Spongiatriol Inhibits Nuclear Factor Kappa B Activation and Induces Apoptosis in Pancreatic Cancer Cells

Esther Guzmán,Tara Pitts,Michael Maher,Alexis Temkin,Amy Wright

doi:10.3390/md11041140

Esther Guzmán, Tara Pitts + Show 3 more

Open Access

https://doi.org/10.3390/md11041140

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Abstract

Pancreatic cancer, the fourth leading cause of cancer death in the US, is highly resistant to all current chemotherapies, and its growth is facilitated by chronic inflammation. The majority of pro-inflammatory cytokines initiate signaling cascades that converge at the activation of the Nuclear Factor Kappa B (NFκB), a signal transduction molecule that promotes cell survival, proliferation and angiogenesis. In an effort to identify novel inhibitors of NFκB, the HBOI library of pure compounds was screened using a reporter cell line that produces luciferin under the transcriptional control of NFκB. Seven compounds were identified through this screen, but in the case of five of them, their reported mechanism of action made them unlikely to be specific NFκB inhibitors. Spongiatriol, a marine furanoditerpenoid that was first isolated in the 1970s, is shown here to inhibit NFκB transcriptional activity in a reporter cell line, to reduce levels of phosphorylated (active) NFκB in the AsPC-1 cell line, to have an IC50 for cytotoxicity in the low micromolar range against the AsPC-1, BxPC-3, MiaPaCa-2 and Panc-1 pancreatic cancer cell lines, and to induce moderate but significant apoptosis in both the AsPC-1 and the Panc-1 cell lines.

Highlights

Pancreatic cancer is the fourth leading cause of cancer death in the United States
Chronic inflammatory diseases that are associated with malignancies include asbestosis and bronchitis with lung cancer, gingivitis with oral squamous cell carcinoma, colitis with colon cancer, skin inflammation with melanoma and pancreatitis with pancreatic cancer [2,4] Pancreatic ductal adenocarcinoma is highly resistant to all current chemotherapies, and its growth is often facilitated by chronic inflammation [5,6,7]
The majority of pro-inflammatory cytokines initiate signaling cascades that converge at the activation of the Nuclear Factor Kappa B (NFκB), a signal transducer, which promotes cell survival, proliferation and angiogenesis [8]

Summary

Introduction

Pancreatic cancer is the fourth leading cause of cancer death in the United States. More than. 44,000 people are expected to be diagnosed with the disease in 2013 and of those, only 26% will survive one year post diagnosis and only 6% will survive five years post diagnosis [1]. In pancreatic cancer and pancreatic cancer cell lines, NFκB is often constitutively activated [9] and its activation correlates with metastatic potential [10]. Spongiatriol, a marine furanoditerpenoid that was first isolated in the 1970s [11], was found to be active in the assays and did not have a reported mechanism of action that explained the inhibition of NFκB. We undertook studies to better understand its effects in pancreatic cancer cell lines

Results and Discussion

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Cell Culture

Caspase-Glo

Intracellular Staining

Conclusions