{"title":"PI3K抑制剂HCD通过上调外源性和内源性凋亡途径促进头颈部鳞状细胞中Caspase的激活。","authors":"Leong-Perng Chan, Ya-Ping Tseng, Hui-Ching Wang, Chen-Yu Chien, Che-Wei Wu, Ling-Feng Wang, Tung-Wen Yen, Po-Chun Wang, Chih-Chuang Liaw, Chia-Hua Liang","doi":"10.1111/jop.70060","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>16-hydroxycleroda-3,13-dien-15,16-olide (HCD), a compound isolated from Polyalthia longifolia var. pendula, has been identified as a PI3K inhibitor. P. longifolia var. pendula is recognized for its diverse pharmacological properties, including antimicrobial, hypotensive, anti-inflammatory, and cytotoxic activities. Considering the pivotal role of PI3K in the regulation of apoptosis in cancer cells, this study aims to investigate the apoptotic effects induced by HCD in head and neck cancer cell models.</p><p><strong>Methods: </strong>The study focused on investigating the mechanism through which HCD induces apoptosis in oral squamous cell carcinoma (OSCC) using SCC25 and SCC180 cells. These cells were treated with HCD at IC<sub>20</sub>, IC<sub>50</sub>, and IC<sub>80</sub> concentrations over periods of 24, 48, and 72 h. Assessments included cell viability, oxidative stress levels using MitoSOX and CellROX, and the analysis of gene and protein expressions related to apoptosis via immunofluorescence staining, flow cytometry, RT-PCR, and western blotting.</p><p><strong>Results: </strong>The results demonstrated that HCD significantly increased the sub-G<sub>1</sub> phase cell population, suppressed clonogenic activity, and promoted mitochondrial ROS production, accompanied by a reduction in glutathione levels. HCD also activated cytochrome c (cyto. c) release and Bax expression while downregulating Bcl-2 expression. Notably, in SCC25 cells, HCD induced apoptosis through the TNF-α/TNF-R and FasL/Fas death domains, leading to caspase cascade activation. Moreover, HCD showed dose-dependent growth inhibition of SCC25 cells, both alone and combined with cisplatin, by enhancing caspase-3 expression.</p><p><strong>Conclusion: </strong>This investigation into HCD's molecular mechanisms in OSCC cells offers insight into developing effective anticancer therapies, highlighting its role in apoptosis induction through oxidative stress, mitochondrial pathways, and death receptor signaling.</p>","PeriodicalId":16588,"journal":{"name":"Journal of Oral Pathology & Medicine","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The PI3K Inhibitor HCD Promotes Caspase Activation in Head and Neck Squamous Cells by Upregulating the Extrinsic and Intrinsic Apoptosis Pathways.\",\"authors\":\"Leong-Perng Chan, Ya-Ping Tseng, Hui-Ching Wang, Chen-Yu Chien, Che-Wei Wu, Ling-Feng Wang, Tung-Wen Yen, Po-Chun Wang, Chih-Chuang Liaw, Chia-Hua Liang\",\"doi\":\"10.1111/jop.70060\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>16-hydroxycleroda-3,13-dien-15,16-olide (HCD), a compound isolated from Polyalthia longifolia var. pendula, has been identified as a PI3K inhibitor. P. longifolia var. pendula is recognized for its diverse pharmacological properties, including antimicrobial, hypotensive, anti-inflammatory, and cytotoxic activities. Considering the pivotal role of PI3K in the regulation of apoptosis in cancer cells, this study aims to investigate the apoptotic effects induced by HCD in head and neck cancer cell models.</p><p><strong>Methods: </strong>The study focused on investigating the mechanism through which HCD induces apoptosis in oral squamous cell carcinoma (OSCC) using SCC25 and SCC180 cells. These cells were treated with HCD at IC<sub>20</sub>, IC<sub>50</sub>, and IC<sub>80</sub> concentrations over periods of 24, 48, and 72 h. Assessments included cell viability, oxidative stress levels using MitoSOX and CellROX, and the analysis of gene and protein expressions related to apoptosis via immunofluorescence staining, flow cytometry, RT-PCR, and western blotting.