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<p>Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide.&#xa0;Probiotics have long been utilized to treat gastrointestinal diseases. Probiotics may play a role in the prevention and treatment of CRC. Additionally, the anti-inflammatory drugs sulfasalazine (SSA) and mesalazine (MESA) have a preventive role in CRC. This study investigates the modulatory antitumor effects of combining the probiotic <i>Lacticaseibacillus rhamnosus</i> GG (LGG) with SSA or MESA and the associated molecular mechanisms in CRC. In vitro studies of LGG-CFS, both alone and in combination with SSA or MESA, were assessed in HCT-116 and HT-29 CRC cells. In vivo, 61 albino rats aged 8 weeks were used and CRC was induced using 1,2-dimethylhydrazine. The 1,2-dimethylhydrazine-induced rats were divided into six groups, each of eight—in addition to the negative control group (received phosphate buffer saline only)—as follows: (I) positive control group (received DMH only), (II) SSA-treated group, (III) MESA-treated group, (IV) LGG-treated group, (V) SSA + LGG-treated group, and (VI) MESA + LGG-treated group. Rats received daily oral doses of SSA (250 mg/kg), MESA (62.5 mg/kg), LGG (1 × 10<sup>9</sup> CFU lactobacilli/1 ml), SSA + LGG, and MESA + LGG for 4 weeks. In both cell lines, the control group (positive control, human cancerous cells without further treatment) exhibited a reduction in annexin V, whereas the specified treatments elevated annexin V levels in both cells, thereby inducing apoptosis. In vivo, positive control rats exhibited upregulation of TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF signaling, and Ki-67, resulting in the induction of proliferation, hypoxia, and angiogenesis and inhibition of apoptosis. All treatment regimens downregulated TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF crosstalk’s, and Ki-67, hence inhibiting proliferation, hypoxia, angiogenesis, and inducing apoptosis. Surprisingly, the combination of LGG with either SSA or MESA demonstrated the greatest efficacy through the aforementioned pathways with the superiority to the LGG + SSA combination in both experimental models. The current findings revealed novel insights into the potential antitumor effects of combining LGG with either SSA or MESA compared to each drug individually in CRC management. Further preclinical and clinical trials are warranted to evaluate this promising regimen compared to standard therapy of CRC.</p>

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Enhanced antitumor efficacy of sulfasalazine and mesalazine in colorectal cancer through modulatory action of Lacticaseibacillus rhamnosus GG

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Rana Karam Elmahdy,
  • Ihab Talaat Abdel-Raheem,
  • Mohammad Mahmoud Abd-Alhaseeb,
  • Asser Ibrahim Ghoneim,
  • Maged Wasfy Helmy

摘要

Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide. Probiotics have long been utilized to treat gastrointestinal diseases. Probiotics may play a role in the prevention and treatment of CRC. Additionally, the anti-inflammatory drugs sulfasalazine (SSA) and mesalazine (MESA) have a preventive role in CRC. This study investigates the modulatory antitumor effects of combining the probiotic Lacticaseibacillus rhamnosus GG (LGG) with SSA or MESA and the associated molecular mechanisms in CRC. In vitro studies of LGG-CFS, both alone and in combination with SSA or MESA, were assessed in HCT-116 and HT-29 CRC cells. In vivo, 61 albino rats aged 8 weeks were used and CRC was induced using 1,2-dimethylhydrazine. The 1,2-dimethylhydrazine-induced rats were divided into six groups, each of eight—in addition to the negative control group (received phosphate buffer saline only)—as follows: (I) positive control group (received DMH only), (II) SSA-treated group, (III) MESA-treated group, (IV) LGG-treated group, (V) SSA + LGG-treated group, and (VI) MESA + LGG-treated group. Rats received daily oral doses of SSA (250 mg/kg), MESA (62.5 mg/kg), LGG (1 × 109 CFU lactobacilli/1 ml), SSA + LGG, and MESA + LGG for 4 weeks. In both cell lines, the control group (positive control, human cancerous cells without further treatment) exhibited a reduction in annexin V, whereas the specified treatments elevated annexin V levels in both cells, thereby inducing apoptosis. In vivo, positive control rats exhibited upregulation of TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF signaling, and Ki-67, resulting in the induction of proliferation, hypoxia, and angiogenesis and inhibition of apoptosis. All treatment regimens downregulated TLR2/AKT/NF-κB, IL-6, IFN-γ/STAT-3/PD-L1, COX-2/HIF-1α/VEGF crosstalk’s, and Ki-67, hence inhibiting proliferation, hypoxia, angiogenesis, and inducing apoptosis. Surprisingly, the combination of LGG with either SSA or MESA demonstrated the greatest efficacy through the aforementioned pathways with the superiority to the LGG + SSA combination in both experimental models. The current findings revealed novel insights into the potential antitumor effects of combining LGG with either SSA or MESA compared to each drug individually in CRC management. Further preclinical and clinical trials are warranted to evaluate this promising regimen compared to standard therapy of CRC.