Abstract
Introduction: BRAF(V600E) inhibitors (BRAFi) including vemurafenib have shown
remarkable clinical efficacy in patients with BRAF(V600E)-mutant melanoma.
However, most patients develop resistance to BRAFi within 6-8 months. Currently, no approved drug can overcome vemurafenib resistance. Parthenolide, a sesquiterpene found in diverse medicinal herbs, exerts anti-melanoma effects, while whether it overcomes vemurafenib resistance in melanoma is still unknown. This study aimed to determine whether parthenolide overcomes vemurafenib resistance in melanoma.
Methods: Vemurafenib-resistant A375 (A375-VR) melanoma cells and A375-VR-
bearing mice were used to evaluate the effects of parthenolide in overcoming
vemurafenib resistance. Molecular assays were performed to investigate the
mechanisms of action of parthenolide.
Results: Parthenolide overcomed vemurafenib resistance in both A375-VR melanoma cells and A375-VR-bearing mice. Drug-targets-disease network analysis identified heat shock protein 90α (Hsp90α) as a key mediator of the effects of the compound. Mechanistic studies revealed that parthenolide directly bound to Hsp90α and dose-dependently inhibited the ATPase activity of Hsp90α. Parthenolide decreased levels of Hsp90 client proteins including RTKs (EGFR, PDGFR-β, Αxl and IGF1-R), B-Raf (V600E), C-Raf and Src, and inhibited their downstream PI3K/Akt, Ras/Raf/MEK and Src/STAT3 pathways in A375-VR cells. A protein synthesis inhibitor cycloheximide diminished the effects of parthenolide on the stability of Hsp90 clients in cultured A375-VR cells. Also, parthenolide inhibited Hsp90 signalling in A375-VR xenografts. In A375-VR cells, parthenolide induced mitochondrial shrinkage, a morphological sign of ferroptosis. Moreover, parthenolide decreased mitochondrial membrane potential (ΔΨm), inhibited GPX4 activity, and elevated levels of Fe2+, LPO, ROS, confirming ferroptosis induction. Parthenolide downregulated protein levels of the ferroptosis suppressors SLC7A11 and GPX4 but not the mRNA levels of them.
Conclusions: We for the first time demonstrated that parthenolide overcomes
vemurafenib resistance in melanoma; and Hsp90 inhibition and ferroptosis induction are possibly involved in parthenolide’s effects. This work facilities the development of parthenolide as a therapeutic agent in treating vemurafenib-resistant melanomas.
remarkable clinical efficacy in patients with BRAF(V600E)-mutant melanoma.
However, most patients develop resistance to BRAFi within 6-8 months. Currently, no approved drug can overcome vemurafenib resistance. Parthenolide, a sesquiterpene found in diverse medicinal herbs, exerts anti-melanoma effects, while whether it overcomes vemurafenib resistance in melanoma is still unknown. This study aimed to determine whether parthenolide overcomes vemurafenib resistance in melanoma.
Methods: Vemurafenib-resistant A375 (A375-VR) melanoma cells and A375-VR-
bearing mice were used to evaluate the effects of parthenolide in overcoming
vemurafenib resistance. Molecular assays were performed to investigate the
mechanisms of action of parthenolide.
Results: Parthenolide overcomed vemurafenib resistance in both A375-VR melanoma cells and A375-VR-bearing mice. Drug-targets-disease network analysis identified heat shock protein 90α (Hsp90α) as a key mediator of the effects of the compound. Mechanistic studies revealed that parthenolide directly bound to Hsp90α and dose-dependently inhibited the ATPase activity of Hsp90α. Parthenolide decreased levels of Hsp90 client proteins including RTKs (EGFR, PDGFR-β, Αxl and IGF1-R), B-Raf (V600E), C-Raf and Src, and inhibited their downstream PI3K/Akt, Ras/Raf/MEK and Src/STAT3 pathways in A375-VR cells. A protein synthesis inhibitor cycloheximide diminished the effects of parthenolide on the stability of Hsp90 clients in cultured A375-VR cells. Also, parthenolide inhibited Hsp90 signalling in A375-VR xenografts. In A375-VR cells, parthenolide induced mitochondrial shrinkage, a morphological sign of ferroptosis. Moreover, parthenolide decreased mitochondrial membrane potential (ΔΨm), inhibited GPX4 activity, and elevated levels of Fe2+, LPO, ROS, confirming ferroptosis induction. Parthenolide downregulated protein levels of the ferroptosis suppressors SLC7A11 and GPX4 but not the mRNA levels of them.
Conclusions: We for the first time demonstrated that parthenolide overcomes
vemurafenib resistance in melanoma; and Hsp90 inhibition and ferroptosis induction are possibly involved in parthenolide’s effects. This work facilities the development of parthenolide as a therapeutic agent in treating vemurafenib-resistant melanomas.
| Original language | English |
|---|---|
| Number of pages | 2 |
| Publication status | Published - 30 Oct 2022 |
| Event | The Global Conference on Evidence-based Traditional Medicine, GCETM 2022 - Virtual, Penang, Malaysia Duration: 29 Oct 2022 → 30 Oct 2022 https://gcetm2022.com/ https://gcetm2022.com/program/ |
Conference
| Conference | The Global Conference on Evidence-based Traditional Medicine, GCETM 2022 |
|---|---|
| Country/Territory | Malaysia |
| City | Penang |
| Period | 29/10/22 → 30/10/22 |
| Internet address |
User-Defined Keywords
- parthenolide
- melanoma
- vemurafenib resistance
- Hsp90 signaling
- ferroptosis