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Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of
Stefania Elena Navone1, Laura Guarnaccia1, Massimiliano D Rizzaro1
1Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
Abstract:
Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.
Insights
Luteolin, a natural flavonoid, combats glioblastoma stem cells (GSCs) by targeting the sphingolipid rheostat. This compound enhances GSC sensitivity to chemotherapy, offering a potential add-on therapy for this aggressive brain tumor.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Glioblastoma (GBM) is an aggressive, incurable brain tumor.
- GBM stem cells (GSCs) are highly therapy-resistant.
- The sphingolipid rheostat (ceramide/sphingosine-1-phosphate balance) is crucial in cancer progression.
Purpose of the Study:
- To investigate luteolin's anti-tumoral efficacy against GSCs.
- To elucidate luteolin's mechanism of action on the sphingolipid rheostat and related pathways.
Main Methods:
- Treatment of primary GSCs with luteolin.
- Analysis of gene and protein expression related to sphingolipid metabolism, cell signaling, cell cycle, apoptosis, and autophagy.
- Assessment of GSC viability and sensitivity to temozolomide (TMZ).
Main Results:
- Luteolin inhibited sphingosine kinase (SphK1/2) and increased sphingosine-1-phosphate lyase (SGPL1) and ceramide synthase 1 (CERS1) expression, favoring ceramide production.
- Luteolin suppressed pro-tumoral signaling pathways (MAPK, RAS/MEK/ERK, PI3K/AKT/mTOR) and cell cycle regulators.
- Luteolin upregulated pro-apoptotic mediators and cell cycle arrest proteins, while inhibiting autophagy.
- Luteolin impaired GSC viability and enhanced sensitivity to TMZ.
Conclusions:
- Luteolin effectively targets GSCs by modulating the sphingolipid rheostat and key cancer-promoting pathways.
- Luteolin demonstrates potential as an add-on therapy to improve glioblastoma treatment outcomes.
- Further research into luteolin's therapeutic application in glioblastoma is warranted.
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