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

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.

Spongian Diterpenes Including One with a Rearranged Skeleton from the Marine Sponge Spongia officinalis

“…To date, about 200 spongian diterpenes and rearranged derivatives have been reported since the first spongian diterpene, named isoagatholactone, was isolated from the sponge Spongia officinalis (family Spongiidae) collected in the Mediterranean . Some of these compounds were reported to possess a variety of pharmaceutical bioactivities, such as cytotoxic, anti-inflammatory, and antiviral properties. − Spongia species of the South China Sea have been rarely chemically investigated, with only three studies reporting three new spongian diterpenes and two novel trinorsesquiterpenoids from the title species and nine sesquiterpene quinones/hydroquinones from S. pertusa , making them an understudied resource of chemical diversity for potential drug discovery efforts. In the course of our continuing research on bioactive molecules from marine invertebrates of the South China Sea, − a specimen of the previously investigated sponge, S. officinalis , was re-collected.…”

NO-Donor Nitrosyl Iron Complex with 2-Aminophenolyl Ligand Induces Apoptosis and Inhibits NF-κB Function in HeLa Cells

“…NF-κB signaling is well recognized as an important molecular crossway that contributes to various diseases, including cancer [67][68][69][70][71][72][73]. Chemical compounds that inhibit NF-κB, either directly or via its upstream regulators, cause cell death and suppress tumor growth [74][75][76][77][78][79][80][81][82][83] or sensitize cancer cells to radiation or chemotherapeutic agents [84][85][86].…”

TNF-α Mediated Increase of HIF-1α Inhibits VASP Expression, Which Reduces Alveolar-Capillary Barrier Function during Acute Lung Injury (ALI)

“…Inflammatory cytokines participate in wide ranges of biological effects, such as the innate immune response, the adaptive immune response during inflammation and inflammation-related diseases. The majority of these functions are achieved via the activation of a signaling cascade by releasing diverse growth factors, such as VEGF and PDEGF, and transcription factors, such as NF-κB and HIF-1α [38] , [39] . The related research by Janek Henes's indicates that NF-κB activation accelerates the increase of alveolar-capillary permeability during TNF-α-induced pneumonia in VASP knockout mice [30] .…”