Related Experiment Video
Updated: Feb 16, 2026
Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors
Published on: October 17, 2025
Crotonoside exhibits selective post-inhibition effect in AML cells via inhibition of FLT3 and HDAC3/6
Yu-Zhi Li1, Si Yu1, Pei-Ao Yan1
1Pharmacy College, Chengdu University of Traditional Chinese Medicine, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, Key Laboratory of Systematic Research, Development and Utilization of Chinese Medicine Resources in Sichuan Province-Key Laboratory Breeding Base of Co-founded by Sichuan Province and MOST, Sichuan, China.
Abstract:
Targeted therapies for the treatment of acute myeloid leukemia (AML), specifically the FLT3 inhibitors, have shown promising results. Nevertheless, it is very unlikely that inhibitors which target a single pathway will provide long-term disease control. Here, we report the characterization of crotonoside, a natural product extracted from Chinese medicinal herb, Croton, for the treatment of AML via inhibition of FLT3 and HDAC3/6. In vitro, crotonoside exhibited selective inhibition in AML cells. In vivo, crotonoside treatment at 70 and 35 mg/kg/d produced significant AML tumor inhibition rates of 93.5% and 73.6%, respectively. Studies on the anti-AML mechanism of crotonoside demonstrated a significant inhibition of FLT3 signaling, cell cycle arrest in G0/G1 phase, and apoptosis. In contrast to classic FLT3 inhibitor; sunitinib, crotonoside was able to selectively suppress the expression of HDAC3 and HDAC6 without altering the expression of other HDAC isoforms. Inhibitors of HDAC3 and HDAC6; RGFP966 and HPOB, respectively, also exhibited selective inhibition in AML cells. Furthermore, we established novel signaling pathways including HDAC3/NF-κB-p65 and HDAC6/c-Myc besides FLT3/c-Myc which are aberrantly regulated in the progression of AML. In addition, crotonoside alone or the combination of sunitinib/RFP966/HPOB exhibited a significant post-inhibition effect in AML cells by the inhibition of FLT3 and HDAC3/6. Inhibitors targeting the FLT3 and HDAC3/6 might provide a more effective treatment strategy for AML. Taken together, the present study suggests that crotonoside could be a promising candidate for the treatment of AML, and deserves further investigations.
Insights
Crotonoside, a natural compound, effectively treats acute myeloid leukemia (AML) by inhibiting FLT3 and HDAC3/6 pathways. This dual-action approach offers a promising new strategy for AML therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Targeted therapies like FLT3 inhibitors show promise for acute myeloid leukemia (AML).
- Single-pathway inhibition is unlikely to achieve long-term AML disease control.
- Natural products offer potential for novel therapeutic strategies.
Purpose of the Study:
- To characterize crotonoside, a natural product from the Croton herb, for AML treatment.
- To investigate crotonoside's mechanism of action, targeting FLT3 and HDAC3/6 pathways.
- To evaluate the therapeutic potential of crotonoside in AML models.
Main Methods:
- In vitro and in vivo studies of crotonoside's effects on AML cells and tumors.
- Analysis of FLT3 signaling, cell cycle, apoptosis, and HDAC isoform expression.
- Investigation of novel signaling pathways involving HDAC3/NF-κB-p65 and HDAC6/c-Myc.
Main Results:
- Crotonoside demonstrated selective inhibition in AML cells and significant tumor inhibition in vivo.
- It induced FLT3 signaling inhibition, G0/G1 cell cycle arrest, and apoptosis.
- Crotonoside selectively suppressed HDAC3 and HDAC6 expression, unlike sunitinib.
Conclusions:
- Crotonoside exhibits potent anti-AML activity through dual inhibition of FLT3 and HDAC3/6.
- Novel pathways (HDAC3/NF-κB-p65, HDAC6/c-Myc) are implicated in AML progression.
- Combined targeting of FLT3 and HDAC3/6 presents a promising therapeutic strategy for AML.
