title: Cytotoxicity and Proteasome Inhibition by Alkaloid Extract from Murraya koenigii Leaves in Breast Cancer Cells-Molecular Docking Studies.
abstract: Murraya koenigii (curry tree) leaves are rich in bioactive compounds such as flavonoids, alkaloids, and coumarins. Alkaloids from M. koenigii leaves have antianalgesic, antiulcerogenic, antiobesity, and antitumor activities. In this study, we tested the cytotoxic and proteasome-inhibitory potential of a total alkaloid extract (TAE) from M. koenigii leaves in the breast cancer cell line MDA-MB-231. The TAE decreased cell viability with an IC50of 14.4 μg/mL and altered growth kinetics of breast cancer cells. TAE (32 μg/mL) arrested cells (35%) in the "S" phase of the cell cycle and induced apoptosis. The 26S proteasome, a multicatalytic protease complex, promotes tumor cell proliferation and protects tumor cells from apoptosis. The TAE and mahanine, a carbazole alkaloid present in M. koenigii leaves, preferentially inhibited the trypsin-like, but not the chymotrypsin-like proteolytic activity of the proteasome with an IC50of 162 μg/mL and 287 μM, respectively. In silico analysis of 26 compounds from M. koenigii leaves revealed significant docking scores for mahanine and two other carbazole alkaloids with the β2 and β5 subunits of the catalytic 20S proteasome. Taken together, this study demonstrates that inhibition of the proteasome is an important biological activity of M. koenigii alkaloids, which may lead to cancer cell death.
authors.affiliation: 1 Department of Endocrinology & Metabolism, National Institute of Nutrition , Hyderabad, India .
authors.forename: Ayesha
authors.initials: A
authors.lastname: Ismail
authors.affiliation: 1 Department of Endocrinology & Metabolism, National Institute of Nutrition , Hyderabad, India .
authors.forename: Bindu
authors.initials: B
authors.lastname: Noolu
authors.affiliation: 1 Department of Endocrinology & Metabolism, National Institute of Nutrition , Hyderabad, India .
authors.forename: Ramesh
authors.initials: R
authors.lastname: Gogulothu
authors.affiliation: 2 Biomedical Informatics Centre, National Institute of Nutrition , Hyderabad, India .
authors.forename: Shyam
authors.initials: S
authors.lastname: Perugu
authors.affiliation: 3 Department of Stem Cell Research, National Institute of Nutrition , Hyderabad, India .
authors.forename: Ajumeera
authors.initials: A
authors.lastname: Rajanna
authors.affiliation: 4 Division of Natural Products Chemistry, Indian Institute of Chemical Technology , Hyderabad, India .
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Babu
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D032101:Murraya; D010936:Plant Extracts / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D002227:Carbazoles; D010936:Plant Extracts; D061988:Proteasome Inhibitors; C465290:mahanine; D046988:Proteasome Endopeptidase Complex
keywords: Murraya koenigii; Rutaceae; alkaloids; breast cancer; proteasome