Gedunin Impacts Pancreatic Cancer Stem Cells Through the Sonic Hedgehog Signaling Pathway

Area of Science:

• Oncology
• Natural Products Chemistry
• Molecular Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis.
• Pancreatic cancer stem cells (PCSCs) drive tumor progression, therapeutic resistance, and metastasis.
• Gedunin (GD), a neem-derived compound, has shown anticancer effects, but its impact on PCSCs is unclear.

Purpose of the Study:

• To evaluate the effects of Gedunin (GD) on pancreatic cancer stem cells (PCSCs).
• To investigate GD's impact on tumor growth, stemness, and metastasis.
• To elucidate GD's mechanism of action, focusing on the sonic hedgehog (Shh) signaling pathway.

Main Methods:

• Functional assays assessed PCSC sphere formation, colony formation, and self-renewal.
• Athymic mice xenograft models evaluated GD's in vivo tumor suppression.
• In vitro and in vivo limiting dilution assays quantified GD's effect on PCSCs.
• Shh signaling pathway markers and stem cell markers were analyzed post-GD treatment.

Main Results:

• GD significantly inhibited tumor growth and reduced PCSC populations in vivo.
• GD decreased PCSC proliferation, self-renewal, and colony-forming capacity.
• GD downregulated key Shh pathway markers (Gli1, Shh), stem cell markers (SOX2, Nanog, Oct4), metastasis-related proteins (MMP-2, -3, -9), and EMT markers.
• GD treatment reduced micrometastatic lesions in multiple organs.

Conclusions:

• Gedunin (GD) is a promising therapeutic candidate for PDAC, targeting both bulk tumor cells and PCSCs.
• GD effectively suppresses tumor growth, stemness, and metastatic spread.
• GD's mechanism involves the downregulation of the Shh signaling pathway, offering potential for improved treatment strategies and patient outcomes.