Anticancer research · 2026
Synergistic Effects of Honokiol on Camptothecin-triggered Apoptosis of Drug-resistant Glioblastoma Cells via CDK1-mediated G2/M Arrest and Intrinsic ROS-Mitochondrion-dependent Pathway.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Yang Chih-Pin, Chen Jui-Tai, Liu Shing-Hwa, Chen Edwin, Chen Ruei-Ming
Аннотация
BACKGROUND/AIM: Temozolomide (TMZ) is the first-line drug for the treatment of glioblastoma multiforme (GBM). Unfortunately, most patients with GBM eventually develop drug resistance. Camptothecin (CPT) and honokiol (HNK) are bioactive ingredients of Camptotheca acuminata and Magnolia officinalis, respectively. Our previous studies showed the benefits of CPT and CPT-containing nanoparticles on suppressing GBM tumorigenesis. However, CPT can have side effects. This study evaluated the synergistic effects of HNK and CPT at low and non-toxic concentrations on the killing of TMZ-resistant glioblastoma cells, as well as the underlying mechanisms.
MATERIALS AND METHODS: Cytotoxicity of HNK and CPT toward normal human astrocytes and mouse cerebral endothelial cells (CECs) was assessed using colorimetric and flow cytometric assays. Synergistic apoptotic effects in human and mouse TMZ-resistant GBM cells were evaluated by viability assays, trypan blue exclusion, DNA fragmentation, flow cytometry, and caspase activity analyses. CDK1 involvement was examined using siRNA knockdown. The roles of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase-9 activation were investigated using fluorogenic assays and antioxidant pretreatment.
RESULTS: Under low and non-toxic concentrations, HNK enhanced CPT-triggered apoptosis of human TMZ-resistant glioblastomas cells. Cotreatment of TMZ-resistant glioblastoma cells with HNK and CPT stimulated production of CDK1 and subsequent G2/M arrest. CDK1 knockdown alleviated these effects. Moreover, HNK sequentially enhanced CPT-triggered production of intracellular ROS, reduced the mitochondrial membrane potential, and activated caspase-9 and cell apoptosis. Suppressing the levels of intracellular ROS attenuated the HNK-induced enhanced effects. The effects of HNK on CPT-induced apoptotic insults were further confirmed in mouse TMZ-resistant glioblastoma cells.
CONCLUSION: HNK synergistically enhances CPT-induced apoptosis in TMZ-resistant glioblastoma cells through CDK1-mediated G2/M arrest and ROS-dependent mitochondrial activation of caspases-9, -3, and -6. Co-administration of HNK may enable effective CPT-based therapy at reduced doses, potentially minimizing CPT-related toxicity and offering a promising strategy for treating drug-resistant GBM.
MATERIALS AND METHODS: Cytotoxicity of HNK and CPT toward normal human astrocytes and mouse cerebral endothelial cells (CECs) was assessed using colorimetric and flow cytometric assays. Synergistic apoptotic effects in human and mouse TMZ-resistant GBM cells were evaluated by viability assays, trypan blue exclusion, DNA fragmentation, flow cytometry, and caspase activity analyses. CDK1 involvement was examined using siRNA knockdown. The roles of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase-9 activation were investigated using fluorogenic assays and antioxidant pretreatment.
RESULTS: Under low and non-toxic concentrations, HNK enhanced CPT-triggered apoptosis of human TMZ-resistant glioblastomas cells. Cotreatment of TMZ-resistant glioblastoma cells with HNK and CPT stimulated production of CDK1 and subsequent G2/M arrest. CDK1 knockdown alleviated these effects. Moreover, HNK sequentially enhanced CPT-triggered production of intracellular ROS, reduced the mitochondrial membrane potential, and activated caspase-9 and cell apoptosis. Suppressing the levels of intracellular ROS attenuated the HNK-induced enhanced effects. The effects of HNK on CPT-induced apoptotic insults were further confirmed in mouse TMZ-resistant glioblastoma cells.
CONCLUSION: HNK synergistically enhances CPT-induced apoptosis in TMZ-resistant glioblastoma cells through CDK1-mediated G2/M arrest and ROS-dependent mitochondrial activation of caspases-9, -3, and -6. Co-administration of HNK may enable effective CPT-based therapy at reduced doses, potentially minimizing CPT-related toxicity and offering a promising strategy for treating drug-resistant GBM.