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Realgar bioleaching solution suppress ras excessive activation by increasing ROS in Caenorhabditis elegans
De Juan Zhi1, Na Feng, Dong Ling Liu
1Institute of Microbiology and Biochemical Pharmacy, School of Pharmaceutics, Lanzhou University, Lanzhou, People's Republic of China, zhidej@lzu.edu.cn.
Abstract:
Although realgar bioleaching solution (RBS) has been proved to be a potential candidate for cancer therapy, the mechanisms of RBS anticancer are still far from being completely understood. Dosed with RBS in C. elegans, the multivulva phenotype resulting from oncogenic ras gain-of-function was inhibited in a dose dependent manner. It could be abrogated by concurrent treatment C. elegans with RBS and the radical scavenger DMSO. However, RBS could not induce DAF-16 nuclear translocation in TJ356 or the increase of HSP 16.2 expression in CL2070, which both could be aroused visible GFP fluorescent variation to represent for oxidative stress generation. Treatment C. elegans with superoxide anion generator paraquat, similar results were also obtained. Our results indicated that RBS suppress excessive activated ras by increasing reactive oxygen species (ROS) in C. elegans. Secondly, ROS induced by RBS significantly accumulated on a higher level in C. elegans with a mutational ras than that with wild ras, thus leading to oxidative stress on ras gain-of-function background rather than on normal ras context. Our results firstly demonstrated that using C. elegans as a model organism for evaluating prooxidant drug candidates for cancer therapy.
Insights
Realgar bioleaching solution (RBS) combats cancer by increasing reactive oxygen species (ROS) to suppress overactive ras. This study validates C. elegans as a model for testing prooxidant cancer drugs.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Realgar bioleaching solution (RBS) shows promise for cancer therapy, but its anticancer mechanisms remain unclear.
- Oncogenic ras activation is a key driver in many cancers.
- Reactive oxygen species (ROS) play a complex role in cancer, acting as both promoters and suppressors.
Purpose of the Study:
- To elucidate the anticancer mechanism of RBS.
- To investigate the role of ROS in RBS's effect on oncogenic ras.
- To establish Caenorhabditis elegans (C. elegans) as a model for evaluating prooxidant anticancer drugs.
Main Methods:
- Administered RBS to C. elegans with a gain-of-function mutation in ras.
- Assessed the multivulva phenotype, a marker for ras hyperactivation.
- Utilized radical scavengers and superoxide anion generators to probe ROS involvement.
- Measured DAF-16 nuclear translocation and HSP 16.2 expression as indicators of oxidative stress.
- Compared ROS levels in C. elegans with mutated ras versus wild-type ras.
Main Results:
- RBS dose-dependently inhibited the multivulva phenotype caused by oncogenic ras.
- This inhibition was abrogated by the radical scavenger DMSO, suggesting a role for ROS.
- RBS did not induce DAF-16 nuclear translocation or HSP 16.2 expression, indicating ROS generation was not the primary mechanism.
- RBS increased ROS levels, particularly in C. elegans with mutated ras, leading to oxidative stress.
- Paraquat, a ROS generator, produced similar results, further supporting the ROS-mediated mechanism.
Conclusions:
- RBS suppresses excessive ras activation by increasing ROS levels in C. elegans.
- The prooxidant effect of RBS is more pronounced on a background of ras gain-of-function, inducing targeted oxidative stress.
- C. elegans serves as an effective model organism for evaluating prooxidant drug candidates in cancer therapy.
