Various leads on her2 cancer

[DeborahNC]

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The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway.

Gulati N, Laudet B, Zohrabian VM, Murali R, Jhanwar-Uniyal M.

Department of Neurosurgery, New YorkMedicalCollege, Valhalla, NY10595, USA.

BACKGROUND: The tumor suppressor gene PTEN, mutated in 40-50% of patients with brain tumors, especially those with glioblastomas, maps to chromosome 10q23.3 and encodes a dual-specificity phosphatase. PTEN exerts its effects partly via inhibition of protein tyrosine kinase B (Akt/Protein Kinase B), which is involved in the phosphatidylinositol (PtdIns) 3-kinase (PI3K)-mediated cell-survival pathway. The naturally occurring bioflavonoid Quercetin (Qu) shares structural homology with the commercially available selective PI3K inhibitor, LY 294002 (LY). Here, the effects of Qu on the Akt/PKB pathway were evaluated. MATERIALS AND METHODS: The human breast carcinoma cell lines, HCC1937, with homozygous deletion of the PTEN gene, and T47D, with intact PTEN, were time-treated with Qu or LY and analyzed for activated levels of Akt by measuring phospho-Akt (p-Akt) levels using immunoblotting analysis. To detect p-Akt, the T47D cells were treated with EGF prior to treatment with or without Qu or LY Cell proliferation after 24-h treatment with Qu or LY was quantified by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Treatment with Qu (25 microM) for 0.5, 1 and 3 h completely suppressed constitutively activated Akt/PKB phosphorylation at Ser-473 in HCC1937 cells. Pre-exposing T47D cells to Qu (25 microM) or LY (10 microM) abrogated EGF-induced Akt/PKB phosphorylation at Ser-473. Both Qu (100 microM) and LY (50 microM) treatments for 24 h significantly decreased cell proliferation, as shown by the MTT assay. CONCLUSION: Pharmacologically safe doses of the naturally occurring bioflavonoid Qu inhibit the PI3K-Akt/PKB pathway, in a manner similar to that of the commercially available LY. Overall, our results indicated that Qu inhibited the constitutively activated-Akt/PKB pathway in PTEN-null cancer cells, and suggest that this compound may have therapeutic benefit against tumorigenesis and cancer progression.