Repurposing Penfluridol in Combination with Temozolomide for the Treatment of Glioblastoma

Area of Science:

• Neuroscience
• Oncology
• Pharmacology

Background:

• Glioblastoma is a highly aggressive brain tumor with limited treatment options.
• Glioma sphere-forming cells (GSCs) contribute to glioblastoma's drug resistance.
• Penflurido (PFD), an oral antipsychotic, crosses the blood-brain barrier and exhibits anticancer properties.

Purpose of the Study:

• To investigate the antitumor effects of penflurido (PFD) on patient-derived glioma sphere-forming cells (GSCs).
• To evaluate the potential of PFD as a repurposed drug for glioblastoma treatment, alone and in combination with temozolomide (TMZ).

Main Methods:

• Utilized five patient-derived GSCs to assess PFD's antiproliferative effects.
• Measured spheroid size, stemness factors (SOX2, OCT4), cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) markers.
• Investigated the role of GLI1 in PFD-induced EMT inhibition.
• Evaluated the efficacy of PFD combined with TMZ in vivo using mouse models.

Main Results:

• PFD demonstrated dose- and time-dependent antiproliferative effects on GSCs.
• PFD significantly suppressed spheroid formation, reduced stemness factors (SOX2, OCT4), and inhibited migration and invasion by decreasing Integrin α6, uPAR, vimentin, and Zeb1.
• PFD inhibited EMT, with GLI1 playing a role in this process.
• Combination therapy of PFD and TMZ significantly reduced tumor growth and improved survival in vivo, with decreased GLI1, SOX2, and vimentin expression.

Conclusions:

• Penflurido exhibits significant antitumor activity against glioblastoma stem cells.
• PFD effectively targets key pathways involved in glioblastoma progression, including stemness and EMT.
• Repurposing penflurido in combination with temozolomide offers a promising therapeutic strategy for glioblastoma.