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

doi:10.1016/j.canlet.2014.11.026

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

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 +5 more·2015·Cancer Letters

DOI 10.1016/j.canlet.2014.11.026

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1016/j.canlet.2014.11.026

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Quercetin-3-rutinoside-7-glucoside, rutin, and isochlorogenic acid B from WS worked better than withanolide and withanone against the chief protease of SARS-CoV2.
“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]

1 retracted

3,3′-Diindolylmethane Enhances Chemosensitivity of Multiple Chemotherapeutic Agents in Pancreatic Cancer
Banerjee, S., Wang, Z., Kong, D., & Sarkar, F. H. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0838 · Cited by 98 · see citing works
Retracted
Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598 · see citing works
Reactive oxygen species, cellular redox systems, and apoptosis
Circu, M. L., & Aw, T. Y. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.12.022 · Cited by 3,340 · see citing works
Mitochondria and cell death: outer membrane permeabilization and beyond
Tait, S. W. G., & Green, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2952 · Cited by 2,593 · see citing works
Adjuvant Chemotherapy With Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer
Oettle, H., Post, S., Neuhaus, P., Gellert, K., Langrehr, J. M., Ridwelski, K., Schramm, H., Fahlke, J., Zuelke, C., Burkart, C., et al. (2007) · JAMA · doi:10.1001/jama.297.3.267 · Cited by 2,418 · see citing works
Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC
Shimizu, S., Narita, M., Tsujimoto, Y., & Tsujimoto, Y. (1999) · Nature · doi:10.1038/20959 · Cited by 2,178 · see citing works
Redox regulation of cell survival
Trachootham, D., Lu, W., Ogasawara, M. A., Valle, N. R.-D., & Huang, P. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1957 · Cited by 1,781 · see citing works
Targeting Apoptosis Pathways in Cancer Therapy
Ghobrial, I. M., Witzig, T. E., & Adjei, A. A. (2005) · CA A Cancer Journal for Clinicians · doi:10.3322/canjclin.55.3.178 · Cited by 1,353 · see citing works
Reactive oxygen species in cancer cells: Live by the sword, die by the sword
Schumacker, P. T. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.015 · Cited by 1,242 · see citing works
Gemcitabine Plus Bevacizumab Compared With Gemcitabine Plus Placebo in Patients With Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303)
Kindler, H. L., Niedzwiecki, D., Hollis, D. R., Sutherland, S., Schrag, D., Hurwitz, H. I., Innocenti, F., Mulcahy, M. F., O'Reilly, E. M., Wozniak, T. F., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.28.1386 · Cited by 848 · see citing works
Apoptosis and cancer: mutations within caspase genes
Ghavami, S., Hashemi, M. M., Ande, S. R., Yeganeh, B., Xiao, W., Eshraghi, M., Bus, C., Kadkhoda, K., Wiecheć, E., Halayko, A. J., et al. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2009.066944 · Cited by 712 · see citing works
Molecular Pathways: Reactive Oxygen Species Homeostasis in Cancer Cells and Implications for Cancer Therapy
Nogueira, V., & Hay, N. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1424 · Cited by 516 · see citing works
The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability
Harris, M. H., & Thompson, C. B. (2000) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400781 · Cited by 514 · see citing works
Caspase-8 and Bid: Caught in the act between death receptors and mitochondria
Kantari‐Mimoun, C., & Walczak, H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.026 · Cited by 502 · see citing works
Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: A phase III-study from the German CONKO-study group
Pelzer, U., Schwaner, I., Stieler, J., Adler, M., Seraphin, J., Dörken, B., Riess, H. B., & Oettle, H. (2011) · European Journal of Cancer · doi:10.1016/j.ejca.2011.04.011 · Cited by 369 · see citing works
Withaferin A Causes FOXO3a- and Bim-Dependent Apoptosis and Inhibits Growth of Human Breast Cancer Cells In vivo
Stan, S. D., Hahm, E., Warin, R., & Singh, S. V. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1510 · Cited by 265 · see citing works
Sensitization for Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by the Chemopreventive Agent Resveratrol
Fulda, S., & Debatin, K. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1656 · Cited by 250 · see citing works
Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species
Hahm, E., de Moura, M. B., Kelley, E. E., Houten, B. V., Shiva, S., & Singh, S. V. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023354 · Cited by 247 · see citing works
Molecular insight in the multifunctional activities of Withaferin A
Berghe, W. V., Sabbe, L., Kaileh, M., Haegeman, G., & Heyninck, K. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.08.027 · Cited by 242 · see citing works
Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma
Yamamoto, S., Tomita, Y., Hoshida, Y., Morooka, T., Nagano, H., Dono, K., Umeshita, K., Sakon, M., Ishikawa, O., Ohigashi, H., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-02-1441 · Cited by 241 · see citing works
Par-4-Dependent Apoptosis by the Dietary Compound Withaferin A in Prostate Cancer Cells
Srinivasan, S., Ranga, R. S., Burikhanov, R., Han, S., & Damodaran, C. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2430 · Cited by 231 · see citing works
Notch-1 Inhibition by Withaferin-A: A Therapeutic Target against Colon Carcinogenesis
Koduru, S. V., Kumar, R., Srinivasan, S., Evers, B. M., & Damodaran, C. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0771 · Cited by 215 · see citing works
Autophagy Activation in Hepatocellular Carcinoma Contributes to the Tolerance of Oxaliplatin via Reactive Oxygen Species Modulation
Ding, Z., Hui, B., Shi, Y., Zhou, J., Peng, Y., Gu, C., Yang, H., Shi, G., Ke, A., Wang, X., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0816 · Cited by 178 · see citing works
Frequent activation of AKT2 kinase in human pancreatic carcinomas
Altomare, D. A., Tanno, S., Rienzo, A. D., Klein–Szanto, A. J., Tanno, S., Skele, K. L., Hoffman, J. P., & Testa, J. R. (2002) · Journal of Cellular Biochemistry · doi:10.1002/jcb.10287 · Cited by 174 · see citing works
Withaferin A induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade
Mandal, C., Dutta, A., Mallick, A., Chandra, S., Misra, L., Sangwan, R. S., & Mandal, C. (2008) · APOPTOSIS · doi:10.1007/s10495-008-0271-0 · Cited by 171 · see citing works
Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2
Mayola, E., Gallerne, C., Esposti, D. D., Martel, C., Pervaiz, S., Larue, L., Debuire, B., Lemoine, A., Brenner, C., & Lemaire, C. (2011) · APOPTOSIS · doi:10.1007/s10495-011-0625-x · Cited by 164 · see citing works
Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress
Kopetz, S., Lesslie, D. P., Dallas, N. A., Park, S. I., Johnson, M., Parikh, N. U., Kim, M. P., Abbruzzese, J. L., Ellis, L. M., Chandra, J., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2246 · Cited by 160 · see citing works
Current concepts and novel targets in advanced pancreatic cancer
Michl, P., & Gress, T. M. (2012) · Gut · doi:10.1136/gutjnl-2012-303588 · Cited by 153 · see citing works
Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (Review)
Libra, M. (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.1312 · Cited by 140 · see citing works
Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma
Liu, C., Gong, K., Mao, X., & Li, W. (2010) · International Journal of Cancer · doi:10.1002/ijc.25817 · Cited by 137 · see citing works
Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation
Oh, J. H., Lee, T. J., Kim, S. H., Choi, Y. H., Lee, S., Lee, J. M., Kim, Y.-H., Park, J., & Kwon, T. K. (2008) · APOPTOSIS · doi:10.1007/s10495-008-0273-y · Cited by 134 · see citing works
Withaferin A Synergizes the Therapeutic Effect of Doxorubicin through ROS-Mediated Autophagy in Ovarian Cancer
Fong, M., Jin, S., Rane, M. J., Singh, R. K., Gupta, R. C., & Kakar, S. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042265 · Cited by 130 · see citing works
Withaferin A inhibits tumor necrosis factor-α-induced expression of cell adhesion molecules by inactivation of Akt and NF-κB in human pulmonary epithelial cells
Oh, J. H., & Kwon, T. K. (2009) · International Immunopharmacology · doi:10.1016/j.intimp.2009.02.002 · Cited by 118 · see citing works
Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP
Lee, T.-J., Um, H. J., Min, D. S., Park, J. W., Choi, K. S., & Kwon, T. K. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.03.022 · Cited by 108 · see citing works
Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
Grogan, P. T., Sleder, K. D., Samadi, A. K., Zhang, H., Timmermann, B. N., & Cohen, M. S. (2012) · Investigational New Drugs · doi:10.1007/s10637-012-9888-5 · Cited by 90 · see citing works
Diosgenin Induces Apoptosis in HepG2 Cells through Generation of Reactive Oxygen Species and Mitochondrial Pathway
Kim, D. S., Jeon, B. K., Lee, Y. E., Woo, W.-H., & Mun, Y. J. (2012) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2012/981675 · Cited by 87 · see citing works
Withaferin A enhances radiation-induced apoptosis in Caki cells through induction of reactive oxygen species, Bcl-2 downregulation and Akt inhibition
Yang, E. S., Choi, M. J., Kim, J. H., Choi, K. S., & Kwon, T. K. (2011) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2011.01.015 · Cited by 81 · see citing works
Low doses of cisplatin or gemcitabine plus Photofrin/photodynamic therapy: Disjointed cell cycle phase-related activity accounts for synergistic outcome in metastatic non–small cell lung cancer cells (H1299)
Crescenzi, E., Chiaviello, A., Canti, G. L., Reddi, E., Veneziani, B. M., & Palumbo, G. A. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-05-0425 · Cited by 80 · see citing works
Natural withanolide withaferin A induces apoptosis in uveal melanoma cells by suppression of Akt and c-MET activation
Samadi, A. K., Cohen, S. M., Mukerji, R., Chaguturu, V., Zhang, X., Timmermann, B. N., Cohen, M. S., & Person, E. A. (2012) · Tumor Biology · doi:10.1007/s13277-012-0363-x · Cited by 70 · see citing works
A novel combination of withaferin A and sorafenib shows synergistic efficacy against both papillary and anaplastic thyroid cancers
Cohen, S. M., Mukerji, R., Timmermann, B. N., Samadi, A. K., & Cohen, M. S. (2012) · The American Journal of Surgery · doi:10.1016/j.amjsurg.2012.07.027 · Cited by 69 · see citing works
Modulation of Reactive Oxygen Species in Pancreatic Cancer
Teoh-Fitzgerald, M. L. T., Sun, W., Smith, B. J., Oberley, L. W., & Cullen, J. J. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0851 · Cited by 69 · see citing works
Role of mitogen‐activated protein kinases and Mcl‐1 in apoptosis induction by withaferin A in human breast cancer cells
Hahm, E., Lee, J., & Singh, S. V. (2013) · Molecular Carcinogenesis · doi:10.1002/mc.22050 · Cited by 68 · see citing works
BBR induces apoptosis in HepG2 cell through an Akt‐ASK1‐ROS‐p38MAPKs‐linked cascade
Hyun, M., Hur, J., Mun, Y., Kim, D., & Woo, W. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22384 · Cited by 46 · see citing works
Oxaliplatin for Pretreated Patients with Advanced or Metastatic Pancreatic Cancer: A Multicenter Phase II Study
Androulakis, N., Syrigos, K., Polyzos, A., Aravantinos, G., Stathopoulos, G. P., Ziras, N., Mallas, K., Vamvakas, L. N., Georgoulias, V., & Research, F. T. H. O. (2005) · Cancer Investigation · doi:10.1081/cnv-46502 · Cited by 42 · see citing works
RLIP76 Regulates PI3K/Akt Signaling and Chemo-Radiotherapy Resistance in Pancreatic Cancer
Leake, K., Singhal, J., Nagaprashantha, L. D., Awasthi, S., & Singhal, S. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034582 · Cited by 40 · see citing works
Oral Poly(ADP-Ribose) Polymerase-1 Inhibitor BSI-401 Has Antitumor Activity and Synergizes with Oxaliplatin against Pancreatic Cancer, Preventing Acute Neurotoxicity
Melisi, D., Ossovskaya, V., Zhu, C., Rosa, R., Ling, J., Dougherty, P. M., Sherman, B. M., Abbruzzese, J. L., & Chiao, P. J. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-0910 · Cited by 40 · see citing works
Oxaliplatin, 5-Fluorouracil, and Leucovorin as Second-Line Treatment for Advanced Pancreatic Cancer
Novarino, A., Satolli, M. A., Chiappino, I., Giacobino, A., Bellone, G., Rahimi, F., Milanesi, E., Bertetto, O., & Ciuffreda, L. (2009) · American Journal of Clinical Oncology · doi:10.1097/coc.0b013e31817be5a9 · Cited by 36 · see citing works
(−)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: Role of topoisomerase IIα inhibition and reactive oxygen species
Takeda, S., Noguchi, M., Matsuo, K., Yamaguchi, Y., Kudo, T., Nishimura, H., Okamoto, Y., Amamoto, T., Shindo, M., Omiecinski, C. J., et al. (2013) · Toxicology · doi:10.1016/j.tox.2012.12.019 · Cited by 29 · see citing works
Role of platinum agents in the management of advanced pancreatic cancer
Saif, M. W., & Kim, R. (2007) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.8.16.2719 · Cited by 24 · see citing works
Gemcitabine and oxaliplatin combination as first-line treatment for advanced pancreatic cancer: a multicenter phase II study
Lee, K. H., Kim, M. K., Kim, Y. H., Ryoo, B. Y., Lim, H. Y., SONG, H. S., Kim, H. K., Lee, M. A., Im, S., Chang, H. M., et al. (2008) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-008-0873-9 · Cited by 19 · see citing works

Flagged first, then by citations

1 of the 51 references couldn’t be matched to a known paper.

