ZSTK474 is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor, which strongly inhibits cancer cell proliferation. Phosphoinositide 3-kinase (PI3K) is a potential target in cancer therapy. Inhibition of PI3K is believed to induce apoptosis. ZSTK474 effectively inhibited the growth of human cancer xenografts in vivo. ZSTK474 treatment suppressed the expression of nuclear cyclin D1 and Ki67 and also the expression of phospho-Akt, both of which are hallmarks of proliferation. We demonstrate that ZSTK474 induces G1arrest along with tumour suppression. Moreover, ZSTK474 suppresses the tumour growth without inducing apoptosis. Interestingly, long-term (3-month) administration of ZSTK474 maintained such increase in G1 cells and tumour suppression. ZSTK474 exerts its in vivo antitumour efficacy via G1 arrest but not via apoptosis as long as it is administered.
|Cell lines||panel of 39 human cancer cell lines|
|Preparation method||Analysis of Cell Proliferation Inhibition
The inhibition of cell proliferation was assessed by measuring changes in total cellular protein in a culture of each cell line in the JFCR panel of cell lines after 48 hours of drug treatment by use of a sulforhodamine B assay. The 50% growth inhibition (GI 50 ) value of the drug was calculated as described previously. The graphic representation of a drug’s mean differential growth inhibition for the cell line panel was based on a calcula-tion that used a set of GI 50 values, as described previously. To analyze the correlation between the mean graphs of drug A and drug B, the COMPARE computer algorithm was developed as previously described by Paull et al. The Pearson correla-tion coefﬁ cient between the mean graphs of drug A and drug B was calculated (n = 39).
|Incubation time||48 h|
|Animal models||Human A549 lung cancer cells, PC-3 prostate cancer cells, and WiDr colon cancer cells tumor xenografts|
|Formulation||5% hydroxypropylcellulose in water|
|Dosages||100, 200, or 400 mg/kg daily from days 0 to 13|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 20 mg/mL|
Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor.
Yaguchi S, et al. J Natl Cancer Inst. 2006 Apr 19;98(8):545-56. PMID: 16622124.
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