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

English version

Autoři: Yongli Li ^aff001; Tengfei Huang ^aff002; Yun Fu ^aff002; Tingting Wang ^aff002; Tiesuo Zhao ^aff002; Sheng Guo ^aff002; Yanjie Sun ^aff003; Yun Yang ^aff002; Changzheng Li ^aff002
Působiště autorů: College of Basic Medical Science, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, P. R. China ^aff001; College of Basic Medical Science, Xinxiang Medical University, Xinxiang, Henan, P. R. China ^aff002; Experimental Teaching Center of Biology and Basic Medicine, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, P. R. China ^aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0215886

Souhrn

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.

Klíčová slova:

Apoptosis – Autophagic cell death – Cancer treatment – Hepatocellular carcinoma – Metastasis – Metastatic tumors – Mouse models – Lysosomes

Zdroje

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

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