Sorted by citations

Natural Products as Anticancer Agents: Current Status and Future Perspectives
Naeem, A., Hu, P., Yang, M. Y., Zhang, J., Liu, Y., Zhu, W., & Zheng, Q. (2022) · Molecules · doi:10.3390/molecules27238367 · Cited by 646 · see citing works
Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects
Paul, S., Chakraborty, S., Anand, U., Dey, S., Nandy, S., Ghorai, M., Saha, S. C., Patil, M. T., Kandimalla, R., Proćków, J., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112175 · Cited by 306 · see citing works
Targeting Cdc20 as a novel cancer therapeutic strategy
Wang, L., Zhang, J., Wan, L., Zhou, X., Wang, Z. P., & Wei, W. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.04.002 · Cited by 251 · see citing works
LAMB3 mediates apoptotic, proliferative, invasive, and metastatic behaviors in pancreatic cancer by regulating the PI3K/Akt signaling pathway
Zhang, H., Pan, Y., Cheung, M., Cao, M. P.-J., Yu, C., Chen, L., Zhan, L., He, Z., & Sun, C. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1320-z · Cited by 176 · see citing works
Phytochemicals in cancer cell chemosensitization: Current knowledge and future perspectives
Khatoon, E., Banik, K., Harsha, C., Sailo, B. L., Thakur, K. K., Khwairakpam, A. D., Vikkurthi, R., Devi, T. B., Gupta, S. C., & Kunnumakkara, A. B. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.06.014 · Cited by 163 · see citing works
Autophagy inhibitor enhance ZnPc/BSA nanoparticle induced photodynamic therapy by suppressing PD-L1 expression in osteosarcoma immunotherapy
Yu, W., Wang, Y., Zhu, J., Jin, L., Liu, B., Xia, K., Wang, J., Gao, J., Liang, C., & Tao, H. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.11.019 · Cited by 139 · see citing works
ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin
Wen, C., Wang, H. H., Wu, X., He, L., Zhou, Q., Wang, F., Chen, S., Huang, L. J., Chen, J., Wang, H., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2035-x · Cited by 129 · see citing works
Reactive Oxygen Species and Targeted Therapy for Pancreatic Cancer
Zhang, L., Li, J., Zong, L., Chen, X., Chen, K., Jiang, Z., Nan, L., Li, X., Li, W., Shan, T., et al. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1616781 · Cited by 127 · see citing works
“The release of superoxide anion, hydrogen peroxide, and hydroxyl radicals by macrophages and neutrophils is sustained by activation of plasma membrane NADPH oxidase [21].”
Background
Withaferin A: From ayurvedic folk medicine to preclinical anti-cancer drug
Hassannia, B., Logie, E., Vandenabeele, P., Berghe, T. V., & Berghe, W. V. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.08.004 · Cited by 124 · see citing works
Emerging mechanisms and applications of ferroptosis in the treatment of resistant cancers
Li, B., Yang, L., Peng, X., Fan, Q., Wei, S., Yang, S., Li, X., Jin, H., Wu, B., Huang, M., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110710 · Cited by 101 · see citing works
Exploring the Multifaceted Therapeutic Potential of Withaferin A and Its Derivatives
Behl, T., Sharma, A., Sharma, L. K., Sehgal, A., Zengin, G., Brata, R. D., Frățilă, O., & BUNGAU, S. G. (2020) · Biomedicines · doi:10.3390/biomedicines8120571 · Cited by 100 · see citing works
“While in vivo methodology evaluated high synergistic antitumor activity in PC xenografts [81].”
BackgroundInfluential
Sensitization of tumor cells to chemotherapy by natural products: A systematic review of preclinical data and molecular mechanisms
Júnior, R. G. D. O., Adrielly, A. F. C., Almeida, J. R. G. D. S., Grougnet, R., Thiéry, V., & Picot, L. (2018) · Fitoterapia · doi:10.1016/j.fitote.2018.02.025 · Cited by 96 · see citing works
“…weekly (i.p.) Xenograft (Mi/M) Synergistic decrease in tumor volume and weight, synergistic induction of apoptosis (pancreatic cancer) Y N Li et al. (2015) [117] α-carotene 5 mg/kg/day (p.o.) PTX 6 mg/kg/day (i.p.) Xenograft (Mi/M) Synergistic decrease in lung metastasis (lung cancer) Y…”
BackgroundInfluential
Polysaccharide from Lentinus edodes combined with oxaliplatin possesses the synergy and attenuation effect in hepatocellular carcinoma
Zhang, Y., Li, Q., Wang, J., Cheng, F., Huang, X., Cheng, Y., & Wang, K. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.04.037 · Cited by 98 · see citing works
Withaferin A Induces Oxidative Stress-Mediated Apoptosis and DNA Damage in Oral Cancer Cells
Chang, H., Li, R.-N., Wang, H.-R., Liu, J.-R., Tang, J., Huang, H., Chan, Y., & Yen, C.-Y. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00634 · Cited by 91 · see citing works
Natural products as chemo-radiation therapy sensitizers in cancers
Nisar, S., Masoodi, T., Prabhu, K. S., Kuttikrishnan, S., Zarif, L., Khatoon, S., Ali, S. M., Shahab Uddin, M. S., Akil, A. A., Singh, M. K., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113610 · Cited by 90 · see citing works
Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal
Kumar, S., Mathew, S. O., Aharwal, R. P., Tuli, H. S., Mohan, C. D., Sethi, G., Ahn, K. S., Webber, K. J., Sandhu, S. S., & Bishayee, A. (2023) · Pharmaceuticals · doi:10.3390/ph16020160 · Cited by 90 · see citing works
Overview of the anticancer activity of withaferin A, an active constituent of the Indian ginseng Withania somnifera
Sivasankarapillai, V. S., Nair, R. M. K., Rahdar, A., BUNGAU, S. G., Zaha, D. C., Aleya, L., & Ţiţ, D. M. (2020) · Environmental Science and Pollution Research · doi:10.1007/s11356-020-09028-0 · Cited by 77 · see citing works
“Western blotting studies the presence of client proteins by inhibiting the HSP90.”
BackgroundInfluential
Withaferin A inhibits Epithelial to Mesenchymal Transition in Non-Small Cell Lung Cancer Cells
Kyakulaga, A. H., Aqil, F., Munagala, R., & Gupta, R. C. (2018) · Scientific Reports · doi:10.1038/s41598-018-34018-1 · Cited by 74 · see citing works
lncRNA‐encoded pep‐AP attenuates the pentose phosphate pathway and sensitizes colorectal cancer cells to Oxaliplatin
Wang, X., Zhang, H., Yin, S., Yang, Y., Yang, H., Yang, J., Zhou, Z., Li, S., Ying, G., & Ba, Y. (2021) · EMBO Reports · doi:10.15252/embr.202153140 · Cited by 71 · see citing works
Dual drug loaded nanoliposomal chemotherapy: A promising strategy for treatment of head and neck squamous cell carcinoma
Mohan, A., Narayanan, S., Gopalan, B., Sethuraman, S., & Krishnan, U. M. (2015) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2015.11.017 · Cited by 64 · see citing works
Withania somnifera (L.) Dunal: Phytochemistry, structure-activity relationship, and anticancer potential
Tewari, D., Chander, V., Dhyani, A., Sahu, S. K., Gupta, P. K., Patni, P., Kalick, L. S., & Bishayee, A. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.153949 · Cited by 63 · see citing works
Phytochemicals, withaferin A and carnosol, overcome pancreatic cancer stem cells as c-Met inhibitors
Aliebrahimi, S., Montasser-Kouhsari, S., Arab, S. S., Shadboorestan, A., & Ostad, S. N. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.07.055 · Cited by 62 · see citing works
Withania somnifera: Progress towards a Pharmaceutical Agent for Immunomodulation and Cancer Therapeutics
Kashyap, V. K., Peasah-Darkwah, G., Dhasmana, A., Jaggi, M., Yallapu, M. M., & Chauhan, S. C. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14030611 · Cited by 61 · see citing works
Photodynamic Therapy Activity of New Porphyrin-Xylan-Coated Silica Nanoparticles in Human Colorectal Cancer
Bretin, L., Pinon, A., Bouramtane, S., Ouk, C., Richard, L., Perrin, M., Chaunavel, A., Carrion, C., Brégier, F., Sol, V., et al. (2019) · Cancers · doi:10.3390/cancers11101474 · Cited by 48 · see citing works
“PDT-induced ROS-generation triggers mitochondrial pore-opening leading to caspase activation and thus induces apoptotic cell death [50,51].”
Background
Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin
Xu, X., Zhao, Y., Zhang, M., He, R., Shi, X., Guo, X., Shi, C.-J., Peng, F., Wang, M., Shen, M., et al. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18020370 · Cited by 59 · see citing works
“Previous studies indicate that inhibition of autophagy enhances the efficacy of anticancer drugs, suggesting that suppression of autophagy may be an effective anti-cancer therapeutic strategy [21-23].”
Background
Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms
Xing, Z., Su, A., Li, M., Zhang, Y., He, T., Qiu, Y., Wei, T., Li, Z., Zhu, J., & Wu, W. (2023) · Drug Design Development and Therapy · doi:10.2147/dddt.s422512 · Cited by 55 · see citing works
Withania somnifera (L.) Dunal: A potential therapeutic adjuvant in cancer
Saggam, A., Tillu, G. S., Dixit, S., Chavan, P., Borse, S., Joshi, K., & Patwardhan, B. (2020) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2020.112759 · Cited by 55 · see citing works
Withania somnifera Ameliorates Doxorubicin-Induced Nephrotoxicity and Potentiates Its Therapeutic Efficacy Targeting SIRT1/Nrf2, Oxidative Stress, Inflammation, and Apoptosis
Hegab, A. M. M., Hassanin, S. O., Mekky, R. H., Abuzahrah, S. S., Hamza, A. A., Talaat, I. M., & Amin, A. (2025) · Pharmaceuticals · doi:10.3390/ph18020248 · Cited by 54 · see citing works
“According to Li et al. [84] withaferin A suppresses the PI3K/AKT pathway, which causes mitochondrial dysfunction.”
A review and outlook in the treatment of osteosarcoma and other deep tumors with photodynamic therapy: from basic to deep
Yu, W., Zhu, J., Wang, Y., Wang, J., Fang, W., Xia, K., Shao, J., Wu, M.-Z., Liu, B., Liang, C., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.16243 · Cited by 51 · see citing works
“ROS decreases the PI3K/AKT signaling pathway, induced by mitochondrial damage, leading to mitochondrion-mediated apoptosis [63].”
