Repurposing Suan-Zao-Ren-Tang as anticancer agents in apoptotic sensitization against non-small cell lung cancer cell
Yu-Chi Hsiao1,2, Yi-Hua Sheng1, Tse-Yu Chen1
1School of Pharmacy, National Taiwan University, No. 33, Linsen S. Rd., Taipei, 100, Taiwan.
Abstract:
Treatment of non-small cell lung cancer (NSCLC) is a high unmet medical need. We repurposed Suan-Zao-Ren-Tang (SZRT), a widely used traditional Chinese medicine in alleviating insomnia, to sensitize vinorelbine-induced anti-NSCLC effect and have unveiled the underlying mechanism. B7E2, the partial purified extract from SZRT, was used through bioactivity-guided fractionation based on anti-proliferative activity in NSCLC cell lines A549 and NCI-H460. Three batches of B7E2 and their individual components were prepared for the examination of components and bioactivity and mechanistic study. B7E2 alone had no cytotoxic effect but its combination with vinorelbine displayed a synergistic activity in killing NSCLC cells. Apoptotic sensitization was verified by a remarkable increase of caspase activation and phosphorylation of Bcl-2 and Bcl-xL. Combination treatment prolonged mitotic arrest and induced a substantial activation of spindle assembly checkpoint (SAC) characterized by BUBR1 phosphorylation at Ser670 and Thr680, and cyclin B1 upregulation. Combination treatment enhanced the interaction between mitotic checkpoint complex (MCC) components, including BUBR1, MAD2, BUB3 and CDC20. Further analysis revealed that SZRT components, including senkyunolide-A, trans-neocnidilide, 3-butylidenephthalide, betulinic acid and linoleic acid, were responsible for B7E2 activities. Three B7E2 batches showed a good chemical similarity and similar activities between batches. The data suggest that B7E2 is a potential chemosensitizer in potentiating vinorelbine-induced anti-NSCLC activity through amplification and prolongation of SAC activation.
Insights
This study repurposed Suan-Zao-Ren-Tang (SZRT), a traditional Chinese medicine, to enhance chemotherapy for non-small cell lung cancer (NSCLC). A purified extract, B7E2, synergized with vinorelbine, sensitizing cancer cells by prolonging mitotic arrest and spindle assembly checkpoint activation.
Area of Science:
- Pharmacology
- Oncology
- Traditional Chinese Medicine
Background:
- Non-small cell lung cancer (NSCLC) treatment faces significant unmet needs.
- Traditional Chinese Medicine (TCM) offers potential avenues for novel therapeutic strategies.
- Vinorelbine is a chemotherapeutic agent used in NSCLC treatment.
Purpose of the Study:
- To investigate the potential of Suan-Zao-Ren-Tang (SZRT), a TCM, as a chemosensitizer for vinorelbine in NSCLC.
- To elucidate the underlying mechanism of action for SZRT's sensitizing effect.
Main Methods:
- Bioactivity-guided fractionation of SZRT to isolate the active component B7E2 using NSCLC cell lines (A549, NCI-H460).
- Assessed the synergistic anti-proliferative effects of B7E2 in combination with vinorelbine.
- Investigated the mechanistic pathways, including apoptosis, mitotic arrest, and spindle assembly checkpoint (SAC) activation.
Main Results:
- B7E2 alone showed no cytotoxicity but synergized with vinorelbine to kill NSCLC cells.
- Combination treatment induced apoptotic sensitization via caspase activation and Bcl-2/Bcl-xL phosphorylation.
- Prolonged mitotic arrest and enhanced spindle assembly checkpoint (SAC) activation were observed, characterized by BUBR1 phosphorylation and cyclin B1 upregulation.
Conclusions:
- B7E2, a partial purified extract of SZRT, acts as a potent chemosensitizer for vinorelbine in NSCLC.
- The mechanism involves amplification and prolongation of SAC activation, leading to enhanced anti-cancer efficacy.
- SZRT components like senkyunolide-A and betulinic acid contribute to B7E2's activity, suggesting potential for novel NSCLC therapeutics.
