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

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.

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

“…Likewise, 4DPG synthesized by Katoch et al (2021) also enhanced the level of Chk2 and attenuated the expression of EMT-related proteins in human colorectal cancer (HCT-116 and SW-620) cell lines. Li et al (2019b ; 2019c ) synthesized 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate PTOX ester (Ptox Pdp ) Compound 44 ( Figure 10 ) and di-2-pyridineketone hydrazone dithiocarbamate S-propionate podophyllotoxin ester (Ptox Dpt ) Compound 45 ( Figure 10 ), both of which exhibited inhibitory effects on the proliferation, migration, and aggressiveness of hepatocellular carcinoma cells in vitro and in vivo experiments. Furthermore, in terms of molecular mechanisms, Ptox Pdp and Ptox Dpt may inhibit the EMT ability of hepatocellular carcinoma cells through down-regulation of the PI3K/AKT/mTOR pathway, causing a reduction of vimentin expression and an increase of E-cadherin expression.…”

“…also enhanced the level of Chk2 and attenuated the expression of EMT-related proteins in human colorectal cancer (HCT-116 and SW-620) cell lines Li et al (2019b;2019c). synthesized 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate PTOX ester (Ptox Pdp ) Compound 44 (Figure10) and di-2-pyridineketone hydrazone dithiocarbamate S-propionate podophyllotoxin ester (Ptox Dpt ) Compound 45 (Figure10), both of which exhibited inhibitory effects on the proliferation, migration, and aggressiveness of hepatocellular carcinoma cells in vitro and in vivo experiments.…”

The ester derivatives obtained by C‐ring modification of podophyllotoxin‐induced apoptosis and inhibited proliferation in Hemangioma Endothelial Cells via downregulation of PI3K/Akt signaling pathway

“…PI3Ks are considered significant causes of chemoresistance in cancer therapy, protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling (Liu et al, 2020). The PI3K/Akt signaling pathway plays an important role in regulating various cell functions, including metabolism, growth, proliferation, survival, transcription, and protein synthesis (Li et al, 2019). Aberrant activation of the PI3K/Akt pathway is one of the most frequently deregulated pathways in cancer cells (Gotting et al, 2020).…”

Podofilox suppresses gastric cancer cell proliferation by regulating cell cycle arrest and the c‑Myc/ATG10 axis

“…The molecular basis by which podofilox inhibits cancer cell proliferation and tumor growth has been investigated in previous studies. For example, podofilox inhibits HCCLM3 and HepG2 cell proliferation and migration by inactivating the PI3K/AKT/mTOR signaling pathway ( 22 ). In HCC cells, podofilox inhibits the PI3K/AKT/mTOR pathway and activates p53( 23 ).…”