Boswellic acid acetate induces differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells.
The aim of the study was to investigate the antitumor and/or preventive effect of BC-4, an isomeric compound isolated from the plant Boswellia carteri Birdw. containing alpha- and beta-boswellic acid acetate in 1:1, MW 498.3. We used the MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) assay to study the growth inhibition activity of BC-4. Tumor cells migration within a three-dimensional collagen matrix was recorded by time-lapse videomicroscopy and computer-assisted cell tracking. Topoisomerase II was isolated from mouse melanoma B16F10 cells and its activity was determined by its ability to cut plasmid pBR322 DNA. The secretion and activity of matrix metalloproteinases (MMPs) from human fibrosarcoma HT-1080 cells were determined by gelatin zymography. BC-4 was a cytostatic compound and could induce the differentiation of B16F10 mouse melanoma cells, blocked the cell population in G1 phase and inhibited topoisomerase II activity. The G1 phase population of B16F10 cells was increased from 57.4 to 87.7%, while S phase population was reduced from 33.3 to 5.9% after treatment with BC-4 at 25 microM concentration for 48 h. BC-4 also inhibited the migration activity of B16F10. BC-4 could induce apoptosis of HT-1080 cells, as proved by acridine orange fluorescence staining, Wright-Giemsa staining, electromicroscopy, DNA fragmentation and flow cytometry. BC-4 inhibited the secretion of MMPs from HT-1080 cells, too. In conclusion, if it turns out that BC-4 is a well tolerated substance, exhibiting no significant toxicity or side effects, being evaluated currently in China, BC-4 is a good candidate for the prevention of primary tumor, invasion and metastasis.
Zhao
Wanzhou
W
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No1 Xiannong Tan Street, Beijing 100050, China. wanzhou.zhao@Roswellpark.org
Entschladen
Frank
F
Liu
Hongyan
H
Niggemann
Bernd
B
Fang
Qicheng
Q
Zaenker
Kurt S
KS
Han
Rui
R
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D053938:DNA Fragmentation; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron; D013778:Tetrazolium Salts; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D013778:Tetrazolium Salts; D014315:Triterpenes; C054625:boswellic acid; D020782:Matrix Metalloproteinases; D004250:DNA Topoisomerases, Type II