Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer

Journal of Experimental & Clinical Cancer Research

Athar Khojah³  Jawwad Ahmad³  Shakir Idris³  Amr Mohamed Mohamed²  Osama Adnan Kensara⁴  Adel Galal El-Shemi¹  Bassem Refaat³ 

[1] Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt;Clinical Laboratory Diagnosis, Department of Animal Medicine, Faculty of Veterinary Medicine, Assiut University, Assiut 71526, Egypt;Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, Makkah, Kingdom of Saudi Arabia;Clinical Nutrition Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, Makkah, Kingdom of Saudi Arabia

关键词: Therapeutic efficacy;    COX-2;    HSP-90;    iNOS;    TGF-β;    β-catenin;    Vitamin D3;    Colon cancer;   

Others  :  1221131
DOI  :  10.1186/s13046-015-0187-9

 received in 2015-06-01, accepted in 2015-07-03,  发布年份 2015

【 摘 要 】

Background

Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer.

Methods

Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU + vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of β-catenin, transforming growth factor-β1 (TGF-β1), TGF-β type 2 receptor (TGF-βR2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, β-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-β1, HSP-90 and COX-2 proteins.

Results

Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P < 0.05); however, their combination resulted in more significant tumouricidal effects (P < 0.05) compared with monotherapy groups. Mechanistically, vitamin D3/5-FU co-therapy significantly decreased the expression of Wnt, β-catenin, iNOS, COX-2 and HSP-90 and significantly increased the expression of DKK-1, TGF-β1, TGF-βR2, smad4 (P < 0.05), in comparison with their corresponding monotherapy groups.

Conclusions

Vitamin D3 and 5-FU synergise together and exhibit better anticancer effects by modulating Wnt/β-catenin pathway, TGF-β1 signals, iNOS, COX-2 and HSP-90. Further studies are required to illustrate the clinical value of vitamin D supplementation during the treatment of colon cancer with 5-FU in human patients.

【 授权许可】

   
2015 Refaat et al.

【 图 表 】

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