The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor–related apoptosis-inducing ligand

Horinaka, Mano; Yoshida, Tatsushi; Shiraishi, Takeshi; Nakata, Susumu; Wakada, Miki; Sakai, Toshiyuki

doi:10.1158/1535-7163.mct-05-0431

Cited by 118 publications

(93 citation statements)

References 36 publications

(29 reference statements)

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“…A small number of similar studies with flavonoids in combination with TRAIL showed that apigenin, luteolin, quercetin and kaempferol synergistically induced apoptosis with TRAIL in human malignant tumor cells [20,[27][28][29][30]. Horinaka et al reported that luteolin increased TRAIL-induced apoptosis in HeLa cells through upregulation of death receptor TRAIL-R2 (DR5) [27].…”

Section: Resultsmentioning

confidence: 99%

Ethanolic Extract of Propolis (EEP) Enhances the Apoptosis- Inducing Potential of TRAIL in Cancer Cells

et al. 2009

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Ethanolic extract of propolis (EEP) is one of the richest sources of phenolic acids and flavonoids. EEP and its phenolic compounds have been known for various biological activities including immunopotentiation, chemopreventive and antitumor effects. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a naturally occurring anticancer agent that preferentially induces apoptosis in cancer cells and is not toxic toward normal cells. We examined the cytotoxic and apoptotic effect of EEP and phenolic compounds identified in propolis in combination with TRAIL on HeLa cancer cells. HeLa cells were resistant to TRAIL-induced apoptosis. Our study demonstrated that EEP and its components significantly sensitize to TRAIL induced death in cancer cells. The percentage of the apoptotic cell after exposure to 50 μg/mL EEP and 100 ng/mL TRAIL increased to 71.10±1.16%. The strongest cytotoxic effect in combination with TRAIL on HeLa cells exhibited apigenin and CAPE at the concentration of 50 μM (58.87±0.75% and 49.59±0.39%, respectively). In this report, we show for the first time that EEP markedly augmented TRAIL mediated apoptosis in cancer cells and confirmed the importance of propolis in chemoprevention of malignant tumors.

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Section: Resultsmentioning

confidence: 99%

Ethanolic Extract of Propolis (EEP) Enhances the Apoptosis- Inducing Potential of TRAIL in Cancer Cells

et al. 2009

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“…In addition, several natural compounds, including dietary flavonoids, sensitize malignant tumor cells to TRAIL (40). The molecular basis for the sensitization of tumor cells by these agents may involve up-regulation of DR4/DR5 (41), down-regulation of the antiapoptotic molecules Bcl-2, Bcl-xL, and c-FLIP, or up-regulation of proapoptotic molecules, including Bax, caspases, and Fas-associated death domain (42).…”

Section: Discussionmentioning

confidence: 99%

Blockade of transforming growth factor-β-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade

Choo

Kawasaki

Singhirunnusorn

et al. 2006

Molecular Cancer Therapeutics

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of the TNF-A ligand family that selectively induces apoptosis in a variety of tumor cells. To clarify the molecular mechanism of TRAILinduced apoptosis, we focused on transforming growth factor-B-activated kinase 1 (TAK1) mitogen-activated protein kinase (MAPK) kinase kinase, a key regulator of the TNF-A-induced activation of p65/RelA and c-Jun NH 2 -terminal kinase/p38 MAPKs. In human cervical carcinoma HeLa cells, TRAIL induced the delayed phosphorylation of endogenous TAK1 and its activator protein TAB1 and TAB2, which contrasted to the rapid response to TNF-A. Specific knockdown of TAK1 using small interfering RNA (siRNA) abrogated the TRAIL-induced activation of p65 and c-Jun NH 2 -terminal kinase/p38 MAPKs. TRAILinduced apoptotic signals, including caspase-8, caspase-3, caspase-7, and poly(ADP-ribose) polymerase, were enhanced by TAK1 siRNA. Flow cytometry showed that the binding of Annexin V to cell surface was also synergistically increased by TRAIL in combination with TAK1 siRNA. In addition, pretreatment of cells with 5Z-7-oxozeaenol, a selective TAK1 kinase inhibitor, enhanced the TRAIL-induced cleavage of caspases and binding of Annexin V. The TAK1-mediated antiapoptotic effects were also observed in human lung adenocarcinoma A549 cells. In contrast, TAK1-deficient mouse embryonic fibroblasts are resistant to TRAIL-induced apoptosis, and treatment of control mouse embryonic fibroblasts with 5Z-7-oxozeaenol did not drastically promote the TRAILinduced activation of a caspase cascade. These results suggest that TAK1 plays a critical role for TRAIL-induced apoptosis, and the blockade of TAK1 kinase will improve the chances of overcoming cancer.

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“…Apigenin also causes cell cycle arrest and sensitizes leukemia cells to vincristine (11). Apigenin has additionally been reported to induce apoptosis of prostate and colon cancer cells through induction of death receptor 5, and to act synergistically with exogenous tumor necrosis factor-related apoptosis-inducing ligand to induce cell apoptosis (12). Furthermore, apigenin enhances the anticancer activity or minimizes the resistance of cancer cells to a number chemotherapeutics, including gemcitabine, paclitaxel, 5-fluorouracil and doxorubicin by inducing apoptosis (13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis

Liu

et al. 2016

Oncology Letters

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Abstract. Epidemiological and experimental evidence suggests that dietary flavonoids, including apigenin, have anticancer roles. Apigenin has been reported to elevate p53, a critical molecule in the induction of apoptosis. The present study aimed to investigate whether apigenin, a dietary flavonoid, improves the cytotoxic effect of cisplatin in a cancer cell culture system, and to elucidate the mechanism of this effect. Multiple tumor cell types were treated with apigenin, cisplatin or both drugs. Cell viability was evaluated, and the cytotoxic effect was determined biochemically and microscopically. Treatment with apigenin increased cisplatin-induced DNA damage and the apoptosis of tumor cells in a p53-dependent manner. Apigenin, when used with cisplatin, inhibited cell proliferation and promoted mitogen-activated protein kinase activation and subsequent p53 phosphorylation, leading to p53 accumulation and upregulation of proapoptotic proteins. Cisplatin is one of the most commonly used chemotherapeutic drugs for malignant tumors, but resistance to this drug occurs. The current results therefore demonstrate that dietary flavonoids may diminish the resistance of cancers to cisplatin.

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The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor–related apoptosis-inducing ligand

Cited by 118 publications

References 36 publications

Ethanolic Extract of Propolis (EEP) Enhances the Apoptosis- Inducing Potential of TRAIL in Cancer Cells

Ethanolic Extract of Propolis (EEP) Enhances the Apoptosis- Inducing Potential of TRAIL in Cancer Cells

Blockade of transforming growth factor-β-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade

Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis

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