Disruption of Porphyrin Homeostasis by Inhih/biting ABCG2 with Cyclohexylmethyl Flavonoids Suppresses Propagation oof Stetem-like Breast Cancer Cells

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Title:	Disruption of Porphyrin Homeostasis by Inhih/biting ABCG2 with Cyclohexylmethyl Flavonoids Suppresses Propagation oof Stetem-like Breast Cancer Cells
Authors:	Wen-Ying Liao (廖紋瑩) Chih-Chuang Liaw (廖志中) Chien-Shu Chen (陳建樹) Guey-Horng Wang (王貴弘) Yuan-Chao Huang Jimmy Susanto Sheng-Chu Kuo (郭盛助) Chia-Ning Shen (沈家寧)
Date:	2011
Issue Date:	2011-06-23 14:56:53 (UTC+8)
Abstract:	Breast cancer stem cells express ATP-binding cassette sub-family G member 2 (ABCG2) and display multidrug resistance. Recent studies have shown that suppression of ABCG2 affects self-renewal of embryonic stem cells and inhibits proliferation of breast cancer cells. We therefore hypothesized that ABCG2 is involved in the maintenance of breast cancer stem cells and that cytotoxic ABCG2 inhibitors can be utilized to eliminate drug-resistant breast cancer stem cells. We have found that the ABCG2+ subpopulation of MCF-7 cells is able to efflux protoporphyrin IX (PPIX), suggesting that the endogenous role of ABCG2 in breast cancer cells is to transport excess porphyrins. Utilizing a porphyrin-efflux assay, we have identified two cytotoxic cyclohexylmethyl flavonoids isolated from Helminthostachys zeylanica that can inhibit ABCG2 by binding to its nucleotide-binding domain. Treatment with ugonin J or K not only inhibited porphyrin efflux and the side-population phenotype, but induced apoptosis in both ABCG2+ and ABCG2- cell populations and suppressed expansion of ABCG2+CD24-/lowCD44+ stem-like breast cancer cells in mammosphere cultures. We also found that the suppressive effect of ugonin J on propagation of stem-like breast cancer cells was mediated by PPIX accumulation, which in turn led to activation of p53 and reduction of Nanog. Overexpression of Nanog counteracted the suppressive effect of ugonin J. In conclusion, the current work identifies two novel cyclohexylmethyl flavonoids that can act as cytotoxic ABCG2 inhibitors to induce apoptosis in breast cancer cells and suppress propagation of stem-like breast cancer cells via reduction of Nanog.
Relation:	2011年台俄有機、藥物與生物化學交流暨藥物化學研討會，起迄日：2011/04/06~2011/04/05，地點：溪頭台大實驗林
Appears in Collections:	[Pharmacy and Science] 2011 Taiwanese-Russian Organic, Medicinal and Bio Chemistry Interactions & PST Medicinal Chemistry Symposium [Dept. of Cosmetic Science and institute of cosmetic science] Proceedings

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