title: Blockade of autophagy enhances proapoptotic potential of BI-69A11, a novel Akt inhibitor, in colon carcinoma.
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.
authors: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors: Ipsita
authors: I
authors: Pal
authors: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors: Sheetal
authors: S
authors: Parida
authors: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors: B N
authors: BN
authors: Prashanth Kumar
authors: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors: Payel
authors: P
authors: Banik
authors: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
authors: Kaushik
authors: K
authors: Kumar Dey
authors: Apollo Gleneagles Hospital, Kolkata, West Bengal, India.
authors: Sandipan
authors: S
authors: Chakraborty
authors: Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India.
authors: Sujit K
authors: SK
authors: Bhutia
authors: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India. Electronic address: mahitosh@smst.iikgp.ernet.in.
authors: Mahitosh
authors: M
authors: Mandal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: C540767:3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D015363:Quinolones; D002738:Chloroquine; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; Autophagy; BI-69A11; Beclin-1; Colon cancer; HSP90