In vitro
As a specific ATM (Ataxia telangiectasia mutated kinase) inhibitor, KU-55933, blocks the phosphorylation of Akt induced by insulin and insulin-like growth factor I in cancer cells that exhibit abnormal Akt activity. Through the downregulation of the synthesis of cyclin D1, KU-55933 induces G1 cell cycle arrest, resulting in inhibiting cancer cell proliferation. KU-55933 completely abrogates rapamycin-induced feedback activation of Akt. Combination of KU-55933 and rapamycin not only induces apoptosis, which is not seen in cancer cells treated only with rapamycin, but also shows better efficacy in inhibiting cancer cell proliferation than each drug alone. Combining KU-55933 with rapamycin may provide a highly effective approach for improving mammalian target of rapamycin-targeted anticancer therapy that is currently hindered by rapamycin-induced feedback activation of Akt. In parental U251 and U87 glioma lines, the addition of KU-55933 to TMZ significantly increased cell killing compared to TMZ alone, But KU-55933 did not sensitize the resistant lines to TMZ, and neither TMZ alone or combined with KU-55933 induced a G2/M arrest.
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