M(2)-A induces apoptosis and G(2)-M arrest via inhibiting PI3K/Akt pathway in HL60 cells.
Amonafide, a naphthalimide derivative, although selected for exploratory clinical trials for its potent anticancer activity, has long been challenged by its unpredictable side effects. In the present study, a novel amonafide analogue, M(2)-A 2-(2-(dimethylamino)ethyl)-6-(thiophene-2-ylmethylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione was ascribed to its potent effects on topoisomerase IIalpha. Moreover, our investigation indicates that M(2)-A induces G(2)/M phase growth arrest through inhibiting PI3K/Akt pathway. M(2)-A inhibits proliferation of HeLa, HL60, HCT-8, A375, MCF-7 and MRC-5 cells, especially inhibits proliferation of HL60 with an IC(50) value of 18.86 microM. M(2)-A can not only induce DNA fragmentation, but also enhance Annexin V-FITC binding of the cells. On the one hand the expression levels of protein Cyclin B1, Cdk1 changed in response to M(2)-A treatment in HL60 cells. On the other hand we observed the inhibition of NF-kappaB nuclear translocation, up-regulation of Bax and down-regulation of Bcl-2, the caspase -3, -9 activity increase in HL60 cells after treated with M(2)-A, which indicated that the mitochondrial pathway was involved in the apoptosis signal pathway. Our results showed that the phosphorylation of p85/PI3K and Akt decreased following M(2)-A treatment. In summary, M(2)-A displayed a significant anti-tumor effect through cell cycle arrest and apoptotic induction in HL60 cells, which suggested that M(2)-A might have therapeutic potential against leukaemia.
Wang
Jin
J
State Key Laboratory of Bioreactor Engineering and School of Pharmacy, East China University of Science and Technology, # 268, 130 Meilong Road, Shanghai 200237, China.
Wu
Aibin
A
Xu
Yufang
Y
Liu
Jianwen
J
Qian
Xuhong
X
D000225:Adenine; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D053644:Naphthalimides / Q000737:chemistry* / Q000494:pharmacology; D063065:Organophosphonates; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D000225:Adenine; D000970:Antineoplastic Agents; D053644:Naphthalimides; D063065:Organophosphonates; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C037020:amonafide