Background
Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS
Yue, T., Zuo, S., Bu, D., Zhu, J., Chen, S., Ma, Y., Ma, J., Guo, S., Wen, L., Zhang, X., et al. (2020) · Journal of Cancer · doi:10.7150/jca.35375 · Cited by 50 · see citing works
“Previous studies have shown that Bcl-2 family proteins also regulate mitochondrial apoptosis pathways [31, 32].”
Background
Withania somnifera (L.) Dunal (Ashwagandha); current understanding and future prospect as a potential drug candidate
Bhat, J. A., Akther, T., Najar, R. A., Rasool, F., & Hamid, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1029123 · Cited by 51 · see citing works
“This offered the strongest proof to yet of the combination therapy of withaferin A and oxaliplatin’s anticancer efficacy in PanCa therapy (Li et al., 2015).”
Background
Withania somnifera Suppresses Tumor Growth of Intracranial Allograft of Glioma Cells
Kataria, H., Sushil Kumar, K., Chaudhary, H., & Kaur, G. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9320-1 · Cited by 47 · see citing works
Dihydroartemisinin induces apoptosis in human gastric cancer cell line BGC-823 through activation of JNK1/2 and p38 MAPK signaling pathways
Zhang, S., Shi, L., Ma, H., Li, H., Li, Y., Lu, Y., Wang, Q., & Li, W. (2016) · Journal of Receptors and Signal Transduction · doi:10.1080/10799893.2016.1203942 · Cited by 46 · see citing works
Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells
Turrini, E., Calcabrini, C., Sestili, P., Catanzaro, E., Gianni, E. D., Diaz, A., Hrelia, P., Tacchini, M., Guerrini, A., Canonico, B., et al. (2016) · Toxins · doi:10.3390/toxins8050147 · Cited by 46 · see citing works
“Many studies have demonstrated the role of WFA inducing oxidative stress as an anticancer strategy on different tumor cell lines, such as prostate cancer, breast cancer, pancreatic cancer, leukemia, and melanoma [30–34].”
Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model
Suman, S., Das, T. P., Moselhy, J., Pal, D., Kolluru, V., Alatassi, H., Ankem, M. K., & Damodaran, C. (2016) · Oncotarget · doi:10.18632/oncotarget.10733 · Cited by 45 · see citing works
Downregulation of TIGAR sensitizes the antitumor effect of physapubenolide through increasing intracellular ROS levels to trigger apoptosis and autophagosome formation in human breast carcinoma cells
Ma, T., Zhang, Y., Zhang, C., Luo, J., & Kong, L. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.07.018 · Cited by 44 · see citing works
Role of ashwagandha methanolic extract in the regulation of thyroid profile in hypothyroidism modeled rats
Abdel-Wahhab, K. G., Mourad, H. H., Mannaa, F. A. E., Morsy, F. A., Hassan, L. K., & Taher, R. F. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-04721-x · Cited by 47 · see citing works
Withaferin A suppresses breast cancer cell proliferation by inhibition of the two-pore domain potassium (K2P9) channel TASK-3
Zúñiga, R., Concha, G., Cayo, Á., Cikutović-Molina, R., Arévalo, B., González, W., Catalán, M. A., & Zúñiga, L. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110383 · Cited by 40 · see citing works
Jolkinolide B sensitizes bladder cancer to mTOR inhibitors via dual inhibition of Akt signaling and autophagy
Sang, J., Gan, L., Zou, M.-F., Lin, Z., Fan, R., Huang, J.-L., Li, W., Tang, G., & Yin, S. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.11.014 · Cited by 40 · see citing works
Anti-proliferation of triple-negative breast cancer cells with physagulide P: ROS/JNK signaling pathway induces apoptosis and autophagic cell death
Yu, P., Zhang, C., Gao, C., Ma, T., Zhang, H., Zhou, M., Yang, Y.-W., Yang, L., & Kong, L. (2017) · Oncotarget · doi:10.18632/oncotarget.19299 · Cited by 38 · see citing works
“Furthermore, emerging evidences illustrated that natural compounds such as Physalin A [51], withaferin A [27] and celastrol [11] can cause ROS-mediated apoptosis and autophagy due to their structure of α, β-unsaturated ketone moieties [52].”
Background
Low Concentration of Withaferin a Inhibits Oxidative Stress-Mediated Migration and Invasion in Oral Cancer Cells
Yu, T., Tang, J., Ou‐Yang, F., Wang, Y., Yuan, S. F., Tseng, K., Lin, L., & Chang, H. (2020) · Biomolecules · doi:10.3390/biom10050777 · Cited by 38 · see citing works
“Withaferin A (WFA), a triterpenoid derived from the root or leaf of the medicinal plant Withania somnifera, is reported to exhibit antiproliferative properties and can induce apoptosis in several types of cancers such as leukemia [5], cervical [6], pancreatic [7], breast [8], lung [9], colorectal [10], and oral [11,12…”
Background
Baicalein inhibits progression of osteosarcoma cells through inactivation of the Wnt/β-catenin signaling pathway
Dai, G., Zheng, D., Wang, Q., Yang, J., Liu, G., Song, Q., Sun, X., Tao, C., Hu, Q., Gao, T., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.20987 · Cited by 36 · see citing works
“In general, there are two major apoptotic pathways: the extrinsic (death receptor-mediated) pathway and the intrinsic (mitochondrial-mediated) pathway, both pathways contribute to the drug induced apoptosis of tumor cells [44, 45].”
Background
Practical Application of “About Herbs” Website
Hou, Y.-N., Deng, G. E., & Mao, J. J. J. (2019) · The Cancer Journal · doi:10.1097/ppo.0000000000000403 · Cited by 35 · see citing works
Synergistic combinations of paclitaxel and withaferin A against human non-small cell lung cancer cells
Kyakulaga, A. H., Aqil, F., Munagala, R., & Gupta, R. C. (2020) · Oncotarget · doi:10.18632/oncotarget.27519 · Cited by 35 · see citing works
“Several studies have used CI and DRI to investigate the synergistic effects of anticancer drugs against breast [32], lung, pancreatic [40] and ovarian [39] cancers.”
Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition
Kalli, M., Mpekris, F., Charalambous, A., Michael, C., Stylianou, C., Voutouri, C., Hadjigeorgiou, A. G., Papoui, A., Martin, J. D., & Stylianopoulos, T. (2024) · Communications Biology · doi:10.1038/s42003-024-07268-1 · Cited by 34 · see citing works
Withanolides: Promising candidates for cancer therapy
Zhang, Q., Yuan, Y., Cao, S., Kang, N., & Qiu, F. (2024) · Phytotherapy Research · doi:10.1002/ptr.8090 · Cited by 34 · see citing works
Mitochondrial depletion of glutaredoxin 2 induces metabolic dysfunction-associated fatty liver disease in mice
Scalcon, V., Folda, A., Lupo, M. G., Tonolo, F., Pei, N., Battisti, I., Ferri, N., Arrigoni, G., Bindoli, A., Holmgren, A., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102277 · Cited by 33 · see citing works
Potential Anticancer Properties and Mechanisms of Action of Withanolides
Samadi, A. K. (2015) · The Enzymes · doi:10.1016/bs.enz.2015.05.002 · Cited by 32 · see citing works
Purinergic receptor P2Y6 contributes to 1‐methyl‐4‐phenylpyridinium‐induced oxidative stress and cell death in neuronal SH‐SY5Y cells
Qian, Y., Xu, S., Yang, X., & Xiao, Q. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24119 · Cited by 29 · see citing works
“MDA is a terminal product of lipid peroxidation (Li et al., 2015).”
Background
Mechanisms of Anti-Tumor Activity of Withania somnifera (Ashwagandha)
Mehta, V., Chander, H., & Munshi, A. (2020) · Nutrition and Cancer · doi:10.1080/01635581.2020.1778746 · Cited by 29 · see citing works
“with apoptosis induction and inactivation of Akt phosphorylation (82).”
Background
Withaferin a Triggers Apoptosis and DNA Damage in Bladder Cancer J82 Cells through Oxidative Stress
Chien, T., Wu, K., Chuang, Y.-T., Yeh, Y., Wang, H., Yeh, B., Yen, C., Yu, T., Wu, W., & Chang, H. (2021) · Antioxidants · doi:10.3390/antiox10071063 · Cited by 25 · see citing works
“5 μM (48 h sulforhodamine B assay), and 1–2 μM (48 h Alamar Blue assay) for oral [12], cervical [13], glioblastoma [14], pancreatic [15], lung [16], and melanoma [17] types.”
T-2 mycotoxin Induces male germ cell apoptosis by ROS-mediated JNK/p38 MAPK pathway
Lee, W.-Y., & Park, H.-J. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.115323 · Cited by 23 · see citing works
Withania somnifera Root Extract Enhances Chemotherapy through ‘Priming’
Henley, A. B., Yang, L., Chuang, K.-L., Sahuri-Arisoylu, M., Wu, L.-H., Bligh, S. W. A., & Bell, J. D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0170917 · Cited by 23 · see citing works
Low Dose Combined Treatment with Ultraviolet-C and Withaferin a Enhances Selective Killing of Oral Cancer Cells
Peng, S., Wang, Y., Lan, T., Lin, L., Yuan, S. F., Tang, J., & Chang, H. (2020) · Antioxidants · doi:10.3390/antiox9111120 · Cited by 22 · see citing works
“For example, the combined treatment of WFA and oxaliplatin showed synergistic antitumor activity in pancreatic cancer cells [16].”
Background
Identification and quantitative analysis of cellular proteins affected by treatment with withaferin a using a SILAC-based proteomics approach
Narayan, M., Seeley, K. W., & Jinwal, U. K. (2015) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2015.09.024 · Cited by 22 · see citing works
Oxidative Stress and AKT-Associated Angiogenesis in a Zebrafish Model and Its Potential Application for Withanolides
Tang, J., Cheng, Y., Chuang, Y.-T., Yang, K., Chang, F., Liu, W., & Chang, H. (2022) · Cells · doi:10.3390/cells11060961 · Cited by 21 · see citing works
2,3-Dihydro-3β-methoxy Withaferin-A Protects Normal Cells against Stress: Molecular Evidence of Its Potent Cytoprotective Activity
Chaudhary, A., Kalra, R. S., Huang, C., Prakash, J., Kaul, S. C., & Wadhwa, R. (2017) · Journal of Natural Products · doi:10.1021/acs.jnatprod.7b00573 · Cited by 20 · see citing works
Mechanism of bioactive polysaccharide from Lachnum sp. acts synergistically with 5‐fluorouracil against human hepatocellular carcinoma
Zong, S., Li, J., Yang, L., Huang, Q., Hou, G., Ye, Z., & Ye, M. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28202 · Cited by 20 · see citing works
“Apoptotic morphological changes in the nuclear chromatin of cells were detected by Hoechst 33258 staining (Li et al., 2015).”
