Abstract
Parthenolide (PT) is a sesquiterpene lactone isolated from Tanacetum parthenium. In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53+/+) colon carcinoma cells and their parental HCT116 knockout p53 (p53-/-) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated EGFR cDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.
Highlights
Parthenolide (PT) is a sesquiterpene lactone isolated from the Mexican-Indian medicinal plant Tanacetum parthenium
We investigated the cytotoxic effect of PT toward breast cancer resistance protein (BCRP)-transfected breast cancer cells, epidermal growth factor receptor (EGFR)-mutated brain cancer cells, and colon cancer cells with a knockout mutation in the tumor suppressor gene 53 (TP53)
EGFR cells exhibited a slight sensitivity toward PT with an IC50 value of 32.7 ± 3.8 μM, which was lower than the IC50 value of wild-type U87.MG cells (46.0 ± 3.8 μM) (Table 1)
Summary
Parthenolide (PT) is a sesquiterpene lactone isolated from the Mexican-Indian medicinal plant Tanacetum parthenium. It has anti-inflammatory properties and is clinically used for migraine treatment (Murphy et al, 1988; Bork et al, 1997). PT is nucleophilic in nature due to its lactone ring and epoxide group. This feature explains, why PT exerts several biological activities, such as anti-cancer activity by inducing extrinsic and intrinsic pathways of apoptosis (Wen et al, 2002; Zhang et al, 2004) without affecting normal cells (Mathema et al, 2012). PT inhibited MCF-7 mammosphere formation and MCF-7 xenograft tumor growth as well as elimination of breast cancer stem cells by NF-κB pathway deactivation (Dandawate et al, 2016)
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