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. 2023 May 31;15(5):e39789.
doi: 10.7759/cureus.39789. eCollection 2023 May.

Antitumor Activity of Luteolin Against Ehrlich Solid Carcinoma in Rats via Blocking Wnt/β-Catenin/SMAD4 Pathway

Heba Aljohani  1 , Ahmed E Khodier  2 , Mohammed M Al-Gayyar  3   4
Affiliations

Antitumor Activity of Luteolin Against Ehrlich Solid Carcinoma in Rats via Blocking Wnt/β-Catenin/SMAD4 Pathway

Heba Aljohani et al. Cureus. .

Abstract

Background Ehrlich solid carcinoma (ESC) is characterized by rapid proliferation and a short survival time. Because Ehrlich ascites carcinoma (EAC) resembles human cancer cells, Ehrlich solid and ascetic forms are commonly used to determine the anticancer effects of various compounds. Luteolin is a flavonoid compound found in many dietary sources, including carrots, peppers, celery, olive oil, peppermint, and oregano. Luteolin has potent anti-inflammatory, antidiabetic, antitumor, and antiapoptotic activities. Aims This study aims to investigate the antitumor activity of luteolin against ESC in rats by affecting the Wnt/β-catenin/SMAD4 pathway. Methods We introduced 0.15 ml of Ehrlich cells (2 × 106) ESC into the left hind thighs of rats. After eight days of inoculation, the rats orally received 25 mg/kg of luteolin daily. We stained sections of tumor tissues with Masson's trichrome. We used another part of the tumor tissue to assess gene and protein expression of Wnt, β-catenin, E-cadherin, and SMAD4. Results Treatment of carcinoma rats with luteolin increased the mean survival time and reduced tumor volume and weight. In addition, examination of tumor tissue stained with Masson's trichrome showed loosely to densely packed collagen fibers in between neoplastic cells and scattered papillary expansion of a loose blue band of collagen expression along the covering adipose connective tissue and extending in a fine strand in between muscle fibers, which was ameliorated by treating rats with luteolin. Finally, treating ESC in rats with luteolin overexpressed E-cadherin and downregulated Wnt, β-catenin, and SMAD4. Conclusions We found luteolin has antineoplastic activity against ESC by reducing tumor size and weight while improving the structure of muscle cells. It works by suppressing Wnt, β-catenin, and SMAD4, resulting in decreased tumor cell proliferation and differentiation. Additionally, luteolin overexpresses E-cadherin, leading to reduced tumor cell invasion and metastasis.

Keywords: e-cadherin; ehrlich solid carcinoma (esc); luteolin; smad4; wnt; β-catenin.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Effect of ESC and 25 mg/kg luteolin on tumor volume over experiment period (a), tumor weight at the last day of the experiment (b), and rats mean survival time (c).
*Significant difference against control group at p<0.05. # significant difference against ESC group at p<0.05. ESC: Ehrlich solid carcinoma.
Figure 2
Figure 2. Muscle sections stained with Masson trichrome in control group (a), Ehrlich solid carcinoma (ESC, b) and ESC treated with 25 mg/kg luteolin (c). Fibrotic area was determined in 10 fields of high field power and expressed as mean ± standard deviation (d).
Black arrow represented loosely to densely packed collagen fibers in between neoplastic cells. Yellow arrows represented scattered papillary expansion of loosely blue band of collagen expression along the covering adipose connective tissue and extending in a fine strands in between muscle fibers. *Significant difference as compared with the control group at p<0.05. #Significant difference as compared with ESC group at p<0.05. Scale bar 100 μm.
Figure 3
Figure 3. Effect of ESC and 25 mg/kg luteolin on gene expression of Wnt.
*Significant difference as compared with control group at p<0.05. #Significant difference as compared with ESC group at p<0.05. ESC: Ehrlich solid carcinoma.
Figure 4
Figure 4. Effect of ESC and 25 mg/kg luteolin β-catenin gene expression (a) and protein level (b).
*Significant difference as compared with control group at p<0.05. #Significant difference as compared with ESC group at p<0.05. ESC: Ehrlich solid carcinoma.
Figure 5
Figure 5. Effect of ESC and 25 mg/kg luteolin on E-cadherin gene expression (a) and protein level (b).
*Significant difference as compared with control group at p<0.05. #Significant difference as compared with ESC group at p<0.05. ESC: Ehrlich solid carcinoma.
Figure 6
Figure 6. Effect of ESC and 25 mg/kg luteolin on gene expression of SMAD4 (a) and its muscle level (b).
*Significant difference as compared with control group at p<0.05. #Significant difference as compared with ESC group at p<0.05. ESC: Ehrlich solid carcinoma.
Figure 7
Figure 7. The mechanism of the protective effects of luteolin in ESC.
ESC: Ehrlich solid carcinoma. Image Credits: The authors of the manuscript.
See this image and copyright information in PMC

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