Premium
In vitro and in vivo antineoplastic activity of a novel bromopyrrole and its potential mechanism of action
Author(s) -
Xiong Sheng,
Pang Huidan,
Fan Jun,
Ge Feng,
Yang Xiaoxia,
Liu Qiuying,
Liao Xiaojian,
Xu Shihai
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00573.x
Subject(s) - in vivo , apoptosis , in vitro , propidium iodide , hela , annexin , flow cytometry , chemistry , cell cycle , mechanism of action , microbiology and biotechnology , biology , programmed cell death , biochemistry
Background and purpose: Many bromopyrrole compounds have been reported to have in vitro antineoplastic activity. In a previous study, we isolated N‐(4, 5‐dibromo‐pyrrole‐2‐carbonyl)‐L‐amino isovaleric acid methyl ester (B6) from marine sponges. Here, we investigated the in vitro and in vivo antineoplastic activity of B6 and its potential mechanism. Experimental approach: The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was used to determine the in vitro antineoplastic activity of B6. Flow cytometry, western blot analysis and morphological observations were used to investigate its mechanism of action. A mouse xenograft model was used to determine its in vivo activity. Key results: B6 inhibited the proliferation of various human cancer cells in vitro , with highest activity on LOVO and HeLa cells. B6 also exhibited significant growth inhibitory effects in vivo in a xenograft mouse model. Acute toxicity analysis suggested that B6 has low toxicity. B6‐treated cells arrested in the G1 phase of the cell cycle and had an increased fraction of sub‐G1 cells. In addition, the population of Annexin V‐positive/propidium iodide‐negative cells increased, indicating the induction of early apoptosis. Indeed, B6‐treated cells exhibited morphologies typical of cells undergoing apoptosis. Western blotting showed cleaved forms of caspase‐9 and caspase‐3 in cells exposed to B6. Moreover, B6‐promoted Ca 2+ release and apoptosis was associated with elevated intracellular Ca 2+ concentration. Conclusions and implications: B6 has significant antineoplastic activity in vitro as well as in vivo . It inhibits tumour cell proliferation by arresting the cell cycle and inducing apoptosis. With its low toxicity, B6 represents a promising antineoplastic, primary compound.