The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells

Kang, Youra; Park, Min A; Heo, Se-Woong; Park, Su‐Young; Kang, Keon Wook; Park, Pil-Hoon; Kim, Jung-Ae

doi:10.1016/j.bbagen.2012.12.005

Cited by 43 publications

(41 citation statements)

References 57 publications

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“…The underlying mechanisms of this are related to the signal transduction and activation of transcription 3 (STAT3) and epidermal growth factor receptor (EGFR) suppression [7], as well as MCF-7/ADR cell stemness reduction [8]. ABCB1 plays a vital role in drug resistance by stimulating drug efflux.…”

Section: Discussionmentioning

confidence: 99%

“…As we have reviewed previously, XN has multiple health benefits, mainly including metabolic syndrome attenuating effects, hepatic protection effects, antimicrobial activity, anti-parasite effects, cancer chemo-preventive effects, cancer therapeutic activity [4], and also inhibitory activities in cancer angiogenesis [5,6]. Interestingly, recent studies have shown that XN could sensitize cancer cells to certain anticancer drugs [7,8]. Moreover, XN was considered to be an inhibitor of the breast cancer resistance protein (ABCG2) transporter [9].…”

Section: Introductionmentioning

confidence: 99%

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Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

Liu

Hoag

et al. 2018

Applied Sciences

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Xanthohumol (XN) is a well-known prenylated flavonoid found in Humulus lupulus L. It is involved in several pharmacological activities, including the sensitization of doxorubicin-resistant breast cancer (MCF-7/ADR) cells to doxorubicin (DOX) through a reduction in cell viability and stemness. In the present study, we revealed another mechanism to further explain the reverse of the drug resistance of XN. In the MCF-7/ADR cell line, we found that XN inhibited the efflux functions of ATP-binding cassette subfamily B member 1 (ABCB1). We also observed that XN was a substrate of ABCB1 and stimulated its ATPase activity. Moreover, our results revealed that XN showed a synergic effect with the ABCB1 substrate colchicine (COL) in the MCF-7/ADR cell line. Further, we showed that XN bound to the central transmembrane domain (TMD) site, overlapping with the DOX binding site. This mechanism was supported by molecular modeling and simulation data, which revealed that XN bound to the ABCB1 transmembrane domain, where doxorubicin also binds, and its binding affinity was stronger than that of doxorubicin, resulting in less protein and ligand position fluctuation. These results support the XN-induced reversal of drug resistance via the inhibition of ABCB1-mediated transport of doxorubicin, stimulating ABCB1 ATPase activity and acting as a substrate of ABCB1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

Liu

Hoag

et al. 2018

Applied Sciences

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“…Our results indicate that the inhibition of PAR2 might be one of the possible targets. Earlier studies have proved its inhibitory effects on proliferation and MMP-9 expression in MDA-MB-231 cells (Kang et al, 2013). The other reported targets of xanthohumol are STAT3 and EGFR (Barreiro et al, 2007) which are also activated by PAR2 expression.…”

Section: Discussionmentioning

confidence: 98%

Protease activated receptor-2 (PAR2): possible target of phytochemicals

Kakarala

Jamil

2014

Journal of Biomolecular Structure and Dynamics

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The use of phytochemicals either singly or in combination with other anticancer drugs comes with an advantage of less toxicity and minimal side effects. Signaling pathways play central role in cell cycle, cell growth, metabolism, etc. Thus, the identification of phytochemicals with promising antagonistic effect on the receptor/s playing key role in single transduction may have better therapeutic application. With this background, phytochemicals were screened against protease-activated receptor 2 (PAR2). PAR2 belongs to the superfamily of GPCRs and is an important target for breast cancer. Using in silico methods, this study was able to identify the phytochemicals with promising binding affinity suggesting their therapeutic potential in the treatment of breast cancer. The findings from this study acquires importance as the information on the possible agonists and antagonists of PAR2 is limited due its unique mechanism of activation.

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“…Stat3 regulates a number of important tumorigenesis pathways, including cell cycle progression, apoptosis, tumor angiogenesis, and tumor cell evasion of the immune system [20,[37][38][39] . In this study, we demonstrated that Stat3 can be inactivated by α-mangostin, which can also downregulate the downstream gene expression of Bcl-xL and Mcl-1.…”

Section: Discussionmentioning

confidence: 99%

α-Mangostin suppresses human gastric adenocarcinoma cells in vitro via blockade of Stat3 signaling pathway

Shan

Cui

et al. 2014

Acta Pharmacol Sin

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Aim: To investigate the anti-tumor effects of α-mangostin, a major xanthone identified in the pericarp of mangosteen (Garcinia mangostana Linn), against human gastric adenocarcinoma cells in vitro, and the mechanisms of the effects. Methods: Human gastric adenocarcinoma cell lines BGC-823 and SGC-7901 were treated with α-mangostin. The cell viability was measured with MTT assay, and cell apoptosis was examined using flow cytometry and TUNEL assay. The expression of the relevant proteins was detected using Western blot. Results: Treatment with α-mangostin (3-10 μg/mL) inhibited the viability of both BGC-823 and SGC-7901 cells in dose-and timemanners. Furthermore, α-mangostin (7 μg/mL) time-dependently increased the apoptosis index of the cancer cells, reduced the mitochondrial membrane potential of the cancer cells, and significantly increased the release of cytochrome c and AIF into cytoplasm. Moreover, the α-mangostin treatment markedly suppressed the constitutive Stat3 protein activation, and Stat3-regulated Bcl-xL and Mcl-1 protein levels in the cancer cells. Conclusion: The anti-tumor effects of α-mangostin against human gastric adenocarcinoma cells in vitro can be partly attributed to blockade of Stat3 signaling pathway.

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The radio-sensitizing effect of xanthohumol is mediated by STAT3 and EGFR suppression in doxorubicin-resistant MCF-7 human breast cancer cells

Cited by 43 publications

References 57 publications

Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

Protease activated receptor-2 (PAR2): possible target of phytochemicals

α-Mangostin suppresses human gastric adenocarcinoma cells in vitro via blockade of Stat3 signaling pathway

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