Abstract
We report the discovery, via a unique high-throughput screening strategy, of a novel bioactive anticancer compound: Thiol Alkylating Compound Inducing Massive Apoptosis (TACIMA)-218. We demonstrate that this molecule engenders apoptotic cell death in genetically diverse murine and human cancer cell lines, irrespective of their p53 status, while sparing normal cells. TACIMA-218 causes oxidative stress in the absence of protective antioxidants normally induced by Nuclear factor erythroid 2-related factor 2 activation. As such, TACIMA-218 represses RNA translation and triggers cell signaling cascade alterations in AKT, p38, and JNK pathways. In addition, TACIMA-218 manifests thiol-alkylating properties resulting in the disruption of redox homeostasis along with key metabolic pathways. When administered to immunocompetent animals as a monotherapy, TACIMA-218 has no apparent toxicity and induces complete regression of pre-established lymphoma and melanoma tumors. In sum, TACIMA-218 is a potent oxidative stress inducer capable of selective cancer cell targeting.
Highlights
IntroductionReactive oxygen species (ROS) are produced at low concentrations and are effectively neutralized by coordinated antioxidant defense systems controlled via Nuclear factor erythroid 2-related factor 2 (Nrf2).[1] In contrast, cancer cells have intrinsically higher levels of reactive oxygen species (ROS), altered amino acid delivery, increased fatty acid oxidation or synthesis and are under constant oxidative stress due to elevated metabolic activities.[1] These dysregulated metabolic activities often result from mutated oncogenes and tumor suppressor genes known to modulate intracellular signaling pathways.[2] As a result, cancer cells are often highly sensitive to exogenous agents capable of increasing oxidative stress levels.[3] So far, numerous anti-neoplastic compounds were developed to target these metabolic pathways.[2] their efficacy was modest for two reasons
In normal cells, reactive oxygen species (ROS) are produced at low concentrations and are effectively neutralized by coordinated antioxidant defense systems controlled via Nuclear factor erythroid 2-related factor 2 (Nrf2).[1]
The initial objective of our High-throughput screening (HTS) analysis was to identify novel small molecules capable of modulating activated T-cell responses (Fig. 1A). [6, 14] The primary screen identified compounds modulating T-cell receptor activation reflected by GFP expression levels
Summary
Reactive oxygen species (ROS) are produced at low concentrations and are effectively neutralized by coordinated antioxidant defense systems controlled via Nuclear factor erythroid 2-related factor 2 (Nrf2).[1] In contrast, cancer cells have intrinsically higher levels of ROS, altered amino acid delivery, increased fatty acid oxidation or synthesis and are under constant oxidative stress due to elevated metabolic activities.[1] These dysregulated metabolic activities often result from mutated oncogenes and tumor suppressor genes known to modulate intracellular signaling pathways.[2] As a result, cancer cells are often highly sensitive to exogenous agents capable of increasing oxidative stress levels.[3] So far, numerous anti-neoplastic compounds were developed to target these metabolic pathways.[2] their efficacy was modest for two reasons
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