1. Blockade of autophagy enhances proapoptotic potential of BI-69A11, a novel Akt inhibitor, in colon carcinoma.
- Author
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Pal I, Parida S, Prashanth Kumar BN, Banik P, Kumar Dey K, Chakraborty S, Bhutia SK, and Mandal M
- Subjects
- Cell Cycle drug effects, Cell Survival drug effects, Chloroquine pharmacology, Colonic Neoplasms metabolism, Drug Synergism, HCT116 Cells, HT29 Cells, Humans, Proto-Oncogene Proteins c-akt genetics, Signal Transduction drug effects, Transfection, Antineoplastic Agents pharmacology, Apoptosis drug effects, Autophagy drug effects, Benzimidazoles pharmacology, Colonic Neoplasms pathology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Quinolones pharmacology
- Abstract
BI-69A11, novel Akt inhibitor, is currently drawing much attention due to its intriguing effect in inducing apoptosis in melanoma, breast, prostate and colon cancer. However, earlier reports reveal that PI3K/Akt/mTOR inhibitors promote autophagy at the early stage as a survival mechanism that might affect its apoptotic potential. It is necessary to investigate whether BI-69A11 mediated apoptosis is associated with autophagy for enhancing its therapeutic efficacy. Here, we found that BI-69A11 induced autophagy at earlier time point through the inhibition of Akt/mTOR/p70S6kinase pathway. Dose-dependent and time-dependent conversion of LC3-I to LC3-II, increased accumulation of LC3-GFP dots in cytoplasm and increase in other autophagic markers such as Beclin-1, firmly supported the fact that BI-69A11 induces autophagy. Atg5, Atg7 and Beclin-1 siRNA mediated genetic attenuation and pre-treatment with pharmacological inhibitor 3-MA and CQ diminished the autophagy and increased the propensity of cell death towards apoptosis. It was also suggested that BI-69A11 mediated interaction between Akt, HSP-90 and Beclin-1 maintained the fine balance between autophagy and apoptosis. Interaction between Beclin-1 and HSP90 is one of the prime causes of induction of autophagy. Here, we also generated a novel combination therapy by pretreatment with CQ that inhibited the autophagy and accelerated the apoptotic potential of BI-69A11. In summary; our findings suggest that induction of autophagy lead to the resistance of colon cancer towards BI-69A11 mediated apoptosis., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
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