Rapamycin sensitizes Akt inhibition in malignant human breast epithelial cells.
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.
Zheng
Jie
J
Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Hudder
Alice
A
Zukowski
Kim
K
Novak
Raymond F
RF
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
C504035:A 443654; D007191:Indazoles; D007211:Indoles; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus