MCL3 exhibited anti-tumor activity mediated by NF-κB/IL-6/State3 pathway in glioma / 中国药理学与毒理学杂志

OBJECTIVE Evidience appears that parthenolide (PN) induces anti-tumor effects by NF-κB signal pathway. MCL3 the derivative of PN,is sesquiterpene lactone synthesized by the group of Professor Pan Xiandao.The study was to explore the anti-tumor activity and mechanism of MCL3 in glioma. METHODS The effect of MCL3 on the proliferation of glioma cell lines was examined by MTT assay. Apoptotic activity was investigated by flow cytometry. The Transwell cell invasion assay was used to determine the effect of MCL3 on the G422 cell invasive ability.The effect of MCL3 on the angio-genesis was analyzed by a capillary-like tube formation assay. The subcutaneously transplanted and orthotopic G422 cell xenograft models were used to detect the effect of MCL3 on tumor growth in vivo. The pathological changes were analyzed by H&E staining. Protein level related to the NF-κB signal pathway was dertimined by Western blotting. The effect of MCL3 on the NF-κB transcriptional activity was examined by a dual-luciferase reporter assay.RESULTS The anti-proliferative activity was observed following treatment with MCL3 for 96 h in G422, U-87 MG, U251 and Hs683 cell lines, and the IC50 was 8.94 μmol·L-1,6.44 μmol·L-1,14.8 μmol·L-1,18.9 μmol·L-1,respectively.The percentage of apop-totic cells increased in MCL3-treated G422 cells,and the apoptosis rate was 26.4%(the apoptosis rate was 5.68% in control group).MCL3 could inhibit the invasion in G422 cells,and the invasive inhibition rate was 43.63%(P<0.01)at 10.0 μmol·L-1.MCL3 inhibited tube formation of EA.hy926 cells,and the inhibitory rate was 81.67%(P<0.01)at 10.0 μmol·kg-1.At 40.00 mg·kg-1,MCL3 supressed tumor growth by 79.03% (P<0.01) in tumor weight in subcutaneously transplanted G422 xenograft models, and by 69.97% (P<0.01) in volume in orthopotic G422 xenograft models. H&E staining demonstrated that MCL3 could decrease tumor angiogenesis and invasion, increased necrosis of tumor cells. The dual-luciferase reporter assay showed that MCL3 inhibited NF-κB transcriptional actvity, and the inhibition rate was 50.07%(P<0.05)at 10.0 μmol·L-1compared with control.Moreover,MCL3 inhibited the phos-phorylation of NF-κB in nuclear mediated by supression of phosphorylated IKKα/β and IκB,and decreased the expression of IL-6 regulated by NF-κB.Eventually,the phosphorylation of State3 decreased following the administration of MCL3, resulting in the downregulation of State3 taget genes, including HIF, VEGF,FAK,MMP-2,MMP-9,Bcl-2 and Bcl-xL.CONCLUSION The anti-tumor effect of MCL3 was partly due to the inhibition of NF-κB/IL-6/State3 pathway in glioma.

Recent progress in synthesis and pharmacological effects of ellipticine and its derivatives / 药学学报

Ellipticine is an alkaloid isolated from natural product with cytotoxicity, which has antitumor and anti-aids activity. Since it was first identified in 1959, a great deal of effort has been devoted to the development of various approaches for synthesis of ellipticine. This review provides a summary for synthesis approaches of ellipticine from different starting materials. The antitumor mechanism and structure-activity relationship are also discussed.

Synthesis and antitumor activity of nitrogen-based thiocolchicine derivatives / 药学学报

<p><b>AIM</b>To search for colchicine derivatives which have high efficacy and low toxicity.</p><p><b>METHODS</b>Colchicine was firstly converted into thiocolchicine, and then it was hydrolyzed to get 7-(N-deacetylthiocolchicine). At last, 7-(N-deacetylthiocolchicine) was amidated to get the target compounds. The chemical structure of these new derivatives was confirmed with 1H NMR, IR, MS, and HR-MS. The cytotoxicity of the compounds was tested by MTT assay. Their in vivo antitumor activity was evaluated against mice tumor H22 and U14.</p><p><b>RESULTS</b>Twelve thiocolchicine derivatives are new compounds.</p><p><b>CONCLUSION</b>In vitro antitumor activity has showed that some of these thiocolchicines possessed cytotoxic activity superior to colchicine. However, in vivo antitumor activity indicated that these derivatives have poor efficacy in mice.</p>

Synthesis and antitumor activity of A-ring modified hexacyclic analogues of camptothecin / 药学学报

<p><b>AIM</b>To improve the biological activity of A-ring modified analogues of camptothecin.</p><p><b>METHODS</b>A-ring modified camptothecins were synthesized from 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin (SN-38) in three or four steps. Their cytotoxicity was evaluated using MTY assay, and their in vivo antitumnor activity against mouse liver cancer H22 was tested. Results Five hexacyclic camptothecins (6a, 6b, 6c, 7a and 7b) are target compounds, and ten camptothecin derivatives are new compounds.</p><p><b>CONCLUSION</b>The modification of a 1,4-oxazine-2-one ring fused with positions 9 and 10 of A-ring will reduce the antitumor activity of camptothecins.</p>

Synthesis and antitumor activity of 20-O-linked camptothecin ester derivatives / 药学学报

<p><b>AIM</b>To improve the profile of 20 (S)-camptothecin, a series of 20-O-linked camptothecin phenoxyacetic acid ester derivatives have been designed.</p><p><b>METHODS</b>These derivatives were synthesized by the method of acylation. Their chemical structures were confirmed with 1HNMR, IR, MS, and HRMS. The cytotoxicities of the compounds were tested by MTT assay. The in vivo antitumor activities of these esters were evaluated against mouse liver tumor H22 in mice.</p><p><b>RESULTS</b>Twelve derivatives of camptothecin ester are new compounds.</p><p><b>CONCLUSION</b>In vitro and in vivo antitumor activity has indicated that some derivatives appeared significantly more effective than topotecan in the H22 mouse liver tumoral model.</p>