Method
RETRACTED: Rotenone restrains the proliferation, motility and epithelial–mesenchymal transition of colon cancer cells and the tumourigenesis in nude mice via PI3K/AKT pathway
Xue, W., Men, S., & Liu, R. (2020) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13320 · Cited by 20 · see citing works
Retracted
Lipopolysaccharides-stimulated macrophage products enhance Withaferin A-induced apoptosis via activation of caspases and inhibition of NF-κB pathway in human cancer cells
Piao, L., Zhao, C., Lu, W.-J., Xiaoli, C., Shi, W., & Lu, L. (2016) · Molecular Immunology · doi:10.1016/j.molimm.2016.10.010 · Cited by 17 · see citing works
The Therapeutic Effects of Withaferin A against Cancer: Overview and Updates
Abeesh, P., & Guruvayoorappan, C. (2023) · Current Molecular Medicine · doi:10.2174/1566524023666230418094708 · Cited by 16 · see citing works
DACH 1 inhibits glioma invasion and tumor growth via the Wnt/catenin pathway
Wang, J., Zou, Y., Wu, X., Chen, M., Zhang, S., Lu, X., & Wang, Q. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s168314 · Cited by 16 · see citing works
“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
Xue, X., Ricci, M., Qu, H., Lindstrom, A. R., Zhang, D., Wu, H., Lin, T., & Li, Y. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.10.013 · Cited by 16 · see citing works
DT-diaphorase triggered theranostic nanoparticles induce the self-burst of reactive oxygen species for tumor diagnosis and treatment
Yan, D., Xu, X., Ren, C., Chen, C., Luo, J., Han, C., & Kong, L. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.02.033 · Cited by 16 · see citing works
Graphene Quantum Dots Induce Autophagy and Reveal Protection Against Hydrogen Peroxide-Induced Oxidative Stress Injury
Hua, S., Yang, L., Gao, T., Jiang, P., Jiang, F., & Liu, Y. (2019) · ACS Applied Bio Materials · doi:10.1021/acsabm.9b00784 · Cited by 15 · see citing works
Traditional Ayurvedic medicines: Pathway to develop anti-cancer drugs
Bhandariab, M., & Sc, A. R. (2015) · Journal of Molecular Pharmaceutics & Organic Process Research · doi:10.4172/2329-9053.1000130 · Cited by 15 · see citing works
“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
Hou, W., Miao, X.-H., Ma, L., Bai, X., Liu, Q., & Song, L. (2017) · African Journal of Traditional Complementary and Alternative Medicines · doi:10.21010/ajtcam.v14i2.33 · Cited by 15 · see citing works
“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
Shao, Q., Feng, Y., Wang, W., Wang, M., Li, B., Tahchi, M. R. E., & Yin, Y. (2019) · Journal of Materials Science · doi:10.1007/s10853-019-04139-7 · Cited by 14 · see citing works
“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
Kumar, P., Banik, S. P., Goel, A., Chakraborty, S., Bagchi, M., & Bagchi, D. (2023) · Journal of the American Nutrition Association · doi:10.1080/27697061.2023.2228863 · Cited by 14 · see citing works
Venom of Viperidae: A Perspective of its Antibacterial and Antitumor Potential
Teodoro, A., Gonçalves, F. J. M., Oliveira, H., & Marques, S. M. (2021) · Current Drug Targets · doi:10.2174/1389450122666210811164517 · Cited by 14 · see citing works
Role of Phytoconstituents in Cancer Treatment: A Review
Kumar, M., Gupta, S., Kalia, K., & Kumar, D. (2024) · Recent Advances in Food Nutrition & Agriculture · doi:10.2174/012772574x274566231220051254 · Cited by 13 · see citing works
Molecular mechanisms of Asparagus racemosus willd. and Withania somnifera (L.) Dunal as chemotherapeutic adjuvants for breast cancer treatment
Prasad, K., Saggam, A., Guruprasad, K. P., Tillu, G. S., Patwardhan, B., & Satyamoorthy, K. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118261 · Cited by 14 · see citing works
Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer
Wu, T., Yu, Y., Tu, X., Ye, L., Wang, J., Xie, C., Kuang, K., Yu, Y., Zhuge, W., Wang, Z., et al. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118754 · Cited by 13 · see citing works
Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives
Marlow, M. M., Shah, S. S., Véliz, E. A., Ivan, M. E., & Graham, R. M. (2016) · Journal of Natural Medicines · doi:10.1007/s11418-016-1020-2 · Cited by 13 · see citing works
The Potential Pharmacological Effects of Natural Product Withaferin A in Cancer: Opportunities and Challenges for Clinical Translation
Devabattula, G., Panda, B., Yadav, R., & Godugu, C. (2024) · Planta Medica · doi:10.1055/a-2289-9600 · Cited by 12 · see citing works
A pharmacognostic approach for mitigating pancreatic cancer: emphasis on herbal extracts and phytoconstituents
Gupta, S., Kumar, A., & Tejavath, K. K. (2021) · Future Journal of Pharmaceutical Sciences · doi:10.1186/s43094-021-00246-y · Cited by 11 · see citing works
“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
Synergistic Inhibition of Pancreatic Cancer Cell Growth and Migration by Gemcitabine and Withaferin A
Szydlak, R. (2024) · Biomolecules · doi:10.3390/biom14091178 · Cited by 10 · see citing works
“To overcome these limitations, combination therapies involving gemcitabine and other chemotherapeutic agents or molecularly targeted drugs have been explored [9,11–14].”
Background
Apaf1 nanoLuc biosensors identified lentinan as a potent synergizer of cisplatin in targeting hepatocellular carcinoma cells
Wang, Z., Qu, K., Zhou, L., Ren, L., Ren, B., Meng, F., Yu, W., Wang, H., & Fan, H. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.08.030 · Cited by 10 · see citing works
Sodium Tanshinone IIA Sulfonate Attenuates Tumor Oxidative Stress and Promotes Apoptosis in an Intermittent Hypoxia Mouse Model
Zhang, X., Chen, X., Sun, P., Su, X.-M., Zeng, H., Zeng, Y., Wang, M., & Luo, X. (2020) · Technology in Cancer Research & Treatment · doi:10.1177/1533033820928073 · Cited by 9 · see citing works
“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
In vitro evidence of the antitumor capacity of Solanaceae and Cucurbitaceae in colon cancer: A systematic review
Mesas, C., Fuel, M., Martínez, R., Prados, J. C., Melguizo, C., & Porres, J. M. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1900058 · Cited by 9 · see citing works
“…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).”
