Journal of neuro-oncology · 2025
Synergistic antitumor and radiosensitizing effects of α-sulfoquinovosyl-acylpropanediol (SQAP) via PI3K/Akt inhibition and DNA repair impairment in glioblastoma.
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Nishiwaki Takayuki, Kudo Urara, Nakamura Shinsuke, Kuse Yoshiki, Harakawa Yoshiaki, You Fukka, Shoda Kenji, Yamada Tetsuya, Takei Hiroaki, Egashira Yusuke, Hara Hideaki, Nakayama Noriyuki, Izumo Tsuyoshi, Shimazawa Masamitsu
Аннотация
PURPOSE: Radiotherapy remains a key treatment modality for glioblastoma (GBM), but therapeutic resistance and radiation-induced toxicity severely limit its efficacy. Therefore, the development of novel, safe, and effective radiosensitizers is urgently needed. α-Sulfoquinovosylacylpropandiol (SQAP), a marine-derived compound, has demonstrated potent radiosensitizing effects in cancer cells by improving tumor oxygenation and interfering with DNA repair. However, its impact on GBM has not yet been investigated. This study aimed to evaluate the biological effects of SQAP on GBM cells and assess its potential as a radiosensitizer for future clinical application.
METHODS: In vitro analyses-including cell viability, colony formation, immunoblotting, quantitative reverse transcription polymerase chain reaction, immunocytochemistry, and cell death/proliferation assays-were conducted to examine SQAP's mechanisms of action. In vivo efficacy and safety were evaluated using a murine intracranial glioma model.
RESULTS: SQAP inhibited GBM cell proliferation while sparing normal astrocytes. In combination with radiotherapy, SQAP significantly reduced colony formation and enhanced cell death without affecting mitosis. SQAP decreased PI3K/Akt phosphorylation and modulated the expression of downstream apoptotic and cell cycle-related proteins. Additionally, SQAP suppressed HIF-1α and VEGF expression. Although SQAP alone did not cause DNA damage, it delayed radiotherapy-induced DNA repair, as shown by prolonged γH2AX expression and reduced 53BP1 nuclear expression.
CONCLUSION: SQAP exerts both antitumor and radiosensitizing effects in GBM models by inhibiting PI3K/Akt signaling, suppressing hypoxia-related pathways, and impairing DNA repair. These findings support its potential as a promising adjunctive agent in GBM therapy.
METHODS: In vitro analyses-including cell viability, colony formation, immunoblotting, quantitative reverse transcription polymerase chain reaction, immunocytochemistry, and cell death/proliferation assays-were conducted to examine SQAP's mechanisms of action. In vivo efficacy and safety were evaluated using a murine intracranial glioma model.
RESULTS: SQAP inhibited GBM cell proliferation while sparing normal astrocytes. In combination with radiotherapy, SQAP significantly reduced colony formation and enhanced cell death without affecting mitosis. SQAP decreased PI3K/Akt phosphorylation and modulated the expression of downstream apoptotic and cell cycle-related proteins. Additionally, SQAP suppressed HIF-1α and VEGF expression. Although SQAP alone did not cause DNA damage, it delayed radiotherapy-induced DNA repair, as shown by prolonged γH2AX expression and reduced 53BP1 nuclear expression.
CONCLUSION: SQAP exerts both antitumor and radiosensitizing effects in GBM models by inhibiting PI3K/Akt signaling, suppressing hypoxia-related pathways, and impairing DNA repair. These findings support its potential as a promising adjunctive agent in GBM therapy.