Abstract
BackgroundSesquiterpene lactones (SL) are plant secondary metabolites that are known for their anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. Considering that several SL-derived drugs are currently in cancer clinical trials, we have tested two SL molecules, 3-β-methoxy-iso-seco-tanapartholide (β-tan) isolated from Achillea falcata and salograviolide A (Sal A) isolated from Centaurea ainetensis, for their anti-tumor properties. We used the mouse epidermal JB6P + cells as a model for tumor promotion and cellular transformation. Key players that are involved in cellular transformation and tumorigenesis are the AP-1 and NF-κB transcription factors; therefore, we assessed how β-tan and Sal A modulate their signaling pathways in JB6P + cells.MethodsThe effects of β-tan and Sal A on the growth of normal and neoplastic keratinocytes and on the tumor promotion-responsive JB6P + cells were determined using the MTT assay. Anchorage-independent cell growth transformation assays were used to evaluate the anti-tumor promoting properties of these SL molecules in JB6P + cells and dual luciferase reporter assays and western blot analysis were used to investigate their effects on tumor promoter-induced AP-1 and NF-κB activities and protein levels of key AP-1 and NF-кB target genes.Resultsβ-tan and Sal A selectively inhibited tumor promoter-induced cell growth and transformation of JB6P + cells at concentrations that do not affect JB6P + and primary keratinocytes basal cell growth. In addition, both molecules reduced basal and tumor promoter-induced NF-κB transcriptional activities, differentially regulated basal and tumor promoter-induced AP-1 transcriptional activities, and modulated key players of the AP-1 and NF-κB signaling pathways.ConclusionsThese results highlight the anti-tumor promoting properties of β-tan and Sal A. These SL molecules isolated from two plant species native to the Middle East may provide opportunities for complementary medicine practices.
Highlights
Sesquiterpene lactones (SL) are plant secondary metabolites that are known for their anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties
We focused on Activator protein-1 (AP-1) and Nuclear factor-κB (NF-κB) signaling pathways, known to play crucial roles in tumor promotion and in epidermal carcinogenesis [19]
Treatment with βtan caused a dose-dependent growth inhibition at 24 h, where a concentration of 10 μg/ml decreased cell growth significantly by 49 ± 7% (p < 0.01) in PAM 212 cells compared to a 6 ± 1% decrease in Primary mouse keratinocytes (PMKs) cell growth (Figure 2A)
Summary
Sesquiterpene lactones (SL) are plant secondary metabolites that are known for their anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. Considering that several SL-derived drugs are currently in cancer clinical trials, we have tested two SL molecules, 3-β-methoxy-iso-seco-tanapartholide (β-tan) isolated from Achillea falcata and salograviolide A (Sal A) isolated from Centaurea ainetensis, for their anti-tumor properties. We used the mouse epidermal JB6P + cells as a model for tumor promotion and cellular transformation. Sal A, which was isolated from Centaurea ainetensis, a species native to Lebanon and the Middle East, was found to possess antiinflammatory [13,14,16] and anti-cancer activities in a mouse colon cancer model and in skin cancer cells at different stages of tumorigenesis [10,12,17]. The JB6P + cells can be transformed to malignancy by tumor promoters, and constitute an ideal model to identify antitumor promoting and chemopreventive agents and to decipher their mechanism of action [19,22,23,24]
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