Potent, cell permeable PI3K inhibitor
PIK-90 is a broad-spectrum PI3K inhibitors that inhibits PI3Kα, PI3Kγ and PI3Kδ with IC50 values of 11, 18 and 58nM, respectively [1].
Studies showed that PIK-90 induced increased levels of secreted IgE at?1 μmol/L, while it inhibited IgE production at doses of greater than 2 μmol/L [2]. PIk-90 has been reported to block Akt phosphorylation. PIK-90 combined with the CDK2 inhibitor has been demonstrated to induce apoptosis in LN229?PTENWT?cells. In addition, PIK-90 combined with siRNA against both CDK1 and CDK2 has shown to induce cell death, whereas PIK-90 combined with siRNA against CDK1 or CDK2 had no apoptotic effect [3].
In vivo, PIK-90?combined with?roscovitine revealed a significant reduction of tumor size in?nude mice implanted with GBM43 cells [3].
参考文献:
[1] Van Keymeulen A1,?Wong K,?Knight ZA,?Govaerts C,?Hahn KM,?Shokat KM,?Bourne HR. To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front. J Cell Biol.?2006 Jul 31;174(3):437-45. Epub 2006 Jul 24.
[2] Zhang TT1,?Okkenhaug K,?Nashed BF,?Puri KD,?Knight ZA,?Shokat KM,?Vanhaesebroeck B,?Marshall AJ. Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol.?2008 Oct;122(4):811-819.e2.
[3] Cheng CK1,?Gustafson WC,?Charron E,?Houseman BT,?Zunder E,?Goga A,?Gray NS,?Pollok B,?Oakes SA,?James CD,?Shokat KM,?Weiss WA,?Fan QW. Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma. Proc Natl Acad Sci U S A.?2012 Jul 31;109(31):12722-7.
Cell experiment: | To determine the viability of CLL B cells, 200 μL cells are removed from the wells of a 24-well plate at the indicated time points and incubated for 15 minutes in fluorescence-activated cell sorter buffer (RPMI+0.5% BSA) containing 40 nM 3,3′-dihexyloxacarbocyanine iodide (DiOC6) and 10 μg/mL Propidium iodide (PI). Within 30 minutes, the cells are then analyzed by flow cytometry. Viable cells show high DiOC6 and low PI fluorescence, whereas apoptotic cells have low DiOC6 and PI fluorescence; necrotic cells are characterized by low DiOC6 and high PI fluorescence. The normal PBMCs are also cultured under the same conditions, with or without the various PI3K inhibitors (e.g., PIK-90, 1 μM and 10 μM), Fludarabine, and with or without stromal cell support, and their viability is also determined by staining with DiOC6 and PI[2]. |
Animal experiment: | Mice[3]Human primary GBM43 cells (106) are injected s.c. just caudal to the left forelimb in 4- to 6-wk-old female BALB/c nu/nu mice. After tumors are established (50-100 mm3), mice are randomly allocated to daily i.p. treatment with 40 mg/kg PIK-90 (DMSO:H2O), 50 mg/kg Roscovitine (DMSO:PBS), 40 mg/kg PIK-90 plus 50 mg/kg Roscovitine, and DMSO:H2O:PBS (control). Tumor diameters are measured with calipers at 3-d intervals, and volumes are calculated. |
参考文献: [1]. Knight ZA, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19;125(4):733-47. | |
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