PMID- 38452695 OWN - NLM STAT- MEDLINE DCOM- 20240326 LR - 20240326 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 127 DP - 2024 May TI - Effectively alpha-Terpineol Suppresses Glioblastoma Aggressive Behavior and Downregulates KDELC2 Expression. PG - 155471 LID - S0944-7113(24)00135-1 [pii] LID - 10.1016/j.phymed.2024.155471 [doi] AB - BACKGROUND: Glioblastoma (GBM) is notorious for the aggressive behaviors and easily results in chemo-resistance. Studies have shown that the use of herbal medicines as treatments for GBM as limited by the blood-brain barrier (BBB) and glioma stem cells. PURPOSE: The aim of this study was to investigate the relationship between GBM suppression and alpha-terpineol, the monoterpenoid alcohol derived from Eucalyptus glubulus and Pinus merkusii. STUDY DESIGN: Using serial in-vitro and in-vivo studies to confirm the mechanism of alpha-terpineol on down-regulating GBM development. METHODS: The 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay was performed to evaluate IC50 of alpha-terpineol to inhibit GBM cell survival. In order to evaluate the impact of GBM aggressive behaviors by alpha-terpineol, the analysis of cell migration, invasion and colony formation were implemented. In addition, the ability of tumor spheres and WB of CD44 and OCT3/4 were evaluated under the impression of alpha-terpineol decreased GBM stemness. The regulation of neoangiogenesis by alpha-terpineol via the WB of angiogenic factors and human umbilical vein endothelial cells (HUVEC) tube assay. To survey the decided factors of alpha-terpineol downregulating GBM chemoresistance depended on the impact of O6-methylguanine-DNA methyltransferase (MGMT) expression and autophagy-related factors activation. Additionally, WB and quantitative real-time polymerase chain reaction (qRT/PCR) of KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2), endoplasmic reticulum (ER) stress, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) cascade signaling factors were examined to explore the mechanism of alpha-terpineol inhibiting GBM viability. Finally, the orthotopic GBM mouse model was applied to prove the efficacy and toxicity of alpha-terpineol on regulating GBM survival. RESULTS: alpha-terpineol significantly suppressed GBM growth, migration, invasion, angiogenesis and temozolomide (TMZ) resistance. Furthermore, alpha-terpineol specifically targeted KDELC2 to downregulate Notch and PI3k/mTOR/MAPK signaling pathway. Finally, we also demonstrated that alpha-terpineol could penetrate the BBB to inhibit GBM proliferation, which resulted in reduced cytotoxicity to vital organs. CONCLUSION: Compared to published literatures, we firstly proved alpha-terpineol possessed the capability to inhibit GBM through various mechanisms and potentially decreased the occurrence of chemoresistance, making it a promising alternative therapeutic option for GBM in the future. CI - Copyright (c) 2024 Elsevier GmbH. All rights reserved. FAU - Jin, Jong-Shiaw AU - Jin JS AD - Department of Pathology, Tungs' Taichung MetroHarbor Hospital, Taichung, 40435, Taiwan. FAU - Chou, Jung-Mao AU - Chou JM AD - Department of Pathology, Taipei City Hospital Renai Branch, Taipei 106, Taiwan. FAU - Tsai, Wen-Chiuan AU - Tsai WC AD - Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan. FAU - Chen, Ying-Chuan AU - Chen YC AD - Department of Physiology and Biophysics, National Defense Medical Center, Taipei, 114, Taiwan. FAU - Chen, Ying AU - Chen Y AD - Department of Biology and Anatomy, National Defense Medical Center, Taipei, 114, Taiwan. FAU - Ong, Jiann-Ruey AU - Ong JR AD - Department of Emergency Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, 235, Taiwan; Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, 110, Taiwan; Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei, 110, Taiwan. FAU - Tsai, Yu-Ling AU - Tsai YL AD - Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan. Electronic address: c909228@gmail.com. LA - eng PT - Journal Article DEP - 20240223 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 21334LVV8W (alpha-terpineol) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - 0 (Cyclohexane Monoterpenes) SB - IM MH - Mice MH - Animals MH - Humans MH - *Glioblastoma/drug therapy/metabolism MH - Phosphatidylinositol 3-Kinases MH - Endothelial Cells/metabolism MH - *Brain Neoplasms/drug therapy MH - TOR Serine-Threonine Kinases MH - Phosphatidylinositol 3-Kinase MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm MH - Mammals MH - *Cyclohexane Monoterpenes OTO - NOTNLM OT - ER stress OT - Glioblastoma OT - KDELC2 OT - Stemness OT - Alpha-terpineol COIS- Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. The study design was approved by the appropriate ethics review board. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. All authors declare that there is no conflict of interest in this study. EDAT- 2024/03/08 00:43 MHDA- 2024/03/26 06:45 CRDT- 2024/03/07 18:14 PHST- 2023/04/18 00:00 [received] PHST- 2024/02/11 00:00 [revised] PHST- 2024/02/20 00:00 [accepted] PHST- 2024/03/26 06:45 [medline] PHST- 2024/03/08 00:43 [pubmed] PHST- 2024/03/07 18:14 [entrez] AID - S0944-7113(24)00135-1 [pii] AID - 10.1016/j.phymed.2024.155471 [doi] PST - ppublish SO - Phytomedicine. 2024 May;127:155471. doi: 10.1016/j.phymed.2024.155471. Epub 2024 Feb 23.