Enhanced bioavailability and cytotoxicity of disodium crocetinate over crocin in HCT-116 colorectal cancer cells: evidence from bioinformatics and experiments

Hassanpour, Mahmoud; Ghaemi, Mehran; Aminlari, Mahmoud; Saberi, Mohammad Reza; AbdolahRamazani, Salman

doi:10.22038/ajp.2026.27944

Enhanced bioavailability and cytotoxicity of disodium crocetinate over crocin in HCT-116 colorectal cancer cells: evidence from bioinformatics and experiments

Articles in Press

Document Type : Original Research Article

Authors

¹ Department of Biochemistry, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

² Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran Department of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran

³ Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

10.22038/ajp.2026.27944

Abstract

Objective: Colorectal cancer (CRC) remains a highly aggressive malignancy. This study directly compared the effects of crocin and disodium crocetinate (DSC) on human CRC HCT-116 cells.
Materials and methods: Crocin was converted to water-soluble DSC using alkali-catalyzed hydrolysis. Cells were treated with varying concentrations of crocin or DSC to assess viability. SYBR green quantitative real-time RT-PCR analyzed transcriptional modulation of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). Molecular docking with MOE software investigated binding modes of crocin and crocetin to the ETS translocation variant 4 (ETV4) protein.
Results: DSC induced a substantially stronger cytotoxic response than crocin, achieving an IC₅₀ of 0.4 mM. In contrast, crocin did not reach 50% growth inhibition within the tested range, resulting in a non-experimentally measurable IC₅₀ estimate of 3.3 mM. DSC treatment led to markedly greater downregulation of both MMP2 and MMP9 compared to crocin, consistent with prior work linking crocetin to inhibition of MAPK, NF-κB, and PI3K/Akt axes upstream of MMP transcription. Docking analysis revealed that crocetin physicochemical profile is vastly more aligned with ETV4 modulation.
Conclusion: Collectively, DSC constitutes a more potent inhibitor of CRC growth and metastatic potential than crocin, offering a mechanistically substantiated candidate for future preclinical evaluation. Crocin and crocetin act through ETV4 as a novel therapeutic target in the MAPK pathway.

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