Qiping Zheng1,2*, Lichun Sun1,3*Jinlei Ye1, Mengli Yang1, Shilei Wang1, Ying Chen1, Xiaojing Zhang1,2, Chen Chen2, Songhai Shen
In the last few decades, many biomolecules obtained from nature exhibit great potential in antitumor application, some of them have made great contributions to clinical treatment. Ansamitocin P3 and paclitaxel are tubulin inhibitors while camptothecin is a Topo I inhibitor. These molecules are known to induce apoptosis of cancer cells and either has been used or show great potential in application of tumor targeted therapy. In this study, we investigated the roles and mechanisms of ansamitocin P3, paclitaxel and camptothecin in inducing apoptosis of human histolytic lymphoma U937 cells. CCK8 assay was performed on U937 cells and the results showed that ansamitocin P3 exhibits great antiproliferative activities with a half-maximal inhibitory concentration (IC 50) at 0.18 ± 0.04 nM, while the IC50 of camptothecin and paclitaxel was 25.09 ± 2.64 and 6.06 ± 1.24 nM respectively. Results of apoptosis analysis by flow cytometry indicated that both early and late apoptotic cells increased significantly after treated with above three biomolecules. Cell cycle analysis results suggested that ansamitocin P3 and paclitaxel arrested cells in the G2/M Phase, while camptothecin arrested cells in G2/M phase at low concentration but S phase at high concentration. Mechanistically, we have performed expression analysis using qRT-PCR and found that ansamitocin P3 and paclitaxel may induce apoptosis of cells by down regulating expression of PCNA and BCL-2, while cells treated with camptothecin showed upregulated P21 but down regulated BCL-2 expression. Moreover, to investigate the in vivo anti-tumor activity of ansamitocin P3, we have shown data in a xenograft tumor model that ansamitocin P3 greatly inhibited tumor growth with little side effect. Taken together, our results suggest the strongest antitumor activity of ansamitocin P3 on lymphoma U937 cells. Ansamitocin P3 has great potential in tumor targeted therapy.
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