دورية أكاديمية
أعرض في EDS

Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species.

التفاصيل البيبلوغرافية
العنوان: Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species.
المؤلفون: Zhu M; Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.; School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China., Tang W; School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China., Tang X; School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China., Zhu Z; School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China., Jiang Y; Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., Sarwar A; School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China.; Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan., Zhang H; Department of Endocrinology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China., Chu D; Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., Zhang Z; Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China zhang2008@xjtu.edu.cn zhangzixi@xjtu.edu.cn., Zhang Y; Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China zhang2008@xjtu.edu.cn zhangzixi@xjtu.edu.cn.; School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Jul 14; Vol. 12 (7). Date of Electronic Publication: 2024 Jul 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
Original Publication: London : BioMed Central, 2013-
مواضيع طبية MeSH: Cantharidin*/pharmacology , Cantharidin*/therapeutic use , Vorinostat*/pharmacology , Vorinostat*/therapeutic use , Lymphoma, T-Cell, Cutaneous*/drug therapy , Lymphoma, T-Cell, Cutaneous*/metabolism , Reactive Oxygen Species*/metabolism , Signal Transduction*/drug effects , Drug Resistance, Neoplasm*/drug effects, Humans ; Animals ; Mice ; Cell Line, Tumor ; Skin Neoplasms/drug therapy ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology
مستخلص: Background: Vorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30-35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.
Purpose: This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.
Methods and Results: In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rβ with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover, cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells. Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo.
Conclusion: Our study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of cantharidin in treating CTCL.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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فهرسة مساهمة: Keywords: Chemotherapy; JAK-STAT; Lymphoma
المشرفين على المادة: IGL471WQ8P (Cantharidin)
58IFB293JI (Vorinostat)
0 (Reactive Oxygen Species)
تواريخ الأحداث: Date Created: 20240714 Date Completed: 20240714 Latest Revision: 20240812
رمز التحديث: 20240813
مُعرف محوري في PubMed: PMC11253763
DOI: 10.1136/jitc-2024-009099
PMID: 39004437
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2024-009099