Journal
MOLECULES
Volume 27, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/molecules27196577
Keywords
arsenite; arenobufagin; gamabufotalin; glioblastoma; DNA damage; cell death; cell cycle arrest; combination therapy
Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI grant [20K07136]
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Combining As-III with arenobufagin enhances cytotoxicity and DNA damage in glioblastoma cells, likely through increased apoptosis, autophagy, and Notch signaling suppression.
The cytotoxicity of a trivalent arsenic derivative (arsenite, As-III) combined with arenobufagin or gamabufotalin was evaluated in human U-87 glioblastoma cells. Synergistic cytotoxicity with upregulated intracellular arsenic levels was observed, when treated with As-III combined with arenobufagin instead of gamabufotalin. Apoptosis and the activation of caspase-9/-8/-3 were induced by As-III and further strengthened by arenobufagin. The magnitude of increase in the activities of caspase-9/-3 was much greater than that of caspase-8, suggesting that the intrinsic pathway played a much more important role in the apoptosis. An increase in the number of necrotic cells, enhanced LDH leakage, and intensified G(2)/M phase arrest were observed. A remarkable increase in the expression level of gamma H2AX, a DNA damage marker, was induced by As-III+arenobufagin. Concomitantly, the activation of autophagy was observed, suggesting that autophagic cell death associated with DNA damage was partially attributed to the cytotoxicity of As-III+arenobufagin. Suppression of Notch signaling was confirmed in the combined regimen-treated cells, suggesting that inactivation of Jagged1/Notch signaling would probably contribute to the synergistic cytotoxic effect of As-III+arenobufagin. Given that both As-III and arenobufagin are capable of penetrating into the blood-brain barrier, our findings may provide fundamental insight into the clinical application of the combined regimen for glioblastoma.
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