TITLE:
In Vitro Model Systems to Investigate Drug Resistance Mechanisms in Pancreatic Cancer Cells
AUTHORS:
Eric Romney, Vinay J. Nagaraj
KEYWORDS:
Pancreatic Cancer, Gemcitabine, Drug-Resistance, Pulse Method, Incremental Method
JOURNAL NAME:
Advances in Biological Chemistry,
Vol.5 No.7,
December
30,
2015
ABSTRACT: With a 5-year survival rate of less than 6%, the diagnosis of pancreatic cancer is devastating news for any patient. Gemcitabine, the most commonly used chemotherapy drug, only improves survival by approximately 1.5 months. A major obstacle to the treatment of pancreatic cancer with gemcitabine is the development of drug resistance. To better understand the precise mechanisms by which patient tumor cells gain resistance to gemcitabine, a cell culture model system that more accurately reflects the development of drug resistance in vivo is required. In this study, cultured pancreatic adenocarcinoma BxPC-3 cells were subjected to two different treatment regimens. The first method—termed pulse method—involves periodically treating separate cultures of BxPC-3 cells with constant predetermined doses of gemcitabine. The second treatment regimen—termed incremental method—consists of treating BxPC-3 cells with increasing doses of gemcitabine from 10 to 100 nM. While all treated cells showed enhanced resistance to gemcitabine, low-dose pulse treatments were sufficient to produce highly drug-resistant cells as evidenced by higher IC50 measurements. Pulse treatments also resulted in slower growth rates and increased doubling time of the drug-resistant cells. Morphological changes indicate cellular abnormalities linked to likely epithelial-to-mesenchymal transition and drug resistance. Our preliminary results indicate that the pulse method may better simulate resistance observed in patients undergoing chemotherapy and may serve as a superior model to investigate drug-resistance. This model can also help with identification of appropriate markers that determine the presence of drug-resistant cells and help clinicians adjust treatment strategies to improve outcomes for patients suffering from pancreatic cancer.