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.
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Authors | Jie Zheng, Alice Hudder, Kim Zukowski, Raymond F Novak |
Journal | Cancer letters
(Cancer Lett)
Vol. 296
Issue 1
Pg. 74-87
(Oct 01 2010)
ISSN: 1872-7980 [Electronic] Ireland |
PMID | 20417028
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright 2010 Elsevier Ireland Ltd. All rights reserved. |
Chemical References |
- A 443654
- Indazoles
- Indoles
- Proto-Oncogene Proteins c-akt
- Sirolimus
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Topics |
- Breast Neoplasms
(drug therapy, enzymology, mortality, pathology)
- Cell Cycle
(drug effects)
- Cell Division
(drug effects)
- Cell Line, Tumor
- Enzyme Activation
- Epithelial Cells
(drug effects, pathology)
- Female
- Fibrocystic Breast Disease
(pathology)
- Flow Cytometry
- Humans
- Immunoblotting
- Indazoles
(pharmacology)
- Indoles
(pharmacology)
- Neoplasm Metastasis
- Proto-Oncogene Proteins c-akt
(antagonists & inhibitors, drug effects)
- Sirolimus
(pharmacology, therapeutic use)
- Survivors
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