosis-body like structures in DAPI stained cell nuclei. Apoptosis induced by C-1748 was also confirmed by flow cytometry analysis of phosphatydylserine externalization, PARP cleavage and mitochondrial dysfunction. To sum up, major cellular response triggered by C-1748 in BxPC-3 cells was cell cycle arrest in G2/M phase and induction of apoptosis. These results highlight the therapeutic potential of C-1748 in pancreatic cancer and support rationale for its further investigation towards this type of malignancy.

Authors (4)