Saikosaponin A Mediates the Anti-Acute Myeloid Leukemia Effect via the P-JNK Signaling Pathway Induced by Endoplasmic Reticulum Stress.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-03-17 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S498458

Xiao-Hong Sun, Yi-Hong Chai, Xiao-Teng Bai, Hong-Xing Li, Pan-Pan Yang, Ya-Ming Xi

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引用次数: 0

Abstract

Objective: This study aims to investigate the antitumor effects of saikosaponin A (SSA) on acute myeloid leukemia (AML) and elucidate its underlying mechanisms, particularly focusing on the endoplasmic reticulum stress (ERS)-mediated MAPK-p-JNK signaling pathway.

Methods: The inhibitory effects of SSA on the proliferation of AML cell lines K562 and HL60 were evaluated using CCK8 and EdU assays. Apoptotic effects induced by SSA were analyzed via flow cytometry. RNA sequencing was performed to identify differentially expressed genes and enriched signaling pathways. Western blot analysis was utilized to confirm the involvement of ERS and activation of the MAPK-p-JNK signaling pathway. Further validation of the potential mechanism of SSA-induced apoptosis was conducted using SP600125 and 4PBA. The in vivo anti-AML efficacy of SSA was assessed using a xenograft model.

Results: SSA exhibited significant inhibitory effects on the proliferation of AML cell lines K562 and HL60, with IC50 values at 12, 24, and 48 hours demonstrating time- and dose-dependency (19.84 μM, 17.86 μM, and 15.38 μM for K562; 22.73 μM, 17.02 μM, and 15.25 μM for HL60, respectively). Western blot analysis demonstrated that SSA induces apoptosis in AML cells through the mitochondrial apoptotic pathway. Transcriptomic profiling and Western blot analyses confirmed that SSA activates the ERS-mediated p-JNK signaling pathway to induce apoptosis in AML, a process that can be reversed by the addition of 4PBA or SP600125. Furthermore, SSA significantly reduced tumor volume and weight in a NOD-SCID mouse xenograft model without causing notable toxicity to the liver, kidneys, lungs, or heart, while also activating the ERS and p-JNK signaling pathways in vivo.

Conclusion: SSA induces apoptosis in AML cells by activating the ERS-mediated p-JNK signaling pathway, exhibiting significant anti-AML effects both in vitro and in vivo, accompanied by a favorable safety profile.

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.