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This preclinical study evaluated two triazoloacridinone compounds, C-1305 and a novel derivative TRA-01AR, in combination with the standard chemotherapy drug 5-fluorouracil for colorectal cancer treatment. Both compounds altered cancer cell metabolism and gene expression related to DNA replication and cell division, with C-1305 showing significant tumor reduction in mouse models when combined with 5-FU, while TRA-01AR demonstrated better tolerability and improved blood flow to tumors but no statistically significant tumor reduction. The compounds shifted cellular energy production from glycolysis toward oxidative phosphorylation, a metabolic change potentially relevant to chemotherapy response.
Why it matters
This research explores ways to enhance the effectiveness of 5-fluorouracil, a widely used but limited colorectal cancer drug, through combination therapy. While C-1305 showed stronger anti-tumor effects, TRA-01AR's improved safety profile and vascular effects suggest it may have therapeutic potential that requires further investigation to understand its distinct mechanism of action.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
5-Fluorouracil (5-FU) remains a cornerstone of colorectal cancer (CRC) therapy, yet its clinical efficacy is limited by resistance, systemic toxicity, and unfavorable pharmacokinetics. Strategies that enhance tumor sensitivity while maintaining tolerability are therefore of considerable interest. Here, we evaluated 5-FU in combination with two triazoloacridinones, C-1305 and a novel BOC-modified derivative, TRA-01AR, using integrated cellular, transcriptomic, bioenergetic, and in vivo approaches. Both compounds induced cytotoxic effects across cancer cell models and produced overlapping but distinct transcriptional responses, primarily affecting DNA replication and cell cycle pathways. Bioenergetic profiling revealed a shift toward oxidative phosphorylation accompanied by reduced glycolysis, indicating modulation of cellular metabolism relevant to chemotherapy response. Interestingly, TRA-01AR exhibited delayed cytotoxicity relative to C-1305, although the underlying mechanism remains to be defined. In vivo, the combination of 5-FU with C-1305 significantly reduced tumor weight in HT-29 xenografts, whereas 5-FU combined with TRA-01AR did not result in a statistically significant reduction compared to 5-FU alone. TRA-01AR was associated with a more favorable systemic profile and increased intratumoral blood flow compared with C-1305. Collectively, these findings indicate that triazoloacridinones modulate transcriptional and metabolic programs relevant to the 5-FU response. While C-1305 demonstrated greater antitumor activity under the tested conditions, TRA-01AR exhibited distinct biological effects, including improved tolerability and vascular modulation. Further studies are required to clarify TRA-01AR’s mechanism of action and assess its potential relevance in CRC-specific therapies.