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

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Cancer progression involves local expansion and metastasis, posing significant therapeutic challenges.
• Developing novel strategies to inhibit these key cancer processes is crucial for effective treatment.

Purpose of the Study:

• To introduce and evaluate a novel dual-functional podophyllotoxin derivative, PtoxPdp.
• To investigate the anti-proliferative and anti-metastatic potential of PtoxPdp.
• To elucidate the underlying molecular mechanisms of PtoxPdp's antitumor activity.

Main Methods:

• Synthesis and characterization of the podophyllotoxin derivative PtoxPdp.
• In vitro assays for anti-proliferative and anti-metastatic activity, assessing matrix metalloproteinase (MMP) levels.
• In vivo studies using a xenograft animal model to evaluate tumor repression compared to etoposide.
• Mechanistic studies involving apoptosis, autophagy, and epithelial-mesenchymal transition (EMT) pathway analysis (PI3K/AKT/mTOR, NF-κB/Snail).

Main Results:

• PtoxPdp demonstrated significant anti-proliferative and anti-metastatic effects, correlating with MMP downregulation.
• In vivo, PtoxPdp exhibited superior tumor repression compared to etoposide in a xenograft model.
• Mechanistic studies indicated PtoxPdp induces apoptosis and autophagy via the PI3K/AKT/mTOR pathway.
• PtoxPdp effectively inhibited EMT by downregulating PI3K/AKT/mTOR and NF-κB/Snail pathways.

Conclusions:

• PtoxPdp is a novel dual-functional compound inhibiting MMPs and Topoisomerase II.
• PtoxPdp shows potent antitumor activity, including anti-proliferation, anti-metastasis, and tumor repression.
• The compound acts through apoptosis, autophagy, and inhibition of EMT via key signaling pathways, identifying it as a promising drug candidate.