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Using novel oxidative phosphorylation inhibitors to attenuate drug resistance in human gliomas
Chia-Kuang Tsai1, Chin-Yu Lin2, Yung-Lung Chang2
1Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
Abstract:
Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor prognosis, worsened by resistance to temozolomide (TMZ). TMZ-induced DNA damage is counteracted by the repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT), promoting tumor recurrence. Targeting oxidative phosphorylation (OXPHOS), essential for cellular energy production, offers a potential therapeutic strategy to overcome TMZ resistance and improve GBM treatment outcomes. Gboxin, a small-molecule drug, selectively inhibits OXPHOS by targeting complex V, with minimal toxicity to normal cells. It accumulates in the mitochondria of GBM cells, exploiting their high membrane potential and pH, thereby inhibiting cell proliferation. This study evaluates Gboxin's efficacy in TMZ-resistant (TMZ-R) GBM. Results show that Gboxin suppresses the growth of both TMZ-sensitive and TMZ-R GBM cells by inhibiting proliferation, inducing apoptosis, and reducing OXPHOS activity. These findings were confirmed in an in vivo model, highlighting Gboxin as a promising therapeutic for both TMZ-sensitive and TMZ-R GBM. See also the graphical abstract(Fig. 1).
Insights
Glioblastoma multiforme (GBM) treatment is challenging due to temozolomide (TMZ) resistance. Gboxin, a novel drug targeting cellular energy production, effectively inhibits GBM growth and overcomes TMZ resistance in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
- Temozolomide (TMZ) resistance, often mediated by O-6-methylguanine-DNA methyltransferase (MGMT), limits treatment efficacy.
- Targeting oxidative phosphorylation (OXPHOS) presents a strategy to overcome TMZ resistance.
Purpose of the Study:
- To evaluate the efficacy of Gboxin, a novel OXPHOS inhibitor, against TMZ-resistant GBM.
- To investigate Gboxin's mechanism of action in GBM cells.
- To assess Gboxin's therapeutic potential in preclinical GBM models.
Main Methods:
- In vitro studies on TMZ-sensitive and TMZ-resistant GBM cell lines.
- Assessment of cell proliferation, apoptosis, and OXPHOS activity.
- In vivo efficacy studies in a GBM xenograft model.
Main Results:
- Gboxin suppressed proliferation and induced apoptosis in both TMZ-sensitive and TMZ-resistant GBM cells.
- Gboxin significantly reduced OXPHOS activity in GBM cells.
- Gboxin demonstrated therapeutic efficacy in an in vivo GBM model, confirming its potential.
Conclusions:
- Gboxin is a promising therapeutic agent for GBM, effective against both TMZ-sensitive and TMZ-resistant tumors.
- Gboxin's mechanism involves inhibition of OXPHOS and induction of apoptosis.
- Targeting OXPHOS with Gboxin offers a viable strategy to overcome temozolomide resistance in glioblastoma.
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