title: In vitro anticancer properties and biological evaluation of novel natural alkaloid jerantinine B.
abstract: Natural products play a pivotal role in medicine especially in the cancer arena. Many drugs that are currently used in cancer chemotherapy originated from or were inspired by nature. Jerantinine B (JB) is one of seven novel Aspidosperma indole alkaloids isolated from the leaf extract of Tabernaemontana corymbosa. Preliminary antiproliferative assays revealed that JB and JB acetate significantly inhibited growth and colony formation, accompanied by time- and dose-dependent apoptosis induction in human cancer cell lines. JB significantly arrested cells at the G2/M cell cycle phase, potently inhibiting tubulin polymerisation. Polo-like kinase 1 (PLK1; an early trigger for the G2/M transition) was also dose-dependently inhibited by JB (IC50 1.5 µM). Furthermore, JB provoked significant increases in reactive oxygen species (ROS). Annexin V+ cell populations, dose-dependent accumulation of cleaved-PARP and caspase 3/7 activation, and reduced Bcl-2 and Mcl-1 expression confirm apoptosis induction. Preclinical in silico biopharmaceutical assessment of JB calculated rapid absorption and bioavailability >70%. Doses of 8-16 mg/kg JB were predicted to maintain unbound plasma concentrations >GI50 values in mice during efficacy studies. These findings advocate continued development of JB as a potential chemotherapeutic agent.
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Mohannad E
authors.initials: ME
authors.lastname: Qazzaz
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Vijay J
authors.initials: VJ
authors.lastname: Raja
authors.affiliation: School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, 43500 Semenyih, Selangor, Malaysia.
authors.forename: Kuan-Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Toh-Seok
authors.initials: TS
authors.lastname: Kam
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Jong Bong
authors.initials: JB
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Pavel
authors.initials: P
authors.lastname: Gershkovich
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham NG7 2RD, UK. Electronic address: tracey.bradshaw@nottingham.ac.uk.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D026121:Indole Alkaloids; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D014750:Vincristine; D000097869:Polo-Like Kinase 1; C000607217:jerantinine B
keywords: Apoptosis; Cell cycle; Natural products; PLK1; Reactive oxygen species; Tubulin