Polyamine Inhibition Reverses Tumor Microenvironment Acidification in Early-Stage Colorectal Cancer: Evidence from a Human Ex Vivo Tissue Model

Rasheed, Inas Abd Al Majed; Khudhur, Amrah Mohammed  Saeed; Saleh, Anas Ahmed

doi:10.31557/APJCP.2026.27.8.2817

Polyamine Inhibition Reverses Tumor Microenvironment Acidification in Early-Stage Colorectal Cancer: Evidence from a Human Ex Vivo Tissue Model

Document Type : Research Articles

Authors

¹ Department of Pathology, Tikrit University, Tikrit, Iraq.

² Department of Physiology, Tikrit University, Tikrit, Iraq.

³ Department of Surgery, Tikrit University, Tikrit, Iraq.

10.31557/APJCP.2026.27.8.2817

Abstract

Objective: Polyamine metabolism is known to be dysregulated in colorectal cancer (CRC), contributing to tumor progression, microenvironment acidification, and immune evasion. This study aimed to investigate the impact of polyamine pathway inhibition using α-difluoromethylornithine (DFMO) on extracellular acidification and energy metabolism in early-stage CRC tissues compared to non-cancerous controls. Methods: A total of 50 individuals (25 early-stage CRC patients and 25 non-cancer controls) provided colorectal tissue samples, which were subjected to a 24-hour ex vivo incubation with or without DFMO. Biochemical assays were performed to measure extracellular pH, lactate, ammonium, and ATP levels, serving as metabolic indicators of tumor activity and viability. Results: The results revealed that untreated CRC tissues exhibited a significantly more acidic environment, higher lactate and ammonium concentrations, and lower ATP content than non-cancerous tissues. DFMO treatment led to a marked reduction in extracellular acidification in CRC samples, evidenced by elevated pH (from 6.47 to 6.87), and reduced lactate (from 10.16 to 6.93 mM) and ammonium (from 80.54 to 58.94 µM) concentrations. ATP levels also declined modestly with DFMO in CRC tissues, indicating an impact on cellular energy metabolism. Non-cancer tissues showed minimal changes in these parameters after DFMO exposure. Statistical analyses using one-way ANOVA showed significant differences (p < 0.001) across groups for all biochemical measures. Univariate linear regression further identified group status and DFMO treatment as independent predictors of ATP, lactate, and ammonium levels. Conclusion: These findings suggest that polyamine inhibition via DFMO can biochemically reprogram the tumor microenvironment in early-stage CRC, reducing metabolic acidity and energy output. This supports the therapeutic rationale for DFMO in disrupting tumor metabolism and enhancing treatment responsiveness. The ex vivo model provides a robust, human-relevant platform for metabolic intervention studies in cancer.

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