Parthenolide

Skin melanoma is a potentially lethal cancer and ranks as the 17th most common cancer worldwide. Overcoming resistance to advanced-stage melanoma is a significant challenge in its treatment. Parthenolide (PAR) is recognized as a potent anticancer small molecule, yet its potential in treating melanoma is poorly investigated.

Our objective was to investigate the apoptotic and anti-metastatic properties of PAR against the A2058 melanoma cells in vitro.

This study employed various assays, such as cytotoxicity, apoptosis, cell cycle analysis, reactive oxygen species (ROS) production, mRNA expressions, western blotting, gelatin zymography, and scratch assay. The synergy between PAR and dacarbazine, a chemotherapy drug for treating skin cancer, was also assessed.

Our study revealed that PAR significantly reduced the viability of A2058 cancer cells, demonstrating greater potency against cancer cells compared to normal L929 cells (IC50: 20 μM vs. 27 μM after 24h). PAR increased ROS production, elevated mRNA expression of pro-apoptotic Bax and NME1 genes, and decreased expression of the MITF gene. PAR induced apoptosis and cell cycle arrest in A2058 cells, as evidenced by the increased proportion of cells in the late apoptotic phase and sub-G1 cell cycle arrest. MMP-2 and MMP-9 mRNA and protein expressions, gelatinase activity, and the migration of A2058 cells were also decreased by PAR, suggesting its potential to suppress cancer cell invasion.

These results, along with the synergic effect with dacarbazine, indicated that PAR may have the potential to be a therapeutic drug for melanoma by triggering apoptosis and suppressing invasion and migration.

Oncogenic mutations in the BRAF gene, particularly the V600E mutation, are present in roughly half of metastatic cutaneous melanoma cases. BRAF inhibitors (BRAFi) have shown significant clinical efficacy; however, their long-term effectiveness is frequently limited by the development of resistance. Parthenolide, a sesquiterpene lactone derived from medicinal herbs, has previously been reported to exhibit anti-melanoma effects and to disrupt signaling pathways associated with BRAFi resistance.

This study aimed to evaluate the potential of parthenolide to overcome resistance to BRAFi in melanoma.

The effects of parthenolide on BRAFi-resistant melanoma cells were assessed using cell viability, apoptosis, and cell cycle assays. In vivo efficacy and safety were evaluated in a BRAFi-resistant melanoma xenograft mouse model. Target identification and validation were performed using network pharmacology, molecular docking, surface plasmon resonance, and Western blotting.

Parthenolide inhibited cell viability and induced apoptosis and S-phase cell cycle arrest in BRAFi-resistant melanoma cells. In vivo, parthenolide significantly suppressed tumor growth and reduced tumor weight in BRAFi-resistant melanoma xenografts without apparent toxicity. Mechanistically, parthenolide stably interacted with the N-terminal ATPase domain of Hsp90α and dose-dependently inhibited its ATPase activity. Hsp90α functions as a chaperone for several oncoproteins involved in signaling pathways driving BRAFi resistance. Parthenolide reduced the levels of several Hsp90α client proteins and inhibited their downstream pathways, including PI3K/Akt, Ras/Raf/MEK, and Src/STAT3, in BRAFi-resistant melanoma cells. Moreover, the Hsp90 activator tamoxifen attenuated the effects of parthenolide in these cells.

Our findings provide the first evidence that parthenolide can overcome BRAFi resistance in melanoma, highlighting its potential as a lead compound for the development of Hsp90α inhibitors to manage BRAFi-resistant cutaneous melanoma.