Parthenolide

Melanoma remains a global health challenge. While targeted therapy with BRAF^V600/MEK inhibitors largely improved the survival and quality of life for advanced melanoma patients, most of them progress due to acquired resistance. Dynamic heterogeneity and phenotypic plasticity of resistant melanoma prompted us to use parthenolide, an agent with an assorted bioactivity profile in combination with agents targeting enhanced pro-survival capacity of resistant melanoma cells. Parthenolide was used in combination with S63845, ABT-263 and ABT-199, BH3-mimetics targeting anti-/pro-apoptotic protein interactions. These drug combinations were investigated in patient-derived drug-naïve melanoma cell lines, their trametinib-resistant counterparts displaying either dedifferentiation neural-crest-like phenotype (MITF^low/NGFR^high) or differentiation phenotype (MITF^high/NGFR^low), and trametinib-resistant cell lines undergoing the phenotype transition after trametinib withdrawal. While parthenolide reduces proliferation and increases senescent cell fraction accompanied with reduction of NF-κB activity and MITF expression, it does not trigger apoptosis in high percentages of melanoma cells. Combination of parthenolide with BH3-mimetics induces externalization of phosphatidylserine, most efficiently with S63845, an inhibitor of pro-survival MCL-1. Parthenolide and S63845 synergize to cause massive apoptosis regardless of melanoma cell phenotypes, which is associated with caspase-3/7 activation, H2AX phosphorylation, and PARP cleavage. Mechanistically, parthenolide combined with S63845 reduces the protein level of MCL-1, upregulates pro-apoptotic NOXA, and prevents S63845-induced reduction of NOXA protein. Collectively, massive apoptosis induced synergistically by parthenolide combined with S63845 in trametinib-resistant melanoma cells displaying various phenotypes justifies exploring the potential of this strategy as a future treatment option for patients with melanoma resistant to therapies targeting MAPK signaling.

Ovarian cancer (OV) is the most prevalent and lethal gynecologic malignancy globally. Cisplatin remains the first-line chemotherapeutic regimen for OV; however, chemotherapy resistance poses a persistent clinical challenge in gynecologic oncology. Parthenolide, a naturally derived phytochemical, exhibits broad-spectrum antitumor activity. Recent studies suggest that parthenolide may reverse cisplatin-resistance in OV when used in combination therapy. This study aims to elucidate the molecular targets and mechanisms underlying parthenolide-mediated reversal of cisplatin-resistance by integrating network pharmacology and molecular docking approaches.

Platinum-resistant and control OV gene expression datasets were retrieved from the gene expression omnibus database. Differentially expressed genes (DEGs) were identified using the limma R package. Cellular enrichment patterns in platinum-resistant and control samples were analyzed via single-sample Gene Set Enrichment Analysis (ssGSEA). Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to identify modules associated with differentially enriched cell types. A protein-protein interaction network of overlapping genes from DEGs and WGCNA-identified genes was constructed to pinpoint hub genes. Receiver operating characteristic (ROC) curves assessed the diagnostic utility of hub genes. Molecular docking and binding pocket analysis were performed to explore parthenolide-protein interactions.

A total of 3582 DEGs were identified between platinum-resistant and control samples, enriched in biological processes (e.g., cell junction assembly), cellular components (e.g., collagen-containing extracellular matrix), and molecular functions (e.g., signaling receptor activation). WGCNA revealed 331 genes correlated with differentially enriched cell types. Subsequent overlap analysis identified 266 immunity-related genes in platinum-resistant OV. Hub genes, including apolipoprotein E, demonstrated diagnostic value via ROC analysis. Molecular docking highlighted β2-microglobulin, brain-derived neurotrophic factor, cellular communication network factor 2, and activator protein-1 as parthenolide targets, with binding pocket analysis identifying critical interaction residues.

This study identifies candidate genes linked to cisplatin-resistance and delineates molecular mechanisms by which parthenolide may counteract resistance, supporting its clinical application in OV therapy.