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已发表论文
木香烃内酯通过双靶向糖原合酶激酶 3β 和 B 细胞淋巴瘤 2 抑制双表达淋巴瘤
Authors Chen J, Liao Q, Yang S, Bian J, Li X, Zhao L, Wen D, Bai D, Yu C, Zhou C, Xu Z
Received 29 July 2025
Accepted for publication 6 December 2025
Published 12 December 2025 Volume 2025:15 Pages 217—233
DOI https://doi.org/10.2147/BLCTT.S556751
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Wilson Gonsalves
Jianhua Chen,1,* Qing Liao,1,2,* Sha Yang,1 Jiaojiao Bian,1 Xianfu Li,3 Lu Zhao,4 Dan Wen,1 Dazhang Bai,5 Chunlei Yu,1 Chunyang Zhou,1 Zhengmin Xu1,6
1Department of Pharmacology Institute of Materia Medica, School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 2Department of Pharmacy, Yingshan County People’s Hospital, Nanchong, Sichuan, 637000, People’s Republic of China; 3Department of Radiotherapy, Nuclear Medicine Department, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 4Sichuan Institute for Drug Control (Sichuan Testing Center of Medical Devices), Chengdu, Sichuan, 637000, People’s Republic of China; 5Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Institute of Neurological Diseases, North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 6Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Skeletal Muscle Disease, Nanchong Traditional Chinese Medicine Hospital, Nanchong, Sichuan, 637000, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zhengmin Xu, North Sichuan Medical College, No. 234 Fuliang Road, Shunqing District, Nanchong, Sichuan, 637000, People’s Republic of China, Email xuzhengmin@nsmc.edu.cn
Background: Dual-expression lymphoma (DEL) is an aggressive subtype with concurrent MYC and BCL2 overexpression. This disease exhibits a poor prognosis and responds poorly to standard R-CHOP therapy,highlighting the urgent need for novel treatments. Alantolactone (ALA), a natural compound, has shown anticancer potential, but its efficacy and mechanism in DEL remain unclear. This study aimed to investigate the anti-tumor effects of ALA against DEL and its underlying dual-targeting mechanism.
Methods: The cytotoxic activity of ALA was assessed in lymphoma cell lines and a normal lymphocyte line. Apoptosis was evaluated by flow cytometry and Western blotting. Network pharmacology, molecular docking, dynamics simulations, and cellular thermal shift assays (CETSA) were utilized to identify and validate direct targets of ALA. The anti-tumor efficacy of ALA was further examined in a DEL xenograft mouse model using PET-CT imaging and survival analysis.
Results: In the present study, the anticancer activity of ALA in DEL was explored in vivo and in vitro. ALA was shown to inhibit DEL growth in vivo with little toxicity to normal tissues. Mechanistically, ALA stabilized active glycogen synthase kinase 3β (GSK3β) (binding affinity: − 15.66 kcal/mol; ΔTm +9°C), enhancing β-catenin degradation and suppressing Wnt-driven oncogenesis. Simultaneously, ALA directly bound BCL2 (− 22.22 kcal/mol), triggering both intrinsic and extrinsic apoptotic pathways. Simultaneously, ALA directly bound BCL2 (binding affinity: − 22.22 kcal/mol), triggering both intrinsic and extrinsic apoptotic pathways. ALA exhibited robust anti-DEL activity across preclinical models. While in vivo it significantly suppressed tumor progression (SUVmax reduction > 50%, p< 0.01) and extended survival (median 50 vs 80 days, p< 0.01) in DEL xenografts. The therapeutic relevance was underscored by clinical correlation showing DEL patients with high GSK3β expression had superior survival outcomes.
Conclusion: ALA exerts potent anti-DEL activity by simultaneously targeting GSK3β in the Wnt pathway and directly inhibiting BCL2, leading to suppressed tumor proliferation and induced apoptosis. Our findings highlight ALA as a promising multi-targeting therapeutic candidate for DEL and propose a novel strategy against this refractory lymphoma.
Keywords: alantolactone, dual-expression lymphoma, Wnt, glycogen synthase kinase 3β, B-cell lymphoma 2, apoptosis
1Department of Pharmacology Institute of Materia Medica, School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 2Department of Pharmacy, Yingshan County People’s Hospital, Nanchong, Sichuan, 637000, People’s Republic of China; 3Department of Radiotherapy, Nuclear Medicine Department, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 4Sichuan Institute for Drug Control (Sichuan Testing Center of Medical Devices), Chengdu, Sichuan, 637000, People’s Republic of China; 5Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Institute of Neurological Diseases, North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 6Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Skeletal Muscle Disease, Nanchong Traditional Chinese Medicine Hospital, Nanchong, Sichuan, 637000, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zhengmin Xu, North Sichuan Medical College, No. 234 Fuliang Road, Shunqing District, Nanchong, Sichuan, 637000, People’s Republic of China, Email xuzhengmin@nsmc.edu.cn
Background: Dual-expression lymphoma (DEL) is an aggressive subtype with concurrent MYC and BCL2 overexpression. This disease exhibits a poor prognosis and responds poorly to standard R-CHOP therapy,highlighting the urgent need for novel treatments. Alantolactone (ALA), a natural compound, has shown anticancer potential, but its efficacy and mechanism in DEL remain unclear. This study aimed to investigate the anti-tumor effects of ALA against DEL and its underlying dual-targeting mechanism.
Methods: The cytotoxic activity of ALA was assessed in lymphoma cell lines and a normal lymphocyte line. Apoptosis was evaluated by flow cytometry and Western blotting. Network pharmacology, molecular docking, dynamics simulations, and cellular thermal shift assays (CETSA) were utilized to identify and validate direct targets of ALA. The anti-tumor efficacy of ALA was further examined in a DEL xenograft mouse model using PET-CT imaging and survival analysis.
Results: In the present study, the anticancer activity of ALA in DEL was explored in vivo and in vitro. ALA was shown to inhibit DEL growth in vivo with little toxicity to normal tissues. Mechanistically, ALA stabilized active glycogen synthase kinase 3β (GSK3β) (binding affinity: − 15.66 kcal/mol; ΔTm +9°C), enhancing β-catenin degradation and suppressing Wnt-driven oncogenesis. Simultaneously, ALA directly bound BCL2 (− 22.22 kcal/mol), triggering both intrinsic and extrinsic apoptotic pathways. Simultaneously, ALA directly bound BCL2 (binding affinity: − 22.22 kcal/mol), triggering both intrinsic and extrinsic apoptotic pathways. ALA exhibited robust anti-DEL activity across preclinical models. While in vivo it significantly suppressed tumor progression (SUVmax reduction > 50%, p< 0.01) and extended survival (median 50 vs 80 days, p< 0.01) in DEL xenografts. The therapeutic relevance was underscored by clinical correlation showing DEL patients with high GSK3β expression had superior survival outcomes.
Conclusion: ALA exerts potent anti-DEL activity by simultaneously targeting GSK3β in the Wnt pathway and directly inhibiting BCL2, leading to suppressed tumor proliferation and induced apoptosis. Our findings highlight ALA as a promising multi-targeting therapeutic candidate for DEL and propose a novel strategy against this refractory lymphoma.
Keywords: alantolactone, dual-expression lymphoma, Wnt, glycogen synthase kinase 3β, B-cell lymphoma 2, apoptosis