Antiproliferative, cell-cycle dysregulation effects of novel asiatic acid derivatives on human non-small cell lung cancer cells.
Asiatic acid (AA) is a pentacyclic triterpene in Centella asiatica known to inhibit proliferation and induce apoptosis in several tumor cell lines. In the current study, we synthesized five AA derivatives and examined their inhibitory activities on growth in non-small cell lung cancer cell lines, A549 and PC9/G. Four derivatives were found to have stronger cell growth inhibitory activity than AA. Among them, compound A-3 showed the most significant antiproliferative effects on tumor. Growth of A549 and PC9/G cells was inhibited by A-3 in a dose- and time-dependent manner. To determine the cellular gene expression changes in A549 and PC9/G cells treated with A-3, Affymetrix GeneChip® Human Genome U133 Plus 2.0 Array were used to screen transcriptome differences. Expression levels of 1121 genes in A549 and 1873 genes in PC9/G were significantly altered upon treatment with 10 µM A-3 after 48 h, with 357 overlapping genes. The signaling pathways molecules involved in the antiproliferative and cell cycle dysregulation effects of A-3 identified using microarray were further validated via Western blot analyses. The results collectively indicate that A-3 induces inhibition of cell proliferation via downregulation of the Ras/Raf/MEK/ERK pathway and cell cycle arrest at G1/S and G2/M.
Department of Biotechnology, Dalian Medical University.
Liang
L
Wang
Jie
J
Xu
Chunhui
C
Zhao
Longxuan
L
Zhao
Bin
B
Feng
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D028041:Centella / Q000737:chemistry* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D053978:Pentacyclic Triterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D059467:Transcriptome; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; C588046:methyl 2alpha-O-carboxypropionyl-3beta,23-isopropylidenedioxyurs-12-ene-28-oate; C017032:asiatic acid; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins