Blockade of autophagy enhances proapoptotic potential of BI-69A11, a novel Akt inhibitor, in colon carcinoma

Ipsita Pal, Sheetal Parida, Prashanth Kumar Bhusetty Nagesh, Payel Banik, Kaushik Kumar Dey, Sandipan Chakraborty, Sujit K. Bhutia, Mahitosh Mandal

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)217-227
Number of pages11
JournalEuropean Journal of Pharmacology
Volume765
DOIs
StatePublished - Oct 15 2015

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Autophagy
Colon
Carcinoma
Apoptosis
Colonic Neoplasms
3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one
Phosphatidylinositol 3-Kinases
Small Interfering RNA
Melanoma
Prostatic Neoplasms
Cytoplasm
Cell Death
Pharmacology
Breast Neoplasms
Beclin-1
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Blockade of autophagy enhances proapoptotic potential of BI-69A11, a novel Akt inhibitor, in colon carcinoma. / Pal, Ipsita; Parida, Sheetal; Bhusetty Nagesh, Prashanth Kumar; Banik, Payel; Kumar Dey, Kaushik; Chakraborty, Sandipan; Bhutia, Sujit K.; Mandal, Mahitosh.

In: European Journal of Pharmacology, Vol. 765, 15.10.2015, p. 217-227.

Research output: Contribution to journalArticle

Pal, Ipsita ; Parida, Sheetal ; Bhusetty Nagesh, Prashanth Kumar ; Banik, Payel ; Kumar Dey, Kaushik ; Chakraborty, Sandipan ; Bhutia, Sujit K. ; Mandal, Mahitosh. / Blockade of autophagy enhances proapoptotic potential of BI-69A11, a novel Akt inhibitor, in colon carcinoma. In: European Journal of Pharmacology. 2015 ; Vol. 765. pp. 217-227.
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AU - Banik, Payel

AU - Kumar Dey, Kaushik

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AU - Bhutia, Sujit K.

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