Antitumor activity of a novel dual functional podophyllotoxin derivative involved PI3K/AKT/mTOR pathway

• Published in: PloS one 2019-09, Vol.14 (9), p.e0215886-e0215886
• Main Authors: Li, Yongli, Huang, Tengfei, Fu, Yun, Wang, Tingting, Zhao, Tiesuo, Guo, Sheng, Sun, Yanjie, Yang, Yun, Li, Changzheng
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Antiviral drugs; Apoptosis; Autophagy; Biology and Life Sciences; Cancer; Cancer therapies; Cell death; Cell growth; Clinical medicine; DNA topoisomerase (ATP-hydrolysing); Epithelial-Mesenchymal Transition - drug effects; Etoposide; Female; Hep G2 Cells; Humans; Hydrazones; Liver cancer; Matrix metalloproteinase; Matrix Metalloproteinase Inhibitors - chemical synthesis; Matrix Metalloproteinase Inhibitors - pharmacology; Matrix Metalloproteinase Inhibitors - therapeutic use; Matrix metalloproteinases; Medicine and Health Sciences; Mesenchyme; Metalloproteinase; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; NF-kappa B - metabolism; NF-κB protein; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; Podophyllotoxin; Podophyllotoxin - analogs & derivatives; Propionic acid; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - metabolism; Research and Analysis Methods; Signal Transduction - drug effects; Snail Family Transcription Factors - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0215886

The progression of cancer through local expansion and metastasis is well recognized, but preventing these characteristic cancer processes is challenging. To this end, a new strategy is required. In this study, we presented a novel dual functional podophyllotoxin derivative, 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester (PtoxPdp), which inhibited both matrix metalloproteinases and Topoisomerase II. This new podophyllotoxin derivative exhibited significant anti-proliferative, anti-metastatic that correlated with the downregulation of matrix metalloproteinase. In a xenograft animal local expansion model, PtoxPdp was superior to etoposide in tumor repression. A preliminary mechanistic study revealed that PtoxPdp induced apoptosis and autophagy via the PI3K/AKT/mTOR pathway. Furthermore, PtoxPdp could also inhibit epithelial-mesenchymal transition, which was achieved by downregulating both PI3K/AKT/mTOR and NF-κB/Snail pathways. Taken together, our results reveal that PtoxPdp is a promising antitumor drug candidate.