Abstract
Pancreatic cancer cell epithelial-to-mesenchymal transition (EMT) is an important contributor to cell invasion and tumor progression. Therefore, targeting EMT may be beneficial for pancreatic cancer treatment. The aim of the present study was to report on the inhibitory effect of the novel compound C150 on the EMT of pancreatic cancer cells. C150 inhibited cell proliferation in multiple pancreatic cancer cells with IC50 values of 1-2.5 μM, while in an non-cancerous pancreatic epithelial cell line hTERT-HPNE the IC50 value was >12.5 μM. C150 significantly inhibited pancreatic cancer cell migration and invasion, as demonstrated by 3-dimensional cell invasion, wound healing and Boyden chamber Transwell migration-invasion assays. Moreover, C150 treatment decreased MMP-2 gene expression in PANC-1 cells and reduced MMP-2 activity in gelatin zymography assay. In an orthotopic mouse model of pancreatic cancer, C150 significantly reduced tumor growth at the dose of 15 mg/kg by intraperitoneal injection three times per week. Furthermore, C150 enhanced protein degradation of Snail, an important EMT-promoting transcription factor, and decreased the expression of the mesenchymal marker N-cadherin, while it increased the expression of the epithelial markers zonula occludens-1 and claudin-1. The findings of the present study suggested that C150 is a novel EMT inhibitor that may be promising for inhibiting pancreatic cancer growth and metastasis.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all cases of pancreatic cancer [1] and is one of the most lethal types of cancer, with an overall 5-year survival rate of only 9% [2]
The effects of C150 (Figure 1A) on cell viability were examined in a panel of human pancreatic cancer cell lines (PANC-1, BxPC-3, MIA PaCa-2, HPAF-II, L3.6pl) and an immortalized human pancreatic duct epithelial cell line, hTERT-HPNE
These data suggested that C150 inhibited pancreatic cancer cell proliferation rather than inducing apoptosis
Summary
Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all cases of pancreatic cancer [1] and is one of the most lethal types of cancer, with an overall 5-year survival rate of only 9% [2]. Gemcitabine as a single agent has been used as first-line chemotherapy for almost three decades [3], but its benefits in terms of survival are limited. A Novel Inhibitor for Pancreatic Cancer EMT a few months, but was associated with increased incidence of treatment-related toxicities [4]. A non-gemcitabine combination regimen comprising oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) has demonstrated a small benefit in terms of survival compared with gemcitabine, but the toxicities of this regimen are severe and have been reported to be intolerable by a significant proportion of the patients [5, 6]. The high mortality rate of PDAC is largely due to early metastasis, which accounts for the poor treatment outcomes [6, 7].
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