College of Basic Medical Science, Sanquan College of Xinxiang Medical University, Xinxiang, Henan, P. R. China.
College of Basic Medical Science, Xinxiang Medical University, Xinxiang, Henan, P. R. China.
PLoS One. 2019 Sep 26;14(9):e0215886. doi: 10.1371/journal.pone.0215886. eCollection 2019.
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.
癌症通过局部扩张和转移的进展是众所周知的，但预防这些特征性的癌症过程是具有挑战性的。为此，需要一种新的策略。在这项研究中，我们提出了一种新型的双重功能鬼臼毒素衍生物，2-吡啶甲醛腙二硫代氨基甲酸盐 S-丙酸酯鬼臼毒素酯（PtoxPdp），它抑制基质金属蛋白酶和拓扑异构酶 II。这种新的鬼臼毒素衍生物表现出显著的抗增殖、抗转移作用，与基质金属蛋白酶的下调相关。在异种移植动物局部扩张模型中，PtoxPdp 在肿瘤抑制方面优于依托泊苷。初步的机制研究表明，PtoxPdp 通过 PI3K/AKT/mTOR 通路诱导细胞凋亡和自噬。此外，PtoxPdp 还可以通过下调 PI3K/AKT/mTOR 和 NF-κB/Snail 通路来抑制上皮-间充质转化。总之，我们的研究结果表明，PtoxPdp 是一种有前途的抗肿瘤药物候选物。
