title: EGCG inhibits properties of glioma stem-like cells and synergizes with temozolomide through downregulation of P-glycoprotein inhibition.
abstract: Combination therapy to inhibit cancer stem cells may have important clinical implications. Here, we examine the molecular mechanisms by which epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, inhibits the stem cell characteristics of glioma stem-like cells (GSLCs) and synergizes with temozolomide (TMZ), a DNA-methylating agent commonly used as first-line chemotherapy in gliomas. GSLCs were enriched from the human glioblastoma cell line U87 using neurosphere culture. Cells were analyzed using flow cytometry, quantitative PCR, and western blotting. Compared to U87 cells, a higher percentage of U87 GSLCs remained in the G0/G1 phase, with downregulation of the cell-cycle protein CylinD1 and overexpression of stem cell markers CD133 and ALDH1. The drug-resistance gene ABCB1 (but not ABCG2 or MGMT) also showed high mRNA and protein expression. The resistance index of U87 GSLCs against TMZ and carmustine (BCNU) was 3.0 and 16.8, respectively. These results indicate that U87 GSLCs possess neural stem cell and drug-resistance properties. Interestingly, EGCG treatment inhibited cell viability, neurosphere formation, and migration in this cell model. EGCG also induced apoptosis, downregulation of p-Akt and Bcl-2, and cleaving PARP in a dose-dependent manner. Importantly, EGCG treatment significantly downregulated P-glycoprotein expression but not that of ABCG2 or MGMT and simultaneously enhanced sensitivity to TMZ. Our study demonstrates that the use of EGCG alone or in combination with TMZ may be an effective therapeutic strategy for glioma.
authors.affiliation: Department of Pathology, Medical School of Jinan University, Guangzhou, 510632, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shao-Xiang
authors.initials: SX
authors.lastname: Wang
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Ma
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Li
authors.forename: Jie-Cheng
authors.initials: JC
authors.lastname: Ye
authors.forename: Si-Ming
authors.initials: SM
authors.lastname: Xie
authors.forename: Bin
authors.initials: B
authors.lastname: Du
authors.forename: Xue-Yun
authors.initials: XY
authors.lastname: Zhong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D014411:Neoplastic Stem Cells; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D050697:Retinal Dehydrogenase / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D003606:Dacarbazine; D002392:Catechin; C045651:epigallocatechin gallate; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C523119:Aldh1a1 protein, rat; D050697:Retinal Dehydrogenase; D000077204:Temozolomide