Cell context‐dependent activities of parthenolide in primary and metastatic melanoma cells

Abstract

Background and purpose: Growing evidence implicates NF-kB as an important contributor to metastasis and increased chemoresistance of melanoma. Here, we report the effects of parthenolide on either untreated, cisplatin-or TNFa-treated melanoma cell lines A375, 1205Lu and WM793, exhibiting different levels of constitutive NF-kB activity. Experimental approach: Electrophoretic mobility shift assay was used to assess changes in NF-kB activity, and real-time PCR to evaluate expression of NF-kB-regulated genes. Cell cycle arrest and apoptosis were assessed by flow cytometry. Cell death was also visualized by fluorescence microscopy. Migration was determined by scratch assay and invasiveness by Matrigel assay. Key results: Parthenolide suppressed both constitutive and induced NF-kB activity in melanoma cells. This was accompanied by down-regulation of cancer-related genes, with NF-kB-binding sites in their promoters, including: Bcl-XL, survivin, cyclin D1, interleukin 8 and matrix metalloproteinase 9. When the various effects of 6 mM parthenolide were compared, apoptosis associated with loss of mitochondrial membrane potential was most efficiently induced in 1205Lu cells, cell cycle arrest in G0/G1 phase was observed in WM793 cells, and high metastatic potential was markedly reduced in A375 cells. These findings not only reflected differences between melanoma cell lines in basal expression of NF-kB-regulated genes, but also suggested other parthenolide targets involved in cell cycle progression, migration, invasiveness and survival. Conclusions: Inhibition of constitutive and therapeutically induced NF-kB pathway by parthenolide might be useful in the treatment of melanoma, although the diversity of changes induced in melanoma cells with different genetic backgrounds indicate context-dependent poly-pharmacological properties of this compound.

Ethyl acetate extract from Selaginella doederleinii Hieron inhibits the growth of human lung cancer cells A549 via caspase-dependent apoptosis pathway

“…The AO/EB morphology results showed that A549 cells treated with 50 and 100 µg • mL -1 of the SDEA extract for 48 hr exhibited obvious morphological changes of apoptosis, in which lots of cells were marked by crescent-shaped or granular yellow-green nuclear staining and with concentrated and asymmetrically localized orange nuclear staining. Accordingly, the cell death was due to apoptosis rather than necrosis (Czyz et al, 2010). Flow cytometry with Annexin V-FITC/PI staining revealed that the SDEA extract increased the proportion of apoptotic A549 cells, confirming that the extract induced apoptosis in A549 cells.…”

Anti-apoptotic proteins on guard of melanoma cell survival

“…Recent studies have indicated that as melanoma cells possess several mechanisms to bypass the effects of drugs targeting B-Raf, it might be necessary to include targeting of Erk signaling in combinatorial therapeutic strategies to overcome the apoptotic resistance of melanoma [112]. The mutational induction of BRAF also enhances NF-jB activity [113], a transcription factor constitutively activated in melanoma [52]. It creates a vicious circle because on one hand, anti-apoptotic regulators such as IAPs, cFLIP, Bcl-2, Bcl-X L and A1 depend on NF-jB but on the other hand, they can also positively fuel the activation of this transcription factor, among others by the interactions with NEMO/IKKc [52,57,61,114].…”

“…The mutational induction of BRAF also enhances NF-jB activity [113], a transcription factor constitutively activated in melanoma [52]. It creates a vicious circle because on one hand, anti-apoptotic regulators such as IAPs, cFLIP, Bcl-2, Bcl-X L and A1 depend on NF-jB but on the other hand, they can also positively fuel the activation of this transcription factor, among others by the interactions with NEMO/IKKc [52,57,61,114]. Furthermore, a functional crosstalk between NFjB and STAT3 in many type of cancers that leads to their increased activation and results in elevated expression of the genes under their control [115], has been also observed in melanoma [116].…”

“…In metastatic melanoma cells with high expression of Bcl-X L , antisense strategy resulted in strong induction of apoptosis [51]. On the other hand, silencing Bcl-X L in the metastatic 1205Lu cell line, with low Bcl-X L constitutive expression [52] , resulted in poor cell death induction [41]. As with Bcl-2 in melanoma, Bcl-X L was found to be involved in the regulation of blood vessel formation through stimulating the expression of pro-angiogenic CXCL8 [53].…”

Targeting NF-κB and HIF-1 Pathways for the Treatment of Cancer: Part I

“…Substantial evidence was collected for the anticancer potential of other natural products, sesquiterpene lactones, derived from Tanacetum parthenium. One of them, parthenolide and its orally bioavailable dimethylamino derivative, were found to inhibit proliferation of various cancer cells by inducing apoptosis and necrosis in vitro mainly but not exclusively via inhibiting NF-jB pathway (Anderson and Bejcek 2008;Czyz et al 2010;Duechler et al 2008;Wen et al 2002). Parthenolide is an especially promising anticancer drug candidate since it exerted potential to target either cancer stem cells or progenitor cells of cancer (Guzman et al 2005;Zhou et al 2008).…”