Powerful tumor cell growth-inhibiting activity of a synthetic derivative of atractyligenin: involvement of PI3K/Akt pathway and thioredoxin system.
BACKGROUND
The semi-synthetic ent-kaurane 15-ketoatractyligenin methyl ester (SC2017) has been previously reported to possess high antiproliferative activity against several solid tumor-derived cell lines. Our study was aimed at investigating SC2017 tumor growth-inhibiting activity and the underlying mechanisms in Jurkat cells (T-cell leukemia) and xenograft tumor models.


METHODS
Cell viability was evaluated by MTT assay. Cell cycle progression, reactive oxygen species (ROS) elevation and apoptotic hallmarks were monitored by flow cytometry. Inhibition of thioredoxin reductase (TrxR) by biochemical assays. Levels and/or activation status of signaling proteins were assessed by western blotting. Xenograft tumors were generated with HCT 116 colon carcinoma cells.


RESULTS
SC2017 displayed cell growth-inhibiting activity against Jurkat cells (half maximal inhibitory concentration values (IC50)<2μM), but low cell-killing potential in human peripheral blood mononuclear cells (PBMC). The primary response of Jurkat cells to SC2017 was an arrest in G2 phase followed by caspase-dependent apoptosis. Inhibition of PI3K/Akt pathway and TrxR activity by SC2017 was demonstrated by biochemical and pharmacological approaches. At least, SC2017 was found to inhibit xenograft tumor growth.


CONCLUSIONS
Our results demonstrate that SC2017 inhibits tumor cell growth in in vitro and in vivo models, but displays moderate toxicity against PBMC. We also demonstrate that SC2017 promotes caspase-dependent apoptosis in Jurkat cells by affecting Akt activation status and TrxR functionality.


GENERAL SIGNIFICANCE
Our observations suggest the semi-synthetic ent-kaurane SC2017 as a promising chemotherapeutic compound. SC2017 has, indeed, shown to possess tumor growth inhibiting activity and be able to counteract PI3K/Akt and Trx system survival signaling.
['Cotugno|Roberta|R|', 'Gallotta|Dario|D|', 'Piaz|Fabrizio Dal|FD|', 'Apicella|Ivana|I|', 'De Falco|Sandro|S|', 'Rosselli|Sergio|S|', 'Bruno|Maurizio|M|', 'Belisario|Maria Antonietta|MA|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D001278:Atractyloside D020169:Caspases D049109:Cell Proliferation D045304:Cytochromes c D045786:Diterpenes, Kaurane D006801:Humans D051379:Mice D019869:Phosphatidylinositol 3-Kinases D051057:Proto-Oncogene Proteins c-akt D013879:Thioredoxins D014407:Tumor Cells, Cultured D023041:Xenograft Model Antitumor Assays
PI3K/Akt Thioredoxin system Ent-kaurane Cell cycle Apoptosis HCT 116 xenograft