The Combinatorial Effect of Ad-IL-24 and Ad-HSV-tk/GCV on Tumor Size, Autophagy, and UPR Mechanisms in Multiple...

Area of Science:

• Oncology
• Gene Therapy
• Molecular Biology

Background:

• Multiple myeloma treatment has evolved significantly over the last decade.
• Adenoviral vectors offer a promising platform for delivering therapeutic genes.
• Understanding tumor growth, autophagy, and unfolded protein response (UPR) is crucial for novel therapeutic strategies.

Purpose of the Study:

• To investigate the combined effects of Adenovector-carrying interleukin-24 (Ad-IL-24) and herpes simplex virus 1 thymidine kinase/ganciclovir (HSV-tk/GCV) on multiple myeloma.
• To analyze the impact on tumor growth, autophagy, and UPR mechanisms in a mouse model.
• To evaluate the individual and combined therapeutic potential of Ad-IL-24 and Ad-HSV-tk/GCV.

Main Methods:

• A mouse model of multiple myeloma was established.
• Six groups of mice received different treatments including Ad-HSV-tk/GCV, Ad-IL-24, Ad-HSV-tk/IL-24, Ad-GFP, and controls.
• Tumor size was measured, and the expression of LC3B (autophagy marker), ASK-1, CHOP, Caspase-3, and ATF-6 (UPR and apoptosis markers) was analyzed via Western blotting and qPCR.

Main Results:

• Ad-HSV-tk/GCV, Ad-HSV-tk/IL-24, and metformin treatments significantly reduced tumor size.
• LC3B expression was elevated in treatment groups, indicating induced autophagy.
• Ad-IL-24 treatment increased CHOP, Caspase-3, and ATF-6 expression, suggesting UPR and apoptosis pathway activation, while decreasing ASK-1 expression.
• Co-administration of Ad-IL-24 and Ad-HSV-tk did not show synergistic effects on tumor size reduction.

Conclusions:

• Adenovector-mediated HSV-tk gene therapy effectively reduces tumor size and induces autophagy in multiple myeloma.
• IL-24 may influence tumor growth and apoptosis but does not enhance the therapeutic efficacy of HSV-tk.
• The combination therapy did not yield synergistic benefits for tumor size control in this model.