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Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3K/AKT pathway in human pancreatic cancer cells
Abstract
Application of oxaliplatin for the treatment of pancreatic cancer (PC) is restricted owing to its toxic side effects and drug resistance. We investigated how withaferin A (WA), a bioactive component isolated from the medicinal plant Withania somnifera, acts synergistically with oxaliplatin on human PC in vitro and in vivo. We found that WA enhanced oxaliplatin-induced growth suppression and apoptosis in PC cells dramatically through a mechanism involving mitochondrial dysfunction and inactivation of the PI3K/AKT pathway. Combination treatment resulted in significant accumulation of intracellular reactive oxygen species (ROS). Pretreatment of cells with the ROS scavenger N-acetylcysteine completely blocked the apoptosis induced by combination treatment, and recovered expression of AKT inactivation, which revealed the important role of ROS in apoptosis and AKT regulation. In vivo, combination therapy showed the strongest anti-tumor effects compared with single agents, without obvious additional toxicity. These results support the notion that combination treatment with oxaliplatin and WA could facilitate development of an effective strategy for PC treatment.
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“Quercetin-3-rutinoside-7-glucoside, rutin, and isochlorogenic acid B from WS worked better than withanolide and withanone against chief protease of SARS-CoV2 [184].”
From Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects (2021) · cites this paper as [184]
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Metadata
- Authors
- Li, X., Zhu, F., Jiang, J., Sun, C., Wang, X., Shen, M., Tian, R., Shi, C., Xu, M., Peng, F., Guo, X., Wang, M., & Qin, R.
- Affiliations
- Tongji Hospital (CN)
- Guiyang Medical University (CN)
- Corresponding author
- Wang, Min
- Qin, Renyi
- ORCID
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 357
- Issue
- 1
- Pages
- 219-230
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2032234787
- Cited by
- 116
- References
- 51
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 14 · 2023: 10 · 2022: 9 · 2021: 11 · 2020: 19 · 2019: 11 · 2018: 6 · 2017: 14 · 2016: 8 · 2015: 7
- FWCI
- 20.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81272659, 81101621, 81160311, 81372353, 81172064, 81301860)
- National “Eleventh Five-Year” Scientific and Technological Support Projects (2006BAI02A13-402)
- Projects of Science Foundation of Hubei Province (2012FFB02401)
- International S&T Cooperation Projects of China (2014DFA31420)
- Research Fund of Young Scholars for the Doctoral Program of Higher Education of China (20110142120014)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacological Effects of Medicinal Plants
- Keywords
- withaferin A, oxaliplatin, pancreatic cancer, combination chemotherapy, synergistic antitumor effect, reactive oxygen species, PI3K/Akt signaling, apoptosis, mitochondrial dysfunction, N-acetylcysteine, drug resistance, Withania somnifera
- MeSH terms
- Oxaliplatin, Animals, Antineoplastic Combined Chemotherapy Protocols, Drug Synergism, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Organoplatinum Compounds, Pancreatic Neoplasms, Prognosis, Random Allocation, Signal Transduction, Apoptosis, Reactive Oxygen Species, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Mice, Withanolides
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