title: Rapamycin sensitizes Akt inhibition in malignant human breast epithelial cells.
abstract: Akt and mTOR are therapeutic targets for the treatment of cancer. The effects of inhibiting mTOR, with rapamycin, and Akt, with A-443654, concurrently, on cell morphology, cell proliferation, the cell cycle, and apoptosis were examined using the benign MCF10A and malignant MCF10CA1a human breast epithelial cells. Rapamycin and A-443654 in combination produced the greatest morphological changes and inhibited cell proliferation by G2/M arrest. Rapamycin and A-443654 in combination induced apoptosis at earlier times and at lower A-443654 concentrations in MCF10CA1a tumor cells than in the benign MCF10A cells. Rapamycin and A-443654 increased p53 and p15(INK4B) protein levels, decreased anti-apoptotic Bcl-2 levels, and increased Bad levels in the MCF10CA1a tumor cells by approximately 5-fold. These results suggest that the combined inhibition of Akt and mTOR may have beneficial therapeutic and safety margin effects.
authors.affiliation: Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.forename: Alice
authors.initials: A
authors.lastname: Hudder
authors.forename: Kim
authors.initials: K
authors.lastname: Zukowski
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Novak
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005348:Fibrocystic Breast Disease / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009362:Neoplasm Metastasis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D017741:Survivors
chemical_list: C504035:A 443654; D007191:Indazoles; D007211:Indoles; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus