A novel synthetic oleanolic acid derivative with amino acid conjugate suppresses tumour growth by inducing cell cycle arrest.
Oleanolic acid (3beta-hydroxy-olean-12-en-28-oic acid; OA) has a wide variety of bioactivities and is used for medicinal purposes in many Asian countries. Various derivatives of OA have been synthesized in attempts to improve the potency. Here we describe the anti-tumour activity of a novel OA derivative, N-[(3beta)-3-(acetyloxy)-28-oxoolean-12-en-28-yl]-glycine methyl ester (AOA-GMe). AOAGMe was a more potent inhibitor of the growth of B16 melanoma cells than its parent compound OA, both in-vitro and in-vivo. AOA-GMe also exhibited dose-dependent inhibition of human K562 leukaemia cells, but had almost no toxicity in normal human peripheral blood mononuclear cells. AOA-GMe induced cell cycle arrest in G0/G1 and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D, cyclin-dependent kinase CDK4 and phosphorylated retinoblastoma protein, and increases in the cyclin-dependent kinase inhibitor p15. OA did not show such activities. These results suggest that AOA-GMe may induce growth arrest in tumour cells through regulation of proteins involved in the cell cycle.
Lu
Xiao-Min
XM
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, 210093, China.
Yi
Hong-Wei
HW
Xu
Jian-Liang
JL
Sun
Yang
Y
Li
Jian-Xin
JX
Cao
Shao-Xian
SX
Xu
Qiang
Q
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4 / Q000187:drug effects / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000187:drug effects / Q000378:metabolism; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear; D008518:Medicine, East Asian Traditional; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D056741:Cyclin D; D050762:Cyclin-Dependent Kinase Inhibitor p15; D016213:Cyclins; C523581:N-((3beta)-3-(acetyloxy)-28-oxoolean-12-en-28-yl)glycine methyl ester; D016160:Retinoblastoma Protein; D009828:Oleanolic Acid; D051358:Cyclin-Dependent Kinase 4; D005998:Glycine