title: Dolastatin, along with Celecoxib, stimulates apoptosis by a mechanism involving oxidative stress, membrane potential change and PI3-K/AKT pathway down regulation.
abstract: BACKGROUND
  Phosphoinositide 3-kinase (PI3-K) is an important regulator of oncogenesis and apoptosis in various types of cancers including colon cancer. A combinatorial strategy of using Cyclooxygenase-2 inhibitor, Celecoxib and Dolastatin, a linear peptide from marine mollusks of Indian Ocean origin has shown anti-neoplastic effects in colon cancer in a rat model.
  
  
  METHODS
  The signal transduction pathway of PI3-K/AKT and the downstream signaling proteins had been studied in an early stage of colon carcinogenesis (DMH induced) by gene and protein expression, apoptotic studies by colonocyte apoptotic bleb assay, intracellular calcium level by fluorescence spectrometry, mitochondrial membrane potential by Rhodamine 123 flow cytometry and Reactive oxygen species measurement. Molecular docking analysis was employed to study the interaction of oncogenic proteins and the ligand, Celecoxib and Dolastatin.
  
  
  RESULTS
  Apoptotic cell index was lowered with DMH while both the drugs increased it and inhibited PI3-K and AKT expression. Docking studies revealed both the proteins targeted by the drugs via an ATP binding site. An increased expression of GSK-3β, pro-apoptotic protein Bad, transcription factor Egr-1, tumor suppressor protein PTEN while a downregulation of G1-associated cell cycle protein, Cyclin D1 and increased intracellular calcium as well as reactive oxygen species were observed. Also, the number of cells having a higher mitochondrial membrane potential was lowered.
  
  
  CONCLUSIONS
  Celecoxib and Dolastatin inhibited the tumor development through regulation of the PI3-K/AKT pathway which can act as a novel target for these drugs.
  
  
  CONCLUSIONS
  The anti-cancer properties of Dolastatin, a peptide isolated from marine mollusks in colorectal cancer is shown.
authors.affiliation: Department of Biophysics, Panjab University, Chandigarh 160014, India.
authors.forename: Honit
authors.initials: H
authors.lastname: Piplani
authors.forename: Chandan
authors.initials: C
authors.lastname: Rana
authors.forename: Vivek
authors.initials: V
authors.lastname: Vaish
authors.forename: Kim
authors.initials: K
authors.lastname: Vaiphei
authors.forename: S N
authors.initials: SN
authors.lastname: Sanyal
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D000068579:Celecoxib; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D018797:Cell Cycle Proteins; D052246:Cyclooxygenase 2 Inhibitors; D047630:Depsipeptides; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C075610:dolastatin 15; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib
keywords: AKT; Celecoxib; Dolastatin; Egr-1; Molecular docking; PI3-K