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The Suppressive Effects of Cytotoxic Agents on Lymphoma Cell Proliferation and Tumor Growth

Mengli Yang1,Haihua Xiao1, Jinping Yang1, Kunxian Feng1, Chengfang Jian1, Tuan Ma1, Andre H. Sun2, Alexander V. Chestkov1, Natalya I. Vasilevich1*, and Lichun Sun1, 3, 4,

Objective: Ansamitocin P3 (AP3) and paclitaxel as tubulin inhibitors and camptothecin (CPT) as a Topo Ⅰ inhibitor are considered to be among the most active natural products. We investigate the roles and mechanisms of AP3, paclitaxel and CPT in inducing apoptosis in human histiocytic lymphoma U937 cells.

Methods and materials: In vitro studies included CCK8 assay to estimate antiproliferative activity and flow cytometry to analyze apoptosis of U937 cells. qRT-PCR was revealed the change in gene expression leading to apoptosis. In vivo experiments were performed with xenograft tumor model using five weeks-old female SCID mice.

Results: CCK8 assay exhibits AP3 as a great antiproliferative activity compound with a half-maximal inhibitory concentration (IC50) at 0.18 ± 0.04 nM, while the IC50s of CPT and paclitaxel were at 25.09 ± 2.64 and 6.06 ± 1.24 nM respectively. Apoptosis analysis indicated that the number of both early and late apoptotic cells increased significantly after treatment with each of three abovementioned biomolecules. Cell cycle analysis suggested that while both AP3 and paclitaxel arrest cells in the G2/M Phase at middle or high concentrations, CPT arrests cells in G2/M phase at low concentration and in the S phase at high concentration. Transcritome’s qRT-PCR found that AP3 and paclitaxel induce apoptosis downregulating the expression of PCNA and BCL-2, and besides that, cells treated with CPT showed upregulated P21 but downregulated BCL-2 expression. The data obtained using xenograft tumor model showed that AP3 greatly inhibits tumor growth with little side effect, which confirms high in vivo anti-tumor activity of this compound.

Conclusion: The obtained results suggest the strongest antitumor activity of AP3 on lymphoma U937 cells and its great potential in tumor-targeted therapy.

Lymphoma cells; Ansamitocin P3; Paclitaxel; Camptothecin; Apoptosis;