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3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway.
- Source :
-
Anti-cancer drugs [Anticancer Drugs] 2014 Apr; Vol. 25 (4), pp. 447-55. - Publication Year :
- 2014
-
Abstract
- The hexokinase inhibitor 3-bromopyruvate (3-BrPA) can inhibit glycolysis in tumor cells to reduce ATP production, resulting in apoptosis. However, as 3-BrPA is an alkylating agent, its cytotoxic action may be induced by other molecular mechanisms. The results presented here reveal that 3-BrPA-induced apoptosis is caspase independent. Further, 3-BrPA induces the generation of reactive oxygen species in MDA-MB-231 cells, leading to mitochondria-mediated apoptosis. These results suggest that caspase-independent apoptosis may be induced by the generation of reactive oxygen species. In this study, we also demonstrated that 3-BrPA induces apoptosis through the downregulation of myeloid cell leukemia-1 (Mcl-1) in MDA-MB-231 breast cancer cells. The results of Mcl-1 knockdown indicate that Mcl-1 plays an important role in 3-BrPA-induced apoptosis. Further, the upregulation of Mcl-1 expression in 3-BrPA-treated MDA-MB-231 cells significantly increases cell viability. In addition, 3-BrPA treatment resulted in the downregulation of p-Akt, suggesting that 3-BrPA may downregulate Mcl-1 through the phosphoinositide-3-kinase/Akt pathway. These findings indicate that 3-BrPA induces apoptosis in breast cancer cells by downregulating Mcl-1 through the phosphoinositide-3-kinase/Akt signaling pathway.
- Subjects :
- Breast Neoplasms metabolism
Caspases metabolism
Cell Line, Tumor
Cell Survival drug effects
Chromones pharmacology
Down-Regulation
Female
Humans
Morpholines pharmacology
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Oncogene Protein v-akt antagonists & inhibitors
Phosphoinositide-3 Kinase Inhibitors
RNA, Small Interfering genetics
Reactive Oxygen Species metabolism
Signal Transduction
Antineoplastic Agents, Alkylating pharmacology
Apoptosis drug effects
Breast Neoplasms pathology
Hexokinase antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein genetics
Oncogene Protein v-akt metabolism
Phosphatidylinositol 3-Kinases metabolism
Pyruvates pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1473-5741
- Volume :
- 25
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Anti-cancer drugs
- Publication Type :
- Academic Journal
- Accession number :
- 24492287
- Full Text :
- https://doi.org/10.1097/CAD.0000000000000081