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Background <p>Colorectal cancer (CRC) remains a major global health challenge, with increasing incidence, particularly among individuals under 50 years of age. Cathelicidin LL-37, a multifunctional antimicrobial peptide, has shown promise in cancer treatment, particularly for its anti-inflammatory effects.</p> Methods <p>Using in vitro and in vivo models, we investigated the anticancer potential of KR-12 amide, the shortest active fragment of LL-37, and its short-chain fatty acid (SCFA)-modified derivatives (acetyl-, propionyl-, and butyryl-KR-12-NH<sub>2</sub>). Peptides were synthesized by Fmoc solid-phase synthesis and purified by RP-HPLC. Their cytotoxicity was assessed in colon cancer HT-29 and normal colon epithelial CCD 841 CoN cell lines using MTT viability assays. In vivo efficacy was evaluated in a mouse (male Balb/C mice) azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated colorectal cancer (CACRC). Tumor burden was quantified by macroscopic and histological scoring, while inflammation was assessed through myeloperoxidase activity, ELISA-based cytokine profiling (IL-1β, IL-6, TNF-α), and microscopic evaluation of colon architecture.</p> Results <p>For all tested compounds, except KR-12-NH<sub>2</sub> modified with butyric acid, the concentrations needed for 50% growth inhibition were lower for colon cancer cell line HT-29 than for healthy colon epithelial cells CCD 841 CoN. The IC₅₀ values for KR-12 amide and propionyl-KR-12-NH<sub>2</sub> against HT-29 cells were 236.7 µM and 309.0 µM, respectively, compared with 347.3 µM and 422.1 µM for CCD 841 CoN cells. In the AOM/DSS-induced murine model, rectal administration of KR-12-NH<sub>2</sub> and propionyl-KR-12-NH<sub>2</sub> significantly reduced total tumor number compared with AOM/DSS-only animals (<i>p</i> = 0.02 and <i>p</i> = 0.03, respectively), accompanied by lower macroscopic (both <i>p</i> &lt; 0.001) and microscopic disease scores (<i>p</i> = 0.005 and <i>p</i> = 0.01). Both compounds also significantly decreased proinflammatory cytokines: rectal KR-12-NH<sub>2</sub> lowered IL-6 levels (<i>p</i> = 0.05), while rectal propionyl-KR-12-NH<sub>2</sub> reduced IL-6 (<i>p</i> = 0.02) and TNF-α (<i>p</i> = 0.01).</p> Conclusions <p>These findings provide a foundation for further investigation of cathelicidin derivatives in colorectal cancer therapy.</p>

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Synthesis and evaluation of KR-12, an LL-37 fragment, and its short-chain fatty acid derivatives: selective cytotoxicity in colorectal cancer cells and anti-tumor efficacy in an azoxymethane/DSS-induced colitis-associated cancer mouse model

  • 期刊论文

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  • 发表日期：

    2025年10月15日

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  • Jakub Włodarczyk,
  • Elżbieta Kamysz,
  • Jakub Fichna

摘要

Background

Colorectal cancer (CRC) remains a major global health challenge, with increasing incidence, particularly among individuals under 50 years of age. Cathelicidin LL-37, a multifunctional antimicrobial peptide, has shown promise in cancer treatment, particularly for its anti-inflammatory effects.

Methods

Using in vitro and in vivo models, we investigated the anticancer potential of KR-12 amide, the shortest active fragment of LL-37, and its short-chain fatty acid (SCFA)-modified derivatives (acetyl-, propionyl-, and butyryl-KR-12-NH2). Peptides were synthesized by Fmoc solid-phase synthesis and purified by RP-HPLC. Their cytotoxicity was assessed in colon cancer HT-29 and normal colon epithelial CCD 841 CoN cell lines using MTT viability assays. In vivo efficacy was evaluated in a mouse (male Balb/C mice) azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated colorectal cancer (CACRC). Tumor burden was quantified by macroscopic and histological scoring, while inflammation was assessed through myeloperoxidase activity, ELISA-based cytokine profiling (IL-1β, IL-6, TNF-α), and microscopic evaluation of colon architecture.

Results

For all tested compounds, except KR-12-NH2 modified with butyric acid, the concentrations needed for 50% growth inhibition were lower for colon cancer cell line HT-29 than for healthy colon epithelial cells CCD 841 CoN. The IC₅₀ values for KR-12 amide and propionyl-KR-12-NH2 against HT-29 cells were 236.7 µM and 309.0 µM, respectively, compared with 347.3 µM and 422.1 µM for CCD 841 CoN cells. In the AOM/DSS-induced murine model, rectal administration of KR-12-NH2 and propionyl-KR-12-NH2 significantly reduced total tumor number compared with AOM/DSS-only animals (p = 0.02 and p = 0.03, respectively), accompanied by lower macroscopic (both p < 0.001) and microscopic disease scores (p = 0.005 and p = 0.01). Both compounds also significantly decreased proinflammatory cytokines: rectal KR-12-NH2 lowered IL-6 levels (p = 0.05), while rectal propionyl-KR-12-NH2 reduced IL-6 (p = 0.02) and TNF-α (p = 0.01).

Conclusions

These findings provide a foundation for further investigation of cathelicidin derivatives in colorectal cancer therapy.