Cited by 116Phytochemicals and Medicinal PlantsPancreatic and Hepatic Oncology ResearchPharmacological Effects of Medicinal Plants

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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

Li, Xu, Zhu, Feng, Jiang, Jianxin, Sun, Chengyi, Wang, Xin, Shen, Ming, Tian, Rui, Shi, Chengjian, Xu, Meng, Peng, Feng, Guo, Xingjun, Wang, Min, Qin, Renyi·2015·Cancer Letters

DOI 10.1016/j.canlet.2014.11.026

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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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DACH 1 inhibits glioma invasion and tumor growth via the Wnt/catenin pathway
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“Thus, GSK-3 β was examined via Western blotting following transfection.”
Influential
Iron-crosslinked Rososome with robust stability and high drug loading for synergistic cancer therapy
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“Recent studies conducted by Li Xu and coauthors [60] suggest the synergistic antitumor activity of withaferin A combined with oxaliplatin.”
Background
WITHAFERIN A INDUCES APOPTOSIS IN RAT C6 GLIOMA CELLS THROUGH REGULATING NF- ΚB NUCLEAR TRANSLOCATION AND ACTIVATION OF CASPASE CASCADE
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“Few studies also indicated that WFA can act as pro-oxidant and thus trigger oxidative stress to induce apoptosis (Vyas and Singh, 2014; Li et al., 2015).”
Background
Drug carrier for sustained release of withaferin A for pancreatic cancer treatment
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“WA could active AKT; then AKT would increase the amount of the reactive oxygen species (ROS), and ROS inhibited signal pathway of the AKT to decrease the expression of AKT [9, 52].”
BackgroundInfluential
Revisiting the Multifaceted Therapeutic Potential of Withaferin A (WA), a Novel Steroidal Lactone, W-ferinAmax Ashwagandha, from Withania Somnifera (L) Dunal
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Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives
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“When reasons for apoptosis induction were checked, it was concluded that the treatment caused mitochondrial membrane damage that leads to high levels of ROS generation that resulted in triggering of apoptosis and ultimately death of the cancer cells [48].”
BackgroundInfluential
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“To overcome these limitations, combination therapies involving gemcitabine and other chemotherapeutic agents or molecularly targeted drugs have been explored [9,11–14].”
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Apaf1 nanoLuc biosensors identified lentinan as a potent synergizer of cisplatin in targeting hepatocellular carcinoma cells
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“Malondialdehyde concentration in the homogenates was determined spectrophotometrically by measuring the presence of thiobarbituric acid reactive substances (utilizing the principle of the thiobarbituric acid colorimetric method).(29,30) Superoxide dismutase was detected by a corresponding assay kit based on the princi…”
Method
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“…few last years, active biological drugs for advanced CRC have been developed, including the monoclonal antibodies cetuximab, panitumumab, bevacizumab, and a recombinant fusion protein (aflibercept) which has very precise indications (Loree and Kopetz 2017; Nappi et al. 2018; Bregni et al. 2020).”
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Chemotherapeutic Effect of Withaferin A in Human Oral Cancer Cells
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“Recently, WA-induced apoptosis has been studied in various cancer cell lines, such as breast [18], prostate [19], pancreatic [20], ovarian [21], lung [22], head and neck cancer cell lines [23].”
Background
Rosmanol Triggers Apoptosis Against MNNG-induced Gastric Carcinogenesis in Rats through Attenuation of the P13K/AKT/HMBG1 Signaling Pathway
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“2a), we found increased ROS levels in HT29 cells, which indicated that L-OHP induced ROS, as previously reported.(7,8) After 72 h’ L-OHP exposure (4 lM), the ROS cell fraction was reduced from 93.”
CRABP2 promotes cell migration and invasion by activating PI3K/AKT and MAPK signalling pathways via upregulating LAMB3 in prostate cancer
Wang, R., Liao, Z., Liu, C., Yu, S., Xiang, K., Wu, T., Feng, J., Ding, S., Yu, T., Cheng, G., et al. (2024) · The Journal of Biochemistry · doi:10.1093/jb/mvae052 · Cited by 6
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Experimental evidence to the untapped potential of Ayurvedic herb, Ashwagandha: Bench-to-Bedside
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Withania somnifera Has Potential to Treat Cancer
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Scientific Evidence for Anticancer Effects of Withania somnifera and Its Primary Bioactive Component Withaferin A
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Anticancer Mechanism of Withania Somnifera and Its Bioactive Compounds : A Short Review Along with Computational Molecular Docking StudyPreprint
Shikder, M., Hasib, T. A., & Kabir, M. L. (2020) · ChemRxiv · doi:10.26434/chemrxiv.13038236 · Cited by 3
“Withaferin-A functions as a cancer chemotherapeutic agent, anti-proliferative agent, anti-oxidant agent, cardioprotective agent and neuroprotective agent [29][30][31][32][33][34].”
Background
A Homodimer of Withaferin A Formed by Base-Promoted Elimination of Acetic Acid from 27-O-Acetylwithaferin A Followed by a Diels–Alder Reaction
Wijeratne, E. M. K., Xu, Y.-M., Padumadasa, C., Astashkin, A. V., & Gunatilaka, A. A. L. (2024) · Journal of Natural Products · doi:10.1021/acs.jnatprod.3c01003 · Cited by 2
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“24,25 In recent years, the research on the mechanism of the killing effect of drugs on tumor cells mainly focuses on the effects of drugs on the proliferation, differentiation and apoptosis of tumor cells, as well as the control of oncogenes and tumor suppressor genes, and immune regulation.”
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Ashwagandha Bioactives for Cancer Treatment: Experimental Evidence and Their Mechanism(s) of Action
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Why Ashwagandha for Healthy Ageing? Evidence from Cultured Human Cells
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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: Li, Xu
Zhu, Feng
Jiang, Jianxin
Sun, Chengyi
Wang, Xin
Shen, Ming
Tian, Rui
Shi, Chengjian
Xu, Meng
Peng, Feng
Guo, Xingjun
Wang, Min
Qin, Renyi
Venue: Cancer Letters
Publisher: Elsevier BV
Published: 2015-02
Volume: 357
Issue: 1
Pages: 219-230
ISSN: 0304-3835 (ISSN-L)
DOI: 10.1016/j.canlet.2014.11.026
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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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

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