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5-Lipoxygenase and cyclooxygenase inhibitory dammarane triterpenoid 1 from Borassus flabellifer seed coat inhibits tumor necrosis factor-α secretion in LPSInduced THP-1 human monocytes and induces apoptosis in MIA PaCa-2 pancreatic cancer cells.

Abstract
Phospholipase A2 (PLA2), Cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX) are arachidonic acid metabolizing enzymes and their inhibitors have been developed as therapeutic molecules for cancer and inflammation related disorders. In the present study, PLA2, COX 1&2 and 5-LOX inhibitory studies of Borassus flabellifer seed coat extract were carried out and substantial 5-LOX inhibitory activity was found. Dammarane triterpenoid 1 (Dammara-20,23-diene-3,25-diol) was isolated according to 5-LOX activity guided isolation, and screened for COX (1 & 2) inhibitory activities. Dammarane triterpenoid 1 inhibited carrageenan-induced rat paw edema and TNF-α secretion levels in lipopolysaccharide (LPS)-induced THP-1 human monocytes. Anticancer activity studies demonstrated the antiproliferative effect of dammarane triterpenoid 1 on various cancer cell lines including MIA PaCa-2 pancreatic, DU145 prostate, HL-60 leukemia and Caco-2 colon cancers. Dammarane triterpenoid 1 showed good antiproliferative activity on MIA PaCa-2 pancreatic cancer cell line with IC50 of 12.36±0.33 µM, among other tested cell lines. Apoptosis inducing activity of dammarane triterpenoid 1 was confirmed based on increased sub-G0 phase cell population in cell cycle analysis, loss of mitochondrian membrane potential, elevated levels of cytochrome c, nuclear morphological changes and DNA fragmentation in MIA PaCa-2 pancreatic cancer cells. Therefore, dammarane triterpenoid skeleton may raise the hope of developing novel anti-inflammatory and anticancer drugs in the future.
AuthorsNagendra Sastry Yarla, Rajaram Azad, Mahaboob Basha, Abdul Rajack, D S V G K Kaladhar, Bharat Kumar Allam, Rajeswara Rao Pragada, Krishna Nand Singh, Sunanda Kumari K, Reddanna Pallu, Umadevi Parimi, Anupam Bishayee, Govinda Rao Duddukuri
JournalAnti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 15 Issue 8 Pg. 1066-77 ( 2015) ISSN: 1875-5992 [Electronic] Netherlands
PMID25642980 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Cyclooxygenase Inhibitors
  • Lipopolysaccharides
  • Lipoxygenase Inhibitors
  • Triterpenes
  • Tumor Necrosis Factor-alpha
  • dammarane
Topics
  • Animals
  • Anti-Inflammatory Agents (isolation & purification, pharmacology)
  • Antineoplastic Agents (isolation & purification, pharmacology)
  • Apoptosis (drug effects)
  • Arecaceae (chemistry)
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cyclooxygenase Inhibitors (isolation & purification, pharmacology)
  • Down-Regulation (drug effects)
  • Edema (chemically induced, immunology, pathology)
  • HL-60 Cells
  • Humans
  • Lipopolysaccharides
  • Lipoxygenase Inhibitors (isolation & purification, pharmacology)
  • Male
  • Monocytes (drug effects, immunology, metabolism)
  • Pancreatic Neoplasms (immunology, metabolism, pathology)
  • Rats
  • Rats, Wistar
  • Seeds (chemistry)
  • Triterpenes (isolation & purification, pharmacology)
  • Tumor Necrosis Factor-alpha (metabolism)

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