Lung Cancer Chemopreventive Activity of Patulin Isolated from Penicillium vulpinum

Abstract

Lung cancer is the most lethal form of cancer in the world. Its development often involves an overactivation of the nuclear factor kappa B (NF-κB) pathway, leading to increased cell proliferation, survival, mobility, and a decrease in apoptosis. Therefore, NF-κB inhibitors are actively sought after for both cancer chemoprevention and therapy, and fungi represent an interesting unexplored reservoir for such molecules. The aim of the present work was to find naturally occurring lung cancer chemopreventive compounds by investigating the metabolites of Penicillium vulpinum, a fungus that grows naturally on dung. Penicillium vulpinum was cultivated in Potato Dextrose Broth and extracted with ethyl acetate. Bioassay-guided fractionation of this extract was performed by measuring NF-κB activity using a HEK293 cell line transfected with an NF-κB-driven luciferase reporter gene. The mycotoxin patulin was identified as a nanomolar inhibitor of TNF-α-induced NF-κB activity. Immunocytochemistry and Western blot analyses revealed that its mechanism of action involved an inhibition of p65 nuclear translocation and was independent from the NF-κB inhibitor α (IκBα) degradation process. Enhancing its interest in lung cancer chemoprevention, patulin also exhibited antiproliferative, proapoptotic, and antimigration effects on human lung adenocarcinoma cells through inhibition of the Wnt pathway.

Identification of Patulin from Penicillium coprobium as a Toxin for Enteric Neurons

“…Due to the observed neurotoxic effects, we also propose that the usage of patulin as a chemopreventive for lung cancer through inhibition of the NF-κB pathway as suggested by a recent publication [54] should be viewed with caution. Though it was discovered that 1.5 µM patulin can inhibit roughly 90% of NF-κB activity in HEK cells, and therefore could serve as a therapeutic agent [54], our findings show that even a third of the tested concentration (0.5 µM) can significantly reduce the viability of neuronal cells. As sensory nerves innervating the lung play an important role in regulating cardiopulmonary functions and defense reflexes [55], severe side effects on neuronal cells using patulin with a therapeutic approach cannot be ruled out.…”

Mechanisms Underlying Biological Effects of Cruciferous Glucosinolate-Derived Isothiocyanates/Indoles: A Focus on Metabolic Syndrome

“…Nrf2 is a transcriptional factor that binds to ARE regions in DNA to induce the expression of major antioxidant enzymes that detoxify ROS ( 126 , 127 ) and can inhibit the nuclear factor kappa B (NF-κB) transcriptional factor. NF-κB activity is linked to cellular processes that promote cancer, such as inflammation, cell proliferation, and angiogenesis and facilitate tumor growth and metastasis ( 128 , 129 ); thus, its inhibition could yield positive effects in the prevention or treatment of cancer. The evidences that SFN and BITC decrease NF-κB activity have been described in the bladder and colon cancer cell lines T24 and T29, respectively ( 130 , 131 ).…”

Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers

“…NF-κB is a redox sensitive complex and can be inhibited by higher antioxidants. Suppression of NF-κB activation is considered as a central mechanism in the prevention of tumor growth [ 24 ]. Majorly BITC, PEITC and SFN involved in the Nrf2-ROS-ARE dependent mechanisms to attenuate the NF-κB activation.…”

“…NF-κB activity is mainly involved in the survival of the tumor cells to prevent from the apoptotic or senescent. Therefore, suppression of NF-κB activation is considered as a central mechanism in the prohibition of tumor growth [ 24 ]. Therefore, knowledge on the mechanism of NF-κB and its interaction with the beta-catenin/cyclin D1 pathway is essential for finding the novel therapeutic agent(s).…”