Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells

Um, Hee Jung; Min, Kyoung‐jin; Kim, Dong-Eun; Kwon, Taeg Kyu

doi:10.1016/j.bbrc.2012.08.133

Cited by 90 publications

(69 citation statements)

References 24 publications

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“…This implies that there are yet other factors that contribute to cell death initiated by these compounds. Several reports have shown that both WA and SFN are effective in the inhibition of pro-inflammatory cytokines, as well as the aberrant expression of epigenetic modifiers [11,13,[33][34][35]. Moreover, Hahm and colleagues reported that WA-induced apoptosis was mediated through reactive oxygen species and Nagalingam et al found that WA inhibited breast tumor formation in vivo through the activation of the ERK/RSK axis, DR5 upregulation, and elevated nuclear accumulation of Elk1 and CHOP in breast cancer [19,36].…”

Section: Discussionmentioning

confidence: 99%

Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells

Royston¹,

Udayakumar²,

Lewis³

et al. 2017

Preprint

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Abstract:With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction between these bioactive compounds in combination. The natural compounds withaferin A (WA), from the Indian winter cherry, and sulforaphane (SFN), from cruciferous vegetables, have numerous anti-cancer effects and some report their ability to regulate epigenetic processes. Our study is the first to investigate the combinatorial effects of low physiologically achievable concentrations of WA and SFN on breast cancer cell proliferation, histone deacetylase1 (HDAC1) and DNA methyltransferases (DNMTs). No adverse effects were observed on control cells at optimal concentrations. There was synergistic inhibition of cellular viability in MCF-7 cells and a greater induction of apoptosis with the combinatorial approach than with either compound administered alone in both MDA-MB-231 and MCF-7 cells. HDAC expression was down-regulated at multiple levels. Lastly, we determined the combined effects of these bioactive compounds on the pro-apoptotic BAX and anti-apoptotic BCL-2 and found decreases in BCL-2 and increases in BAX. Taken together, our findings demonstrate the ability of low concentrations of combinatorial WA and SFN to promote cancer cell death and regulate key epigenetic modifiers in human breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells

Royston¹,

Udayakumar²,

Lewis³

et al. 2017

Preprint

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show abstract

“…Reactive oxygen species serve a role in the pro-apoptotic effect of WA in various types of cancer, including leukemia (20) and renal cancer (21). Proteasome inhibition, the induction of endoplasmic reticulum stress, downregulation of Akt serine/threonine kinase phosphorylation and the downregulation of Janus kinase/signal transducer and activator of transcription 3 signaling are also suggested to contribute to cancer cell apoptosis following WA treatment (4,22,23). Transcription factors, including nuclear factor-κB (NF-κB) and mitogen-activated protein kinases, contribute to WA-mediated induction of apoptosis of leukemia (4,24), glioblastoma (25) and breast cancer (26).…”

Section: Discussionmentioning

confidence: 99%

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Kim

Hwang

et al. 2017

Oncology Letters

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Abstract. Human gastric adenocarcinoma (AGS) is one of the most common types of malignant tumor and the third-leading cause of tumor-associated mortality worldwide. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, exhibits antitumor activity in a variety of cancer models. However, to the best of our knowledge, the direct effect of WA on AGS cells has not previously been determined. The present study investigated the effects of WA on the proliferation and metastatic activity of AGS cells. WA exerted a dose-dependent cytotoxic effect on AGS cells. The effect was associated with cell cycle arrest at the G2/M phase and the expression of apoptotic proteins. Additionally, WA treatment resulted in a decrease in the migration and invasion ability of the AGS cells, as demonstrated using a wound healing assay and a Boyden chamber assay. These results indicate that WA directly inhibits the proliferation and metastatic activity of gastric cancer cells, and suggest that WA may be developed as a drug for the treatment of gastric cancer.

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“…Furthermore, STAT3 activation promotes angiogenesis by inducing vascular endothelial growth factor (VEGF) (10), and also stimulates invasion and metastasis by increasing the expression of matrix metalloproteinases (MMPs) (11). The pathway is considered as a major molecular target of interest in a number of cancer types, including melanoma (12), renal carcinoma (13) and breast cancer (14).…”

Section: Introductionmentioning

confidence: 99%

Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways

Zhang

Gao

Yang

2017

Experimental and Therapeutic Medicine

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Abstract. Osteosarcoma (OS) is the most commonly diagnosed tumor of the bones in children and young adults. Even with conventional therapies the 5-year survival rate is ~65% in patients with OS. Considering the side effects and aggressiveness of malignant bone tumors, research is focussing on multi-targeted strategies in treatment. Cucurbitacin B, a triterpenoid compound has been demonstrated to induce apoptosis in various cancer cell types. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling cascades and mitogen activated protein kinases (MAPK) signalling cascades are critical regulators of tumorigenesis. The present study assessed the influence of cucurbitacin B on the viability and expression of MAPKs and proteins of the JAK2/STAT3 cascades in human OS cells (U-2 OS). Cucurbitacin B (20-100 µM) significantly reduced cell viability (P<0.05) and induced apoptosis, as assessed by MTT and Annexin V/propidium iodide staining, along with inhibiting cell migration. Gelatin zymography revealed supressed activities of matrix metalloproteinase (MMP-)2 and 9. Furthermore, cucurbitacin B effectively upregulated the apoptotic pathway and caused the effective inhibition of MAPK signalling and JAK2/STAT3 cascades. Multifold suppression of vascular endothelial growth factor by cucurbitacin B was also observed, indicating inhibition of angiogenesis. Thus, by downregulating major pathways-MAPK and JAK2/STAT3 and MMPs, cucurbitacin B has potent anti-proliferative and anti-metastatic effects that require further investigation with regards to cancer treatment.

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Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells

Cited by 90 publications

References 24 publications

Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells

Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells

Withaferin A inhibits the proliferation of gastric cancer cells by inducing G2/M cell cycle arrest and apoptosis

Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways

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