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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Panaxynol, a natural Hsp90 inhibitor, effectively targets both lung cancer stem and non-stem cells
Huong Thuy Le1, Huy Truong Nguyen2, Hye-Young Min3
1Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Abstract:
Cancer stem-like cells (CSCs) contribute to tumor recurrence and chemoresistance. Hence, strategies targeting CSCs are crucial for effective anticancer therapies. Here, we demonstrate the capacities of the non-saponin fraction of Panax ginseng and its active principle panaxynol to inhibit Hsp90 function and viability of both non-CSC and CSC populations of NSCLC in vitro and in vivo. Panaxynol inhibited the sphere forming ability of NSCLC CSCs at nanomolar concentrations, and micromolar concentrations of panaxynol suppressed the viability of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance with minimal effect on normal cells derived from various organs. Orally administered panaxynol significantly reduced lung tumorigenesis in KrasG12D/+ transgenic mice and mice carrying NSCLC xenografts without detectable toxicity. Mechanistically, panaxynol disrupted Hsp90 function by binding to the N-terminal and C-terminal ATP-binding pockets of Hsp90 without increasing Hsp70 expression. These data suggest the potential of panaxynol as a natural Hsp90 inhibitor targeting both the N-terminal and C-terminal of Hsp90 with limited toxicities.
Insights
Panaxynol, derived from Panax ginseng, effectively targets cancer stem-like cells (CSCs) and non-CSCs in non-small cell lung cancer (NSCLC). This natural compound inhibits Hsp90, reducing tumor growth and chemoresistance with minimal toxicity.
Area of Science:
- Oncology
- Pharmacology
- Natural Products Chemistry
Background:
- Cancer stem-like cells (CSCs) drive tumor recurrence and chemoresistance in non-small cell lung cancer (NSCLC).
- Targeting CSCs is essential for developing effective anticancer therapies.
- Heat shock protein 90 (Hsp90) is a crucial molecular chaperone implicated in cancer progression.
Purpose of the Study:
- To investigate the potential of panaxynol, a component of Panax ginseng, as an Hsp90 inhibitor for targeting NSCLC CSCs.
- To evaluate the efficacy and safety of panaxynol in preclinical models of NSCLC.
Main Methods:
- In vitro assays assessing sphere formation, cell viability, and chemoresistance of NSCLC CSCs and non-CSCs.
- In vivo studies using KrasG12D/+ transgenic mice and NSCLC xenograft models.
- Mechanistic studies involving Hsp90 ATP-binding pocket interactions and Hsp70 expression analysis.
Main Results:
- Panaxynol inhibited NSCLC CSC sphere formation at nanomolar concentrations.
- Micromolar panaxynol suppressed viability of NSCLC cells and chemoresistant sublines with minimal toxicity to normal cells.
- Oral administration of panaxynol reduced lung tumorigenesis and xenograft growth in vivo without detectable toxicity.
- Panaxynol disrupted Hsp90 function by binding to its N-terminal and C-terminal ATP-binding pockets, without increasing Hsp70 levels.
Conclusions:
- Panaxynol demonstrates potent anticancer activity against both CSCs and non-CSCs in NSCLC.
- Panaxynol acts as a natural Hsp90 inhibitor with dual N-terminal and C-terminal binding.
- Panaxynol shows promise as a therapeutic agent for NSCLC with a favorable safety profile.
