Open AccessAntitumor activity of a novel dual functional podophyllotoxin derivative involved PI3K/AKT/mTOR pathway
Author(s) -
Yongli Li,
Tengfei Huang,
Yun Fu,
Tingting Wang,
Tiesuo Zhao,
Sheng Guo,
Yanjie Sun,
Yun Yang,
Changzheng Li
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0215886
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , podophyllotoxin , cancer research , chemistry , downregulation and upregulation , autophagy , apoptosis , pharmacology , biology , biochemistry , stereochemistry , gene
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 (Ptox Pdp ), 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, Ptox Pdp was superior to etoposide in tumor repression. A preliminary mechanistic study revealed that Ptox Pdp induced apoptosis and autophagy via the PI3K/AKT/mTOR pathway. Furthermore, Ptox Pdp 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 Ptox Pdp is a promising antitumor drug candidate.