2. Academic Validation
  3. Parthenolide inhibits Hsp90α ATPase activity and overcomes acquired BRAF-inhibitor resistance in cutaneous melanoma

Parthenolide inhibits Hsp90α ATPase activity and overcomes acquired BRAF-inhibitor resistance in cutaneous melanoma

  • Phytomedicine. 2025 Oct:146:157151. doi: 10.1016/j.phymed.2025.157151.
Xiao-Qi Wang 1,  Xiao-Fei Yu 1,  Amy Sze-Man Li 1,  Rui-Xuan Han 1,  Li Wang 1,  Jia-Ying Wu 1,  Ying Wu 1,  Jin-Jin He 1,  Bin Liu 2,  Wilson Man-Shan Tsui 3,  Guang-Hua Lu 4,  Huanbiao Mo 5,  Xiu-Qiong Fu 6,  Zhi-Ling Yu 7
Affiliations

Affiliations

  • 1 Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China.
  • 2 Department of Traditional Chinese Medicine, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
  • 3 Department of Pathology, Tseung Kwan O Hospital, Tseung Kwan O, Hong Kong SAR, China.
  • 4 State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 5 Department of Nutrition, Georgia State University, Atlanta, GA 30303, USA.
  • 6 Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China. Electronic address: makyfu@hkbu.edu.hk.
  • 7 Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China. Electronic address: zlyu@hkbu.edu.hk.
PMID: 40815947 DOI: 10.1016/j.phymed.2025.157151
Abstract

Background: 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.

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

Study design and methods: 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.

Results: 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.

Conclusion: 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.

Keywords

BRAF inhibitor resistance; Cutaneous melanoma; Hsp90α; Parthenolide.

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