Abstract.A gemcitabine (GEM)-resistant human pancreatic cancer cell line (PANC-1RG7) was established in vitro by gradually increasing GEM concentrations and cloning cell cultures to develop a cellular model of acquired drug resistance studies. We found that PANC-1RG7 cells exhibited significantly different morphological characteristics from parental cells. PANC-1RG7 cells grew slowly (p<0.05), yet the cell cycle remained unchanged (p>0.05). PANC-1RG7, with a resistance index to GEM of 39.9, showed cross-resistance characteristics to methotrexate, gefitinib, cisplatin and 5-fluorouracil. The proliferation inhibition of GEM was significantly reduced in vivo (p<0.05). The known resistance-associated genes and proteins we detected remained unchanged, with the exception of cytidine deaminase, multidrug resistance-related protein and breast cancer resistance protein genes, which decreased; by contrast, 5'-nucleotidase, ribonucleotide reductase (RRM) 1 and RRM2 proteins increased (p<0.05). Therefore, a cell line with acquired GEM resistance was established successfully. Resistance was acquired by overexpressing RRM1 and RRM2 proteins. IntroductionPancreatic cancer is a common digestive malignant tumor with low resection rate, high mortality rate and poor prognosis, as the characteristics of this tumor are masked. Pancreatic cancer patients who cannot undergo surgery are subjected to chemotherapy as a fundamental treatment modality; this modality is also a key component of systemic therapy (1).In pancreatic cancer chemotherapy, gemcitabine (GEM) was initially recommended as a first-line drug by the Food and Drug Administration (USA) in 1997. Since then, research on combination chemotherapies, such as cytotoxic drugs [5-fluorouracil (2), cisplatin (3) and capecitabine (4)] and biological agents [erlotinib (5), cetuximab (6) and bevacizumab (7)], as second-line modes of chemotherapy has been extensively conducted. Although GEM is currently the preferred drug for single chemotherapeutic applications in pancreatic cancer, the inherent and acquired resistance of cancer cells to GEM prevents the efficient improvement of the clinical benefit and survival of patients. Furthermore, the efficiency of this treatment is very low (12%) (8); as such, this drawback should be resolved in clinical applications. However, related studies have shown that the prognosis of pancreatic cancer in the past 10 years has remained unchanged.The resistance to GEM is induced by several factors. Although numerous mechanisms have been presented, the main mechanism remains unclear. This resistance is affected by several key molecular factors, including deficiencies in drug uptake, activation of DNA repair pathways, resistance to apoptosis, enhancement of tumor microenvironments, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes and conversion to an epithelial-mesenchymal transition-like phenotype. Hence, GEM-resistance mechanisms involved in pancreatic cancer should be investigated;...
Objective To investigate the effects of cucurmosin (CUS) on proliferation and drugs resistance in gemcitabine (GEM) human pancreatic cancer cell PANC-1RG7. Methods The ultrastructural changes of PANC-1RG7 cells after CUS intervention were observed by transmission electron microscope. Flow Cytometer (FCM) was used to detect the effect of CUS on the growth cycle of PANC-1RG7 cells. We used colony formation experiment, Sulforhodamine B assays and subcutaneous implantation tumor model to observe the proliferation inhibition and reversal drug-resistance reversion of CUS on PANC-1RG7 in vitro and in vivo. Western blot was used to observe the expressions of RRM1, RRM2, PI3K, Akt, mTOR and other proteins related to apoptosis after CUS intervention. Results After CUS intervention, PANC-1RG7 cells were obviously apoptotic with large number of vacuoles and apoptotic bodies. Compared with parental cell PANC-1, GEM-resistant cell PANC-1 was more sensitive to CUS. The combination of GEM and CUS at different concentrations showed synergistic effect. At the concentration of CUS with the inhibition rate of 10%, the reversal multiples and the reversal efficiency were 1.78±0.65 and 50.13±16.87%, respectively. Subcutaneous implantation tumor model confirmed the proliferation inhibitory effect of CUS in vitro. Western blot confirmed that CUS down-regulated the expressions of RRM1, RRM2, PI3K, Akt and mTOR. Conclusion CUS can significantly inhibit PANC-1RG7 cell proliferation in vivo and in vitro, and can reverse cell GEM-resistance.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.