Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in the USA. To date, systemic chemotherapy combined with radiation therapy (chemoradiotherapy, CRT), represents the standard treatment for PC. However, many patients with pancreatic ductal adenocarcinoma (PDAC) are unable to benefit from the advances in chemotherapy, namely nab-paclitaxel (NP) and gemcitabine (GEM), due to the rapid development of drug resistance. Reduced sensitivity of PDAC to chemotherapy or acquired resistance to gemcitabine is attributed to multiple factors including nucleoside transporters, efflux proteins, inactivation of apoptosis pathways, and enzymatic deactivation of GEM by cytidine deaminase (CDA). In this study, we sought to develop novel gemcitabine analogs (GEM-As) with an aim to overcome the resistance mechanisms and enhance cytotoxic effect in pancreatic cancer cells. Based on preliminary in silico and in vitro data, we selected four chemically modified analogs of gemcitabine, termed as GL-302, GL-282, GL-349, and GL-351, and evaluated their cytotoxic activity against pancreatic cancer cell line AsPC-1 in vitro as well as in SCID mouse xenograft models. Our novel GEM-As, especially GL-302 and GL-282, showed higher tumor cytotoxic ability than gemcitabine in in-vitro, while GL-282 was able to significantly reduce the tumor growth, compared to gemcitabine, in mouse xenograft model of AsPC-1 cells. Higher tumor cytotoxic activity of selected GEM-As, especially GL-282, was associated with insensitivity to metabolic deactivation by CDA and higher accumulation in the tumor (lower efflux), compared to GEM, the parent molecule. Our results demonstrate that the GEM-As circumvent drug resistance mechanisms and have potential therapeutic utility in PDAC patients.

Overcoming drug resistance in pancreatic ductal adenocarcinoma using gemcitabine analogs

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