</p><p><strong>Results: </strong>The results demonstrated that HCD significantly increased the sub-G<sub>1</sub> phase cell population, suppressed clonogenic activity, and promoted mitochondrial ROS production, accompanied by a reduction in glutathione levels. HCD also activated cytochrome c (cyto. c) release and Bax expression while downregulating Bcl-2 expression. Notably, in SCC25 cells, HCD induced apoptosis through the TNF-α/TNF-R and FasL/Fas death domains, leading to caspase cascade activation. Moreover, HCD showed dose-dependent growth inhibition of SCC25 cells, both alone and combined with cisplatin, by enhancing caspase-3 expression.</p><p><strong>Conclusion: </strong>This investigation into HCD's molecular mechanisms in OSCC cells offers insight into developing effective anticancer therapies, highlighting its role in apoptosis induction through oxidative stress, mitochondrial pathways, and death receptor signaling.</p>\",\"PeriodicalId\":16588,\"journal\":{\"name\":\"Journal of Oral Pathology & Medicine\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-09-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Oral Pathology & Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/jop.70060\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"DENTISTRY, ORAL SURGERY & MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Oral Pathology & Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/jop.70060","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"DENTISTRY, ORAL SURGERY & MEDICINE","Score":null,"Total":0}
The PI3K Inhibitor HCD Promotes Caspase Activation in Head and Neck Squamous Cells by Upregulating the Extrinsic and Intrinsic Apoptosis Pathways.
Background: 16-hydroxycleroda-3,13-dien-15,16-olide (HCD), a compound isolated from Polyalthia longifolia var. pendula, has been identified as a PI3K inhibitor. P. longifolia var. pendula is recognized for its diverse pharmacological properties, including antimicrobial, hypotensive, anti-inflammatory, and cytotoxic activities. Considering the pivotal role of PI3K in the regulation of apoptosis in cancer cells, this study aims to investigate the apoptotic effects induced by HCD in head and neck cancer cell models.
Methods: The study focused on investigating the mechanism through which HCD induces apoptosis in oral squamous cell carcinoma (OSCC) using SCC25 and SCC180 cells. These cells were treated with HCD at IC20, IC50, and IC80 concentrations over periods of 24, 48, and 72 h. Assessments included cell viability, oxidative stress levels using MitoSOX and CellROX, and the analysis of gene and protein expressions related to apoptosis via immunofluorescence staining, flow cytometry, RT-PCR, and western blotting.
Results: The results demonstrated that HCD significantly increased the sub-G1 phase cell population, suppressed clonogenic activity, and promoted mitochondrial ROS production, accompanied by a reduction in glutathione levels. HCD also activated cytochrome c (cyto. c) release and Bax expression while downregulating Bcl-2 expression. Notably, in SCC25 cells, HCD induced apoptosis through the TNF-α/TNF-R and FasL/Fas death domains, leading to caspase cascade activation. Moreover, HCD showed dose-dependent growth inhibition of SCC25 cells, both alone and combined with cisplatin, by enhancing caspase-3 expression.
Conclusion: This investigation into HCD's molecular mechanisms in OSCC cells offers insight into developing effective anticancer therapies, highlighting its role in apoptosis induction through oxidative stress, mitochondrial pathways, and death receptor signaling.
期刊介绍：
The aim of the Journal of Oral Pathology & Medicine is to publish manuscripts of high scientific quality representing original clinical, diagnostic or experimental work in oral pathology and oral medicine. Papers advancing the science or practice of these disciplines will be welcomed, especially those which bring new knowledge and observations from the application of techniques within the spheres of light and electron microscopy, tissue and organ culture, immunology, histochemistry and immunocytochemistry, microbiology, genetics and biochemistry.
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