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.
Highlights
Tumor progression through local expansion and metastasis has been well documented
We proposed a new strategy that combined the structural unit of a metal ion chelator with a Topo II inhibitor, in an attempt to achieve the goal of both inhibiting tumor cell growth via Topo II inhibition and inactivating metalloproteinase by chelation, when administered intravenously
2-pyridinealdehyde hydrazone dithiocarbamate S-propionate through catalysis with DMAP/ DCC in dichloromethane at room temperature
Summary
Tumor progression through local expansion and metastasis has been well documented. An approach to efficiently inhibit tumor metastasis is urgently required in clinical practice. Numerous strategies have been proposed to address this; improvements have been achieved in cancer treatment, efficient approaches for different cancers are still lacking and need to be solved. Etoposide as a topoisomerase (Topo) II inhibitor is widely used in clinical practice. Etoposide is a podophyllotoxin (Ptox) derivative isolated from the Podophyllum species [3], but severe side-effects and multidrug resistance (MDR) often result in treatment failure. To overcome the current limitations, numerous approaches have been made to modify the structure of Ptox [4], including esterification and amination at position 4 to produce 40-demethylepipodophyllotoxin (DMEP)
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