MK615 inhibits pancreatic cancer cell growth by dual inhibition of Aurora A and B kinases

Okada, Toshie; Sawada, Tokihiko; Osawa, Tatsushi; Adachi, Masakazu; Kubota, Keiichi

doi:10.3748/wjg.14.1378

Cited by 32 publications

(26 citation statements)

References 27 publications

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“…mK615 is a neutral ph extract mixture of the ume fruit that contains several triterpenoids. it has been reported to exert anti-cancer effects against gastric (3), breast (7), hepatocellular (8), colon (9) and pancreatic cancer (10). here, we demonstrated that the ume extract mK615 at a neutral ph suppressed cutaneous and in-transit metastatic lesions in a patient with mm.…”

Section: Discussionsupporting

confidence: 54%

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Advanced malignant melanoma responds to Prunus mume Sieb. Et Zucc (Ume) extract: Case report and in vitro study

Matsushita

Tada²,

Kikuchi³

et al. 2010

Experimental and Therapeutic Medicine

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Abstract. malignant melanoma (mm) is an aggressive chemoresistant skin cancer characterized by rapid metastasis and a poor prognosis. therefore, the development of innovative effective therapies is critical. mK615 is an extract from the Japanese apricot Prunus mume Sieb. Et Zucc (ume). at a neutral ph, it contains natural chemical substances such as triterpenoids that exert anti-neoplastic effects in several types of cancers. We found that in patients with advanced mm, mK615 dramatically suppressed the cutaneous in-transit metastasis of the disease. pre-and post-treatment comparison of tumors showed that the apoptotic index was significantly increased by MK615. In vitro studies, MTT assay, flow cytometric cell cycle analysis and immunofluorescence microscopy revealed that MK615 inhibited the growth of SK-mEl28 cells in a dose-dependent manner, increased the proportion of cells in sub-G1 phase and induced apoptosis. We further examined the expression of the receptor for advanced glycation end products (raGE). raGE is a multi-ligand receptor that binds to a novel cytokine, high mobility group box protein 1 (hmGB1), as well as advanced glycation end products. there is evidence that raGE/hmGB1 interactions enhance cell invasion in mm. here, we present Western blotting and immunofluorescence microscopy data indicating that mK615 inhibited the expression of raGE in SK-mEl28 cells, and suppressed the release of hmGB1 by SK-MEL28 cells. Our findings suggest that MK615 may be a valuable tool for treating mm and other malignant tumors.

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Section: Discussionsupporting

confidence: 54%

“…the extract of ume has been reported to exert anticancer effects against gastric (3), breast (7), hepatocellular (8), colon (9) and pancreatic cancers (10). the mechanisms underlying these effects include the induction of apoptosis (3,7) and autophagy (9) and the suppression of aurora a kinase (8,10) in cancer cells.…”

mentioning

confidence: 99%

Advanced malignant melanoma responds to Prunus mume Sieb. Et Zucc (Ume) extract: Case report and in vitro study

Matsushita

Tada²,

Kikuchi³

et al. 2010

Experimental and Therapeutic Medicine

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“…Despite these reports, Ume substances have not yet been used to treat disease in clinical settings (25)(26)(27)(28); possibly, such use is dependent on the outcome of future clinical trials in humans. In this study, the Ume extract fraction (F4), abundant in triterpenoid/OA, inhibited HMGB1 release, suggesting that an antioxidant effect of triterpenoid is involved in the inhibition of HMGB1 release.…”

Section: Discussionmentioning

confidence: 99%

“…Isolation of Ume extract was performed as described previously (25)(26)(27)(28). Briefly, Ume extract was concentrated and dried with a rotary evaporator.…”

Section: Methodsmentioning

confidence: 99%

“…The health benefits of Ume are now being widely recognized and strengthened by recent studies that have shown Ume extracts to have strong anticancer and antiproliferative effects in in vivo and in vitro settings (25)(26)(27)(28). These studies have also indicated that Ume might possess strong anti-inflammatory effects (25)(26)(27)(28). A recent study by Adachi et al (25) isolated 7 triterpenoids from Ume extract.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of HMGB1 release inhibition from RAW264.7 cells by oleanolic acid in Prunus mume Sieb. et Zucc.

Kikuchi

Hashiguchi²,

Masuda³

et al. 2009

Int J Mol Med

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Abstract. High mobility group box-1 protein (HMGB1), primarily from the nucleus, is released into the extracellular milieu either passively from necrotic cells or actively through secretion by monocytes/macrophages. Extracellular HMGB1 acts as a potent inflammatory agent by promoting the release of cytokines such as tumor necrosis factor (TNF)-·, has procoagulant activity, and is involved in death due to sepsis. Accordingly, HMGB1 is an appropriate therapeutic target. In this study, we found that an extract of Prunus mume Sieb. et Zucc. (Ume) fruit (Ume extract), an abundant source of triterpenoids, strongly inhibited HMGB1 release from lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells. The inhibitory effect on HMGB1 release was enhanced by authentic oleanolic acid (OA), a naturally occurring triterpenoid. Similarly, the HMGB1 release inhibitor in Ume extract was found to be OA. Regarding the mechanisms of the inhibition of HMGB1 release, the OA or Ume extract was found to activate the transcription factor Nrf2, which binds to the antioxidative responsive element, and subsequently the heme oxygenase (HO)-1 protein was induced, indicating that the inhibition of HMGB1 release from LPS-stimulated RAW264.7 cells was mediated via the Nrf2/HO-1 system; an essentially antioxidant effect. These results suggested that natural sources of triterpenoids warrant further evaluation as 'rescue' therapeutics for sepsis and other potentially fatal systemic inflammatory disorders.

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Health Benefits from Pomegranates and Stone Fruit, Including Plums, Peaches, Apricots and Cherries

Tomás‐Barberán

Ruiz

Valero

et al. 2013

Bioactives in Fruit

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MK615 inhibits pancreatic cancer cell growth by dual inhibition of Aurora A and B kinases

Cited by 32 publications

References 27 publications

Advanced malignant melanoma responds to Prunus mume Sieb. Et Zucc (Ume) extract: Case report and in vitro study

Advanced malignant melanoma responds to Prunus mume Sieb. Et Zucc (Ume) extract: Case report and in vitro study

Mechanism of HMGB1 release inhibition from RAW264.7 cells by oleanolic acid in Prunus mume Sieb. et Zucc.

Health Benefits from Pomegranates and Stone Fruit, Including Plums, Peaches, Apricots and Cherries

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