TACIMA-218: A Novel Pro-Oxidant Agent Exhibiting Selective Antitumoral Activity

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.

Intratumoral administration of unconjugated Accum™ impairs the growth of pre‐established solid lymphoma tumors

“…Among all enriched and modulated pathways (all genes were mapped to human orthologs for pathway analyses), we found that the expression of several genes involved in oxidative phosphorylation ( PDHB , FDX1 , ETF1 , COX10 , and ALDH6A1 ) and ROS production ( PRDX6 , PRNP , and EGLN2 ) was enhanced in Accum™ compared with PBS‐treated EL4 cells (Figure 2A). Since ROS production was previously reported to be one of the mechanisms driving cancer cell death, we next validated our observation by staining Accum™‐treated EL4 cells with the ROS indicator MitoSOX 31,33 . As shown in Figure 2B, ROS level increased indeed from 36% after 1 h of Accum™ treatment to 78% at 8 h post treatment.…”

“…However, the discovery of such small molecules is complex and tedious, as it involves the identification and development of drugs capable of specifically targeting cancer cells. 31,37 Their aim is to interact with proteins or other cellular targets (including signaling pathways) to modulate their activity. 1 Although some of these compounds can be derived from natural products, most small molecules are discovered through high-throughput screening (HTS).…”

“…The urgent need for novel anticancer therapeutics fuels active research in this field. However, the discovery of such small molecules is complex and tedious, as it involves the identification and development of drugs capable of specifically targeting cancer cells 31,37 . Their aim is to interact with proteins or other cellular targets (including signaling pathways) to modulate their activity 1 .…”

“…To monitor the involvement of ROS in Accum™-induced cell death, cancer cells were first treated with 5-10 mM of NAC or 10 μM of MitoTEMPO. 31 One hour later, Accum™ was added and cell death was assessed the following day by Annexin-V staining. A similar approach was used when all components were used simultaneously.…”

Recent Advances in Cancer Drug Discovery Through the Use of Phenotypic Reporter Systems, Connectivity Mapping, and Pooled CRISPR Screening

“…Furthermore, administration of InhiTinib to mice with large, pre-established tumors significantly prolonged their survival ( El-Kadiry et al, 2020 ). Despite differences in its molecular structure, TACIMA-218 triggered similar effects on various cancer cell lines irrespective of their p53 status, with the exception that it mainly targeted mitochondrial activity ( Abusarah et al, 2021 ).…”