Background
Chemotherapeutic Effect of Withaferin A in Human Oral Cancer Cells
Yang, I., Kim, L., Shin, J., & Cho, S. (2015) · Journal of Cancer Therapy · doi:10.4236/jct.2015.68080 · Cited by 8 · see citing works
“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
Niu, Y.-B., Velu, P., Khalid, A., Zyoud, S. H., Kazi, M., & Li, Y. (2024) · Combinatorial Chemistry & High Throughput Screening · doi:10.2174/0113862073297703240613073134 · Cited by 7 · see citing works
Essential Oil Extracted from Lippia sidoides Cham. (Verbenaceae) Induces Cell Cycle Arrest, Apoptosis, and Antimigratory Effects in Melanoma Cells
Volpe-Fix, A. R., Sales, F. S., Caperuto, L. C., Lago, J. H. G., & Machado, J. (2024) · Chemistry & Biodiversity · doi:10.1002/cbdv.202401530 · Cited by 7 · see citing works
Identification and Characterization of CD107a as a Marker of Low Reactive Oxygen Species in Chemoresistant Cells in Colorectal Cancer
Kitahara, T., Haraguchi, N., Takahashi, H., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Yamamoto, H., Doki, Y., & Mori, M. (2016) · Annals of Surgical Oncology · doi:10.1245/s10434-016-5671-8 · Cited by 7 · see citing works
“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 · see citing works
Micro- and nanoplastic exposure and metabolic disruption: A review on their emerging role in the pathogenesis of diabetes
Song, Y., Lyu, S., Wang, R., Hou, X., Tong, X., Fang, Y., Zhang, Z., Liu, A., Yang, M. G., Li, Y., et al. (2025) · NanoImpact · doi:10.1016/j.impact.2025.100590 · Cited by 5 · see citing works
Synergistic and toxicity-attenuating effects of Periplaneta americana extract CII-3 combined with cisplatin on lewis lung cancer-bearing mice
Liu, X., Guo, M., Yang, Q., Shi, M., Liu, G., & Peng, F. (2020) · Pharmacognosy Magazine · doi:10.4103/pm.pm_499_19 · Cited by 3 · see citing works
Experimental evidence to the untapped potential of Ayurvedic herb, Ashwagandha: Bench-to-Bedside
Wadhwa, R., & Kaul, S. C. (2023) · International Journal of Ayurveda Research · doi:10.4103/ijar.ijar_6_23 · Cited by 3 · see citing works
Withania somnifera Has Potential to Treat Cancer
Halder, B., & Thakur, S. S. (2017) · Springer eBooks · doi:10.1007/978-3-319-59192-6_10 · Cited by 3 · see citing works
Scientific Evidence for Anticancer Effects of Withania somnifera and Its Primary Bioactive Component Withaferin A
Sehrawat, A., Samanta, S. K., Kim, S., Hahm, E., & Singh, S. V. (2017) · Springer eBooks · doi:10.1007/978-3-319-59192-6_8 · Cited by 3 · see citing works
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 · see citing works
“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 · see citing works
Exploring the therapeutic potential of withaferin A by modulating key oncosignaling pathways
Chauhan, P., Mallick, M. N., Rab, S. O., Saeed, M., Alkhulaifi, F. M., Lakhanpal, S., Singh, A. V., Pandey, P., Verma, M., & Khan, F. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05006-4 · Cited by 2 · see citing works
Synergistic and Toxicity-reducing Effects of Periplaneta americana Extract CⅡ-3 Combined with CTX on H22 Tumor Bearing Mice
Yuan, R., Liu, G., Guo, M., & Liu, X. (2023) · Indian Journal of Pharmaceutical Education and Research · doi:10.5530/ijper.57.4.135 · Cited by 2 · see citing works
“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.”
Background
Ashwagandha Bioactives for Cancer Treatment: Experimental Evidence and Their Mechanism(s) of Action
Wadhwa, R., Garg, S., Kaul, A., & Kaul, S. C. (2017) · Springer eBooks · doi:10.1007/978-3-319-59192-6_7 · Cited by 2 · see citing works
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.v1 · Cited by 2 · see citing works
Molecular insights into withaferin A: A holistic approach to cancer therapy
Islam, M. R., Rauf, A., Rakesh, M. M., Akash, S., Fakir, M. N. H., Islam, M. S., Naba, A. F., Al-Imran, M. I. K., Alomar, T. S., Ogaly, H. A., et al. (2024) · Inorganic Chemistry Communications · doi:10.1016/j.inoche.2024.113316 · Cited by 1 · see citing works
Current progress of CDC20 in cancer development and targeting CDC20 for cancer therapy
Chen, Y., Gao, S., Yang, P., Liu, S., Zhang, W., Wang, J., & Jing, H. (2026) · Carcinogenesis · doi:10.1093/carcin/bgag021 · Cited by 1 · see citing works
WithaniaSomnifera: A New Approach To Cancer
Shah, D. R., Palaskar, S. J., Pawar, R., & Punse, R. R. (2018) · Annals of Applied Bio-Sciences · doi:10.21276/aabs.1838 · Cited by 1 · see citing works
“WS promoted growth suppression and apoptosis through ROSmediated mitochondrial dysfunction and by inhibition of the PI3K/AKT pathway whereas in invivo, showed potential anti-tumor effects compared to single factor administered, without much side effects and toxicity.[38] Further studies of WA on PC cell lines like Pan…”
Background
Why Ashwagandha for Healthy Ageing? Evidence from Cultured Human Cells
Wadhwa, R., Garg, S., Khurana, M., & Kaul, S. C. (2021) · Healthy ageing and longevity · doi:10.1007/978-3-030-83017-5_28 · Cited by 1 · see citing works

Inhibition of PI3K/AKT signaling via ROS regulation is involved in Rhein-induced apoptosis and enhancement of oxaliplatin sensitivity in pancreatic cancer cells
Liu, Y., Shi, C., He, Z., Zhu, F., Wang, M., He, R., Zhao, C., Shi, X., Zhou, M., Pan, S., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.49514 · Cited by 93 · see citing works
A Novel Combination Therapy With Arsenic Trioxide and Parthenolide Against Pancreatic Cancer Cells
Wang, W., Adachi, M., Zhang, R., Zhou, J., & Zhu, D. (2009) · Pancreas · doi:10.1097/mpa.0b013e3181a0b6f2 · Cited by 43 · see citing works
Synergistic Inhibition of Pancreatic Cancer Cell Growth and Migration by Gemcitabine and Withaferin A
Szydlak, R. (2024) · Biomolecules · doi:10.3390/biom14091178 · Cited by 10 · see citing works
Oxymatrine synergistically enhances antitumor activity of oxaliplatin in colon carcinoma through PI3K/AKT/mTOR pathway
Liu, Y., Bi, T., Wang, Z., Wu, G., Qian, L., Gao, Q., & Shen, G. (2016) · APOPTOSIS · doi:10.1007/s10495-016-1297-3 · Cited by 67 · see citing works
Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells
Kasukabe, T., Honma, Y., Okabe‐Kado, J., Higuchi, Y., Kato, N., & Kumakura, S. (2016) · Oncology Reports · doi:10.3892/or.2016.4867 · Cited by 93 · see citing works

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 › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks