International Journal of Radiation Research

en Specific inhibitors of PI3K, mTOR and AR exhibit strong synergism and radiosensitization in human prostate cell lines Radiation Biology Radiation Biology تحقيق بديع Original Research <div style="text-align: justify;">Background: Single agent use of chemotherapy in prostate cancer is very limiting, as large doses are often required for tumour control and can lead to elevated systemic toxicity. Targeting of survival proteins of the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinases (PI3K), mammalian target of rapamycin (mTOR) and androgen receptor (AR) pathways with cocktails of specific inhibitors might yield optimum therapeutic benefit with minimal toxicity. Materials & Methods: The modes of interaction of the dual inhibitor of PI3K and mTOR (NVP-BEZ235), EGFR inhibitor (AG-1478), and AR inhibitor (MDV3100) in in vitro cultures of four human prostate cell lines (DU145, LNCaP, BPH-1 and 1542N) were evaluated as cocktails, using clonogenic cell survival, subsequent to validation of the androgen dependency. Components of cocktails (Cocktail 1 (AG-1478 and NVP-BEZ235), Cocktail 2 (NVP-BEZ235 and MDV3100), and Cocktail 3 (MDV3100 and AG-1478)) were used at equivalent concentrations for 50% cell killing. Combination indices (CI) for the cocktails were determined and used as descriptors of inhibitor interaction. Radiomodulatory effects of inhibitor cocktails were also evaluated. Results: Inhibitor cocktails selectively showed strong to very strong synergism and radiosensitization. Concurrent inhibition of PI3K/mTOR and AR could potentially be of better therapeutic benefit than inhibition of EGFR and PI3K/mTOR or AR and EGFR, as the potential benefit of EGFR targeting was found to be limited. Conclusion: These data may guide the design of potent treatment approaches for prostate cancer.</div> Prostate, cell survival, phosphoinositide 3-kinases, mTOR serine-threonine kinases, androgen receptors, EGF receptors. 211 223 http://ijrr.com/browse.php?a_code=A-10-1-1313&slc_lang=en&sid=1 S. Maleka 7900319475328460029759 7900319475328460029759 No Department of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa A.M. Serafin 7900319475328460029760 7900319475328460029760 No Department of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa J.M. Akudugu jakudugu@sun.ac.za 7900319475328460029761 7900319475328460029761 Yes Department of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa