dactolisib and Uterine-Cervical-Neoplasms

Cancer continues to be a growing burden, especially in the resource limited regions of the world, and more effective and affordable therapies are highly desirable. In this study, the effect of X-ray irradiation and four inhibitors, viz. those against epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin (mTOR) and B-cell lymphoma 2 (Bcl-2) was evaluated in lung, breast, and cervical cancer cell lines, including normal cell lines to determine and compare the potential therapeutic benefit of these treatment modalities. A clonogenic survival assay was used to determine the radiosensitivity and cytotoxicity of inhibitors of EGFR, PI3K/mTOR, and Bcl-2 in the cell lines. From the data, the equivalent dose at which 50% of the cell populations were killed, for cancer and normal cells, was used to determine the relative cellular sensitivity to X-ray irradiation and inhibitor treatment. It was found that breast cancer cell lines were more sensitive to X-ray irradiation, whilst cervical and lung cancer cell lines were more sensitive to EGFR and PI3K/mTOR inhibitor therapy. These data suggest that patients with breast cancer possessing similar characteristics to MDA-MB-231 and MCF-7 cells may derive therapeutic benefit from X-ray irradiation, whilst EGFR and PI3K/mTOR inhibitor therapy may potentially benefit cancer patients possessing cancers similar to HeLa and A549 cells.

Topics: Aniline Compounds; Breast Neoplasms; Cell Line; Cell Survival; ErbB Receptors; Female; Humans; Imidazoles; Lung Neoplasms; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Quinazolines; Quinolines; Radiation Tolerance; Sulfonamides; TOR Serine-Threonine Kinases; Tyrphostins; Uterine Cervical Neoplasms; X-Rays

NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor that shows dramatic effects on many tumors, but its effects on cervical carcinoma cells are largely unknown. In the present study, we investigated the effects of NVP-BEZ235 on the proliferation and invasion of cervical carcinoma cells in vitro and clarified its mechanism of action. In cellular settings with human cervical carcinoma cell lines, this molecule effectively and specifically blocked dysfunctional PI3K/mTOR pathway activation, suppressed cell growth in a time- and concentration-dependent manner, led to G1 cell cycle arrest, and induced apoptosis. NVP-BEZ235 suppressed HeLa cell invasiveness and metastasis by inhibiting the PI3K/Akt/MMP-2 pathway. We further demonstrated that NVP-BEZ235 treatment in combination with cisplatin or carboplatin induced a synergistic anti-tumoral response in cervical carcinoma cells. These findings suggested that NVP-BEZ235 could regulate growth and invasion of cervical carcinoma cells; thus it may provide a potential therapy for cervical carcinoma.

Topics: Apoptosis; Female; Humans; Imidazoles; Phosphoinositide-3 Kinase Inhibitors; Quinolines; Signal Transduction; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms