title: PARP cleavage and perturbance in mitochondrial membrane potential by 3-α-propionyloxy-β-boswellic acid results in cancer cell death and tumor regression in murine models.
abstract: BACKGROUND
  Apoptotic induction in cancer cells has become a major focus of anticancer therapeutics. In this regard, β-boswellic acids, naturally occurring pentacyclic triterpenes, have demonstrated antiproliferative and cytotoxic effects against different types of cancers. Surprisingly, not much has been reported regarding the chemical modifications or preparation of structural analogs of the key constituents of β-boswellic acid.
  
  
  OBJECTIVE
  The anticancer activity of 3-α-propionyloxy-β-boswellic acid (POBA) was investigated and this article reports for the first time that the triterpenoid ring of the boswellic acid derivative POBA is targeting the PI3K pathway.
  
  
  METHODS
  Induction of apoptosis of the semi-synthetic derivative of β-boswellic acid-POBA in vitro was analyzed using a battery of human cancer cell lines followed by cell cycle phase distribution, further validated by DNA fragmentation, and was found to cause mitochondrial membrane potential loss with ultrastructural changes, as observed by electron microscopy studies and expression study using PARP cleavage, as well as validated by in vivo anti-tumor activity.
  
  
  RESULTS
  The cytotoxicity data revealed the sensitivity of various human cancer cell lines of varied tissue origin to β-boswellic acid, which robustly induced cell cycle arrest, DNA fragmentation and loss of mitochondrial membrane potential. Morphological studies of the effects of POBA revealed loss of surface projections, chromatin condensation, apoptotic body formation and POBA-mediated PARP cleavage. For in vivo therapeutic experiments, murine tumor models were treated with POBA and the treatment resulted in a significantly higher level of growth inhibition and apoptosis was significantly induced.
  
  
  CONCLUSIONS
  These findings demonstrate that acyl substituents/groups in the main skeleton of β-boswellic acid have the potential to be potent chemotherapeutic agents.
authors: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (Council of Scientific & Industrial Research), Canal Road, Jammu-Tawi 180001, India.
authors: Yasrib
authors: Y
authors: Qurishi
authors: Abid
authors: A
authors: Hamid
authors: Parduman R
authors: PR
authors: Sharma
authors: Zahoor Ahmad
authors: ZA
authors: Wani
authors: Dilip M
authors: DM
authors: Mondhe
authors: Shashank K
authors: SK
authors: Singh
authors: Mohmmad Afzal
authors: MA
authors: Zargar
authors: Samar S
authors: SS
authors: Andotra
authors: Bhahwal Ali
authors: BA
authors: Shah
authors: Subhash C
authors: SC
authors: Taneja
authors: Ajit Kumar
authors: AK
authors: Saxena
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D014315:Triterpenes; C578189:3-alpha-propionyloxy-beta-boswellic acid; C054625:boswellic acid