title: PBI-05204, a supercritical CO₂ extract of Nerium oleander, inhibits growth of human pancreatic cancer via targeting the PI3K/mTOR pathway.
abstract: Introduction Oleandrin, a cardiac glycoside, exerts strong anti-proliferative activity against various human malignancies in in vitro cells. Here, we report the antitumor efficacy of PBI-05204, a supercritical C0₂ extract of Nerium oleander containing oleandrin, in a human pancreatic cancer Panc-1 orthotopic model. Results While all the control mice exhibited tumors by the end of treatment, only 2 of 8 mice (25%) treated for 6 weeks with PBI-05204 (40 mg/kg) showed dissectible tumor at the end of the treatment period. The average tumor weight (222.9 ± 116.9 mg) in mice treated with PBI-05204 (20 mg/kg) was significantly reduced from that in controls (920.0 ± 430.0 mg) (p < 0.05). Histopathologic examination of serial sections from each pancreas with no dissectible tumor in the PBI-05204 (40 mg/kg) treated group showed that the pancreatic tissues of 5/6 mice were normal while the remaining mouse had a tumor the largest diameter of which was less than 2.3 mm. In contrast, while gemcitabine alone did not significantly reduce tumor growth, PBI-05204 markedly enhanced the antitumor efficacy of gemcitabine in this particular model. Ki-67 staining was reduced in pancreatic tumors from mice treated with PBI-05204 (20 mg/kg) compared to that of control, suggesting that PBI-05204 inhibited the proliferation of the Panc-1 tumor cells. PBI-05204 suppressed expression of pAkt, pS6, and p4EPB1 in a concentration-dependent manner in both Panc-1 tumor tissues and human pancreatic cancer cell lines, implying that this novel botanical drug exerts its potent antitumor activity, at least in part, through down-regulation of PI3k/Akt and mTOR pathways.
authors.affiliation: Department of General Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0462, Houston, TX, 77030, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.forename: Patrea
authors.initials: P
authors.lastname: Rhea
authors.forename: Lin
authors.initials: L
authors.lastname: Tan
authors.forename: Carrie
authors.initials: C
authors.lastname: Cartwright
authors.forename: Ho-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Murali K
authors.initials: MK
authors.lastname: Ravoori
authors.forename: Crandell
authors.initials: C
authors.lastname: Addington
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.forename: Vikas
authors.initials: V
authors.lastname: Kundra
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000096:biosynthesis*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D030007:Nerium; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis*; D000093542:Gemcitabine
chemical_list: D002301:Cardiac Glycosides; D010936:Plant Extracts; D003841:Deoxycytidine; C546842:MTOR protein, human; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine