Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells
Piperine, a phytochemical alkaloid, exhibits notable anticancer properties in several cancer cell types. In this study, we investigated the mechanisms by which piperine induces cell death and apoptosis in colorectal cancer (CRC) cells, focusing on oxidative stress and key signaling pathways. Using M...
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MDPI AG
2025-07-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/7/892 |
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| author | Wan-Ling Chang Jyun-Yu Peng Chain-Lang Hong Pei-Ching Li Soi Moi Chye Fung-Jou Lu Huei-Yu Lin Ching-Hsein Chen |
| author_facet | Wan-Ling Chang Jyun-Yu Peng Chain-Lang Hong Pei-Ching Li Soi Moi Chye Fung-Jou Lu Huei-Yu Lin Ching-Hsein Chen |
| author_sort | Wan-Ling Chang |
| collection | DOAJ |
| description | Piperine, a phytochemical alkaloid, exhibits notable anticancer properties in several cancer cell types. In this study, we investigated the mechanisms by which piperine induces cell death and apoptosis in colorectal cancer (CRC) cells, focusing on oxidative stress and key signaling pathways. Using MTT assay, flow cytometry, gene overexpression, and Western blot analysis, we observed that piperine significantly reduced cell viability, triggered G1 phase cell cycle arrest, and promoted apoptosis in DLD-1 cells. In addition, piperine effectively suppressed cell viability and induced apoptosis in other CRC cell lines, including SW480, HT-29, and Caco-2 cells. These effects were associated with increased intracellular reactive oxygen species (ROS) generation, mediated by the regulation of mitochondrial complex III, NADPH oxidase, and xanthine oxidase. Additionally, piperine modulated signaling pathways by inhibiting phosphoinositide 3-kinase (PI3K)/Akt, activating p38 and p-extracellular signal-regulated kinase (ERK). Pretreatment with antimycin A, apocynin, allopurinol, and PD98059, and the overexpression of p-Akt significantly recovered cell viability and reduced apoptosis, confirming the involvement of these pathways. This study is the first to demonstrate piperine induces apoptosis in CRC cells through a multifaceted oxidative stress mechanism and by critically modulating PI3K/Akt and ERK signaling pathways. |
| format | Article |
| id | doaj-art-946bb282fb91436e84c39cfd8f3a49e9 |
| institution | DOAJ |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-946bb282fb91436e84c39cfd8f3a49e92025-08-20T03:13:36ZengMDPI AGAntioxidants2076-39212025-07-0114789210.3390/antiox14070892Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer CellsWan-Ling Chang0Jyun-Yu Peng1Chain-Lang Hong2Pei-Ching Li3Soi Moi Chye4Fung-Jou Lu5Huei-Yu Lin6Ching-Hsein Chen7Department of Anesthesiology, Chang Gung Memorial Hospital at Chiayi, No. 8, West Section of Jiapu Road, Puzi City 613016, Chiayi County, TaiwanDepartment of Anesthesiology, Chang Gung Memorial Hospital at Chiayi, No. 8, West Section of Jiapu Road, Puzi City 613016, Chiayi County, TaiwanDepartment of Anesthesiology, Chang Gung Memorial Hospital at Chiayi, No. 8, West Section of Jiapu Road, Puzi City 613016, Chiayi County, TaiwanDepartment of Anesthesiology, Chang Gung Memorial Hospital at Chiayi, No. 8, West Section of Jiapu Road, Puzi City 613016, Chiayi County, TaiwanSchool of Health Science, Division of Applied Biomedical Science and Biotechnology, IMU University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, Kuala Lumpur 57000, MalaysiaInstitute of Medicine, Chung Shan Medical University, No. 110, Section 1, Jianguo North Road, Taichung City 402306, TaiwanDepartment of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, A25-303 Room, Life Sciences Hall, No. 300, Syuefu Road, Chiayi City 600355, TaiwanDepartment of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, A25-303 Room, Life Sciences Hall, No. 300, Syuefu Road, Chiayi City 600355, TaiwanPiperine, a phytochemical alkaloid, exhibits notable anticancer properties in several cancer cell types. In this study, we investigated the mechanisms by which piperine induces cell death and apoptosis in colorectal cancer (CRC) cells, focusing on oxidative stress and key signaling pathways. Using MTT assay, flow cytometry, gene overexpression, and Western blot analysis, we observed that piperine significantly reduced cell viability, triggered G1 phase cell cycle arrest, and promoted apoptosis in DLD-1 cells. In addition, piperine effectively suppressed cell viability and induced apoptosis in other CRC cell lines, including SW480, HT-29, and Caco-2 cells. These effects were associated with increased intracellular reactive oxygen species (ROS) generation, mediated by the regulation of mitochondrial complex III, NADPH oxidase, and xanthine oxidase. Additionally, piperine modulated signaling pathways by inhibiting phosphoinositide 3-kinase (PI3K)/Akt, activating p38 and p-extracellular signal-regulated kinase (ERK). Pretreatment with antimycin A, apocynin, allopurinol, and PD98059, and the overexpression of p-Akt significantly recovered cell viability and reduced apoptosis, confirming the involvement of these pathways. This study is the first to demonstrate piperine induces apoptosis in CRC cells through a multifaceted oxidative stress mechanism and by critically modulating PI3K/Akt and ERK signaling pathways.https://www.mdpi.com/2076-3921/14/7/892piperineapoptosiscell cycle arrestoxidative stressPI3K/AktMAPK |
| spellingShingle | Wan-Ling Chang Jyun-Yu Peng Chain-Lang Hong Pei-Ching Li Soi Moi Chye Fung-Jou Lu Huei-Yu Lin Ching-Hsein Chen Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells Antioxidants piperine apoptosis cell cycle arrest oxidative stress PI3K/Akt MAPK |
| title | Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells |
| title_full | Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells |
| title_fullStr | Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells |
| title_full_unstemmed | Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells |
| title_short | Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells |
| title_sort | piperine induces apoptosis and cell cycle arrest via multiple oxidative stress mechanisms and regulation of pi3k akt and mapk signaling in colorectal cancer cells |
| topic | piperine apoptosis cell cycle arrest oxidative stress PI3K/Akt MAPK |
| url | https://www.mdpi.com/2076-3921/14/7/892 |
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