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

PLoS One. 2019 Sep 26;14(9):e0215886. doi: 10.1371/journal.pone.0215886. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Hep G2 Cells
  • Humans
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Matrix Metalloproteinase Inhibitors / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / metabolism
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Podophyllotoxin / analogs & derivatives*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Snail Family Transcription Factors / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • Protein Kinase Inhibitors
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Podophyllotoxin

Grants and funding

This work was supported by the National Natural Science Foundation of China, 21571153 to CL; the Science and Technology Department of Henan Province, 14300510012 and152300410118 to CL; the Sanquan College of Xinxiang Medical University, SQTD201703 to CL; the Sanquan College of Xinxiang Medical University, SQTD201903 to YL and the Key Research Project Funding Program of Higher Educational Institutions of Henan Province, 19A310021 to YL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.