PI3K inhibitor D-116883 is effective in in vitro models of ovarian cancer.

BACKGROUND D-116883 (Aeterna Zentaris GmbH, Frankfurt, Germany) is an orally effective drug that acts via inhibition of phosphatidylinositol 3-kinase (PI3K). The PI3K/AKT signal transduction pathway is involved in ovarian cancer tumorigenesis. Phosphatase and Tensin homolog (PTEN) loss and other activating mutations frequently contribute to the activation of this pathway. We tested whether D-116883 exerts cytostatic effects in in vitro models of ovarian cancer and analyzed the induced programmed cell death. MATERIALS AND METHODS We evaluated the potency of D-116883 in four ovarian carcinoma cell lines with different cellular assays. The effects of D-116883 on cell proliferation was analysed by crystal-violet staining and tetrazolium salt [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT] assay. The capacity for anchorage-independent growth was analyzed in two ovarian carcinoma cell lines without and with D-116883 addition by using the soft agar assay. Fluorescence activated cell sorting (FACS) cell cycle analyses were performed. Cells were incubated with multicaspase inhibitor benzyloxycarbonyl-val-ala-asp(OMe)-fluoromethylketone (zVAD) and inhibitor of necroptosis necrostatin. RESULTS Growth inhibition occurred in all ovarian carcinoma cell lines studied (A2780, A2780cis, OAW42 and SKOV3) in a micromolar range (IC(50)<1 μM). By using soft agar assay, a reduced capacity for anchorage-independent growth, a hallmark of tumor cells, caused by D-116883 was demonstrated. Cell cycle analyses showed that D-116883 dose-dependently increased apoptotic cells. Multicaspase inhibitor zVAD and inhibitor of necroptosis necrostatin did not abrogate the growth-inhibiting effect of the compound. CONCLUSION PI3K inhibitor D-116883 showed substantial cytotoxic effects in various in vitro models of ovarian cancer. Our results make D-116883 a good candidate for further ovarian cancer research including in vivo experiments.

[1]  B. Weber,et al.  Frequent genetic abnormalities of the PI3K/AKT pathway in primary ovarian cancer predict patient outcome , 2011, Genes, chromosomes & cancer.

[2]  Junying Yuan,et al.  Alternative cell death mechanisms in development and beyond. , 2010, Genes & development.

[3]  Robert C. Bast,et al.  The biology of ovarian cancer: new opportunities for translation , 2009, Nature Reviews Cancer.

[4]  M. Murawska,et al.  PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients , 2009, Cancer biology & therapy.

[5]  T. Thompson,et al.  Perifosine induces differentiation and cell death in prostate cancer cells. , 2008, Cancer letters.

[6]  Tak W. Mak,et al.  Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis , 2006, Nature Reviews Cancer.

[7]  Huan Yang,et al.  The Akt/PKB pathway: molecular target for cancer drug discovery , 2005, Oncogene.

[8]  A. Lash,et al.  Frequent Mutation of the PIK3CA Gene in Ovarian and Breast Cancers , 2005, Clinical Cancer Research.

[9]  Andrew K Godwin,et al.  AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth , 2004, Oncogene.

[10]  G. Mills,et al.  The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. , 2001, Seminars in oncology.

[11]  D. Alberts.  Treatment of refractory and recurrent ovarian cancer. , 1999, Seminars in oncology.

[12]  Massimo Libra,et al.  Akt as a therapeutic target in cancer. , 2008, Expert opinion on therapeutic targets.

[13]  C. Rodenburg,et al.  Chemotherapy in advanced ovarian cancer , 2004, Journal of Cancer Research and Clinical Oncology.

[14]  S. Cole,et al.  Use of the MTT assay for rapid determination of chemosensitivity of human leukemic blast cells. , 1988, Leukemia research.