Abstract
Epithelial-mesenchymal transition (EMT) involves metastasis and drug resistance; thus, a new EMT reversing agent is required. It has shown that wild-type p53 can reverse EMT back to epithelial characteristics, and iron chelator acting as a p53 inducer has been demonstrated. Moreover, recent study revealed that etoposide could also inhibit EMT. Therefore, combination of etoposide with iron chelator might achieve better inhibition of EMT. To this end, we prepared di-2-pyridineketone hydrazone dithiocarbamate S-propionate podophyllotoxin ester (PtoxDpt) that combined the podophyllotoxin (Ptox) structural unit (etoposide) with the dithiocarbamate unit (iron chelator) through the hybridization strategy. The resulting PtoxDpt inherited characteristics from parent structural units, acting as both the p53 inducer and topoisomerase II inhibitor. In addition, the PtoxDpt exhibited significant inhibition in migration and invasion, which correlated with downregulation of matrix metalloproteinase (MMP). More importantly, PtoxDpt could inhibit EMT in the absence or presence of TGF-β1, concomitant to the ROS production, and the additional evidence revealed that PtoxDpt downregulated AKT/mTOR through upregulation of p53, indicating that PtoxDpt induced EMT inhibition through the p53/PI3K/AKT/mTOR pathway.
Highlights
Metastasis is a hallmark of cancer and one of the urgent tasks to be solved in a clinical practice
It has been shown that epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), involve a metastatic process, and EMT is a key metastasis-promoting step in many cancers [2], but MET may favor to metastatic inhibition or attenuating drug resistance [3,4,5]
Recent studies demonstrated that some topoisomerase II (Topo II) inhibitors, including etoposide, could inhibit EMT and attenuate metastasis [24, 25], which hinted that etoposide derivatives can be used as a library of the EMT inhibitor
Summary
Metastasis is a hallmark of cancer and one of the urgent tasks to be solved in a clinical practice. Insight into the molecular, cellular, and clinical mechanisms underlying metastatic progression is required in order to develop new diagnostic and therapeutic strategies to prevent and treat metastases. During EMT, epithelial cells lose their junctions and apical-basal polarity and undergo a change in the signaling programmers, developing an invasive phenotype [6]. The investigations reveal that EMT progression is characterized by loss of the epithelial marker E-cadherin; the mesenchymal markers, such as N-cadherin and vimentin, are increased. When tumor cells acquire invasive mesenchymal phenotypes, the motility and invasiveness of them are increased, favoring dissemination from the local site and infiltration into the vascular tumor [7]. Since EMT plays an essential role in cancer metastasis, restoration of MET may Oxidative Medicine and Cellular Longevity efficiently slow dissemination of tumor cells [8]. Targeting EMT is one of the options in cancer therapy [9,10,11]
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