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Redox-related antimelanoma activity of ATN-224
Valerie Trapp1, Kristy Lee, Fernando Doñate
1Clinical Pharmacology and Developmental Therapeutics, University of California Irvine Chao Family Comprehensive Cancer Center, Orange, California, USA.
Abstract:
Melanoma cells characteristically produce increased levels of reactive oxygen species (ROS) because of the metal-binding properties of melanin and loss of structural integrity of the melanosome. Agents that deplete gluthathione or inhibit superoxide dismutase, thereby blocking ROS scavenging mechanisms, may be selectively toxic to melanoma. To determine whether the inhibition of ROS scavenging could potentiate alkylator activity, we evaluated the activity of tetrathiomolybdate (ATN-224), a superoxide dismutase inhibitor, alone and in combination with temozolomide, on five melanoma cell lines. We also determined whether the ATN-224 would act synergistically with other agents that interfere with ROS scavenging. We found that the combination of ATN-224 and temozolomide generally exhibited additive cytotoxic effects on the cell lines tested. ATN-224 acted synergistically with buthionine sulfoximine, an agent that causes gluthathione depletion. Combinations of ATN-224 with arsenic trioxide, which may deplete glutathione, or disulfiram, an agent that interferes with recycling of glutathione, were antagonistic. These data suggest that strategically tailoring combination regimens that include ATN-224 and target ROS may be a viable approach to advance the treatment of melanoma.
Insights
Targeting reactive oxygen species (ROS) in melanoma may enhance chemotherapy. Combining superoxide dismutase inhibitor ATN-224 with glutathione-depleting agents showed synergistic effects, suggesting a new melanoma treatment strategy.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Melanoma cells exhibit elevated reactive oxygen species (ROS) due to melanin properties and melanosome instability.
- Inhibiting ROS scavenging mechanisms may selectively target melanoma cells.
Purpose of the Study:
- To investigate if inhibiting ROS scavenging potentiates alkylator activity in melanoma.
- To evaluate the efficacy of ATN-224, a superoxide dismutase inhibitor, alone and in combination with temozolomide.
- To explore synergistic effects of ATN-224 with other ROS scavenging inhibitors.
Main Methods:
- Assessed the cytotoxic effects of ATN-224 and temozolomide on five melanoma cell lines.
- Determined synergistic, additive, or antagonistic interactions between ATN-224 and agents affecting glutathione levels (buthionine sulfoximine, arsenic trioxide, disulfiram).
Main Results:
- The combination of ATN-224 and temozolomide showed generally additive cytotoxic effects.
- ATN-224 exhibited synergistic effects with buthionine sulfoximine (glutathione depletion).
- Combinations of ATN-224 with arsenic trioxide or disulfiram were antagonistic.
Conclusions:
- Targeting ROS scavenging mechanisms, particularly with agents like ATN-224, holds promise for melanoma treatment.
- Strategic combination regimens involving ATN-224 and agents that modulate ROS may advance melanoma therapy.
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