title: BI-69A11 enhances susceptibility of colon cancer cells to mda-7/IL-24-induced growth inhibition by targeting Akt.
abstract: BACKGROUND
  Akt and its downstream signalling pathways contribute to the aetiology and progression of colorectal carcinoma (CRC). Targeting the Akt pathway is an attractive strategy but few chemotherapeutic drugs have been used to treat CRC with only limited success. BI-69A11, a small molecule inhibitor of Akt, efficiently inhibits growth in melanoma cells. Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 promotes cancer-selective apoptosis when delivered by a tropism-modified replication incompetent adenovirus (Ad.5/3-mda-7). However, Ad.5/3-mda-7 displays diminished antitumour efficacy in several CRC cell lines, which correlates with the expression of K-RAS.
  
  
  METHODS
  The individual and combinatorial effect of BI-69A11 and Ad.5/3-mda-7 in vitro was studied by cell viability, cell cycle, apoptosis and invasion assays in HT29 and HCT116 cells containing wild type or mutant K-ras, respectively. In vivo HT29 tumour xenografts were used to test the efficacy of the combination treatment.
  
  
  RESULTS
  BI-69A11 inhibited growth and induced apoptosis in CRC. However, combinatorial treatment was more effective compared with single treatment. This combination showed profound antitumour and anti angiogenic effects in vitro and in vivo by downregulating Akt activity.
  
  
  CONCLUSIONS
  BI-69A11 enhances the antitumour efficacy of Ad.5/3-mda-7 on CRC overexpressing K-RAS by inducing apoptosis and regulating Akt activity thereby warranting further evaluation in treating CRC.
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India.
authors.forename: I
authors.initials: I
authors.lastname: Pal
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India.
authors.forename: S
authors.initials: S
authors.lastname: Rajput
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India.
authors.forename: K K
authors.initials: KK
authors.lastname: Dey
authors.affiliation: R.G.Kar Medical College, Kolkata, West Bengal 700004, India.
authors.forename: S
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Institute of Life Science, Bhubneswar, Odisha 751023, India.
authors.forename: R
authors.initials: R
authors.lastname: Dash
authors.affiliation: 1] Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA [2] VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Das
authors.affiliation: 1] Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA [2] VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA [3] VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: E
authors.initials: E
authors.lastname: Barile
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: De
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pellecchia
authors.affiliation: 1] Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA [2] VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA [3] VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India.
authors.forename: M
authors.initials: M
authors.lastname: Mandal
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
chemical_list: D001562:Benzimidazoles; D007378:Interleukins; D051057:Proto-Oncogene Proteins c-akt; D015363:Quinolones; D000099180:Interleukin-24; C540767:3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one