Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines

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.

Inhibition of HIF-1α through Suppression of NF-κB Activation by Compounds Isolated from Senecio graveolens

“…Besides, the isolated compounds did not show a cytotoxicity higher than 100 μM on the noncancerous cell line (PBMCs) by the MTT assay. However, in the LDH assay, phanurane, damsine, and scoparone compounds showed CC 50 Our results corroborate the cytotoxic activity of damsine described by Saeed et al [23], who observed cytotoxic activity (as measured by the resazurin reduction assay) at 24 h of damsine treatment on brain and colon cancer cell lines U87 MG/U87 ΔEGFR and HCT116. P53 + / + /HCT116 P53 -/with CC 50 s of 154.4 ± 8.9/24.1 ± 1.5 μM and 32.5 ± 6/133.6 ± 18.4 μM, respectively.…”

“…Regarding the mechanism of inhibitory action over HIF-1α by the compounds isolated from the dichloromethane/methanol ex-tract of S. graveolens, we could indicate, based on the bioinformatic experiment conducted by Dawood et al [50], that sesquiterpene lactones inhibiting NF-κB also possess the ability to inhibit HDAC (histone deacetylase). The latter leads to the inhibition of HIF-α in different tumour cell lines.…”

“…This phenomenon is suggested as a mechanism of collateral sensitivity [49]. In the case of scoparone, like other coumarins, it would cause degradation of HIF-1α, weakening glycolysis and all activities related to apoptosis in tumour cells [50]. Finally, regarding phanurane, there is no clear mechanism of its activity on HIF-1α.…”

“…The isolation led to the characterisation of phanurane (1), damsine (2), and scoparone (3), first reported in the S. graveolens species. Phanurane (1) showed inhibitory activity of hypoxia-inducible factor 1-alpha on the cancer cell lines U-373 MG (IC 50 . This study corroborates the cytotoxic activity of the isolated compounds through the inhibition of hypoxia-inducible factor 1-alpha as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cells.…”

Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Cancer Treatment?

“…Therefore, drugs that target both DNMT and HDAC enzymes could be an alternative approach to single target agents, with improved efficacy (Table 4). [101,102], Leukemia [103], Myeloma [104], Colon Cancer [102] Resveratrol Natural Compound (not approved) HDAC and DNMT1 Nonsmall Cell Lung Cancer [105], Breast Cancer [106,107], Thyroid Cancer [108] Berberine is a natural compound used for the treatment of parasitic and fungal infections which has been repurposed as DNMT and HDAC dual inhibitor [109]. Regarding DNMT inhibition, in a multiple myeloma cell line, berberine downregulated DNMT1 and DNMT3A gene expression and activity, restoring p53 expression through DNA hypomethylation [99].…”