L-Arginine as an Adjuvant Chemosensitizer: Enhancement of Intestinal Permeability and Cytotoxic Activity of Doxorubicin

Background/Objectives: Doxorubicin is an anthracycline chemotherapeutic agent widely used in the treatment of breast cancer. However, its clinical utility is limited by the drug’s resistance development, low oral bioavailability, and dose-dependent side effects. The semi-essential amino acid, L-arginine, has gained attention as a potential adjuvant that could improve the drug distribution and cytotoxic effectiveness of chemotherapeutics. This study aimed to explore the multifunctional effect of L-arginine on the intestinal absorption and anti-breast cancer activity of doxorubicin. Methods: The rabbit in situ intestinal perfusion technique was employed to investigate the membrane transport parameters of doxorubicin both in the absence and presence of L-arginine. Furthermore, the effect of L-arginine on the cytotoxic activity of doxorubicin against breast cancer cells (MCF-7) was assessed using the MTT assay. Results: Co-perfusion of L-arginine with doxorubicin enhanced the fraction of doxorubicin absorbed, with a recorded 4.3-fold enhancement in the jejuno-ileum and a 1.5-fold enhancement in the colon segment. In MCF-7 cells, co-treatment with L-arginine resulted in a significant potentiation of doxorubicin cytotoxicity. At L-arginine concentrations of 10 μM and 50 μM, the recorded IC50 decreased from 41.3 μM to 8.2 μM and to 22.1 μM, respectively. The superior efficacy of 10 μM L-arginine compared to 50 μM reflected a biphasic concentration-dependent response. Conclusions: L-arginine modulated two critical aspects of doxorubicin efficacy, intestinal absorption and cytotoxic activity. The biphasic response emphasizes the importance of L-arginine dose optimization. These findings support the potential of L-arginine as a safe adjuvant for developing oral doxorubicin formulations. This approach can reduce the dose-related toxicity of doxorubicin and improve therapeutic outcomes.