Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:M(2)-A induces apoptosis and G(2)-M arrest via inhibiting PI3K/Akt pathway in HL60 cells. 1943 48

Previous studies have reported that 8-c [6-(2-(2-(dimethylamino)ethylamino)ethylamino)-2-octyl-1H-benzo[de]isoquinoline-1,3(2H)-dione], a novel amonafide analogue, was generated as a new anticancer candidate. However, little is known about its activity in chemoresistant cells. In this study, the antitumor effects of 8-c on the multi-drug-resistant human colorectal carcinoma cancer cell lines HCT-116/L-OHP and HCT-8/VCR have been investigated for the first time. 8-c showed similar concentration-dependent inhibitory activities against multi-drug-resistant cells and corresponding parental cell lines by the MTT assay after 48 h of treatment. 8-c treatment resulted in the induction of apoptosis, as evidenced by fluorescent staining analysis, comet assay data, and the increase in the number of apoptotic cells as detected by flow cytometry. Western blot, qPCR, and siRNA techniques were used to elucidate the molecular mechanism. Our study suggested that the apoptotic effect of 8-c can be attributed to the upregulation of p53, caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP) and the downregulation of Bcl-2. Furthermore, ERCC1 is essential for nucleotide excision repair. ERCC1 expression was correlated with sensitivity to chemotherapy in various colon cancer cell lines. It is intriguing that decreases in ERCC1 protein and mRNA levels were also observed in the HCT-116/L-OHP and HCT-8/VCR cells after exposure to 8-c. Further transient transfection of multi-drug-resistant cells with ERCC1 siRNA enhanced 8-c-induced cytotoxicity. In contrast, epidermal growth factor-induced increase in ERCC1 protein levels was shown to rescue cell viability upon 8-c treatment. These findings suggest that 8-c has a strong potential to be developed as a new antitumor agent for the treatment of multi-drug-resistant colon cancer cells, and is worthy of further studies.
 ...
PMID:Induction of apoptosis and suppression of ERCC1 expression by the potent amonafide analogue 8-c in human colorectal carcinoma cells. 2342 74