Article

Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model.

Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
European journal of cancer (Oxford, England: 1990) (impact factor: 4.12). 03/2010; 46(10):1900-9. DOI:10.1016/j.ejca.2010.02.021 pp.1900-9
Source: PubMed

ABSTRACT Although 5-fluorouracil (5-FU)-based adjuvant chemotherapy is widely used in the treatment of colorectal cancer, novel therapeutic strategies need to be explored. It has been reported that autophagy is extensively implicated in cancer. However, the function of autophagy is not fully understood. In the present study, apoptosis induced by 5-FU in 3 human colon cancer cell lines (HCT116, DLD-1, and DLD-1/5-FU (a specific 5-FU-resistant sub-line)) was measured using MTT assay, DNA fragmentation assay, Hoechst 33342 staining, and caspase-3 immunoblotting. The autophagy activation induced by 5-FU treatment was revealed by microtubule-associated protein 1 light chain 3 (LC3) immunofluorescence and immunoblotting and p62 immunoblotting. Inhibition of autophagy by 3-methyladenine (3-MA) or small interference RNA targeting Atg7 (Atg7 siRNA) significantly augmented 5-FU-induced apoptosis. This synergistic effect of 5-FU and 3-MA was further confirmed in the DLD-1 xenograft tumour model. Tumour growth was suppressed more significantly with combination treatment than 5-FU treatment alone. In conclusion, autophagy was activated as a protective mechanism against 5-FU-induced apoptosis and its inhibition could be a promising strategy for adjuvant chemotherapy in colon cancer.

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Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

3-MA
 
5-FU treatment
 
5-FU)-based adjuvant chemotherapy
 
5-FU-induced apoptosis
 
adjuvant chemotherapy
 
apoptosis induced
 
Atg7 siRNA
 
autophagy activation induced
 
combination treatment
 
DLD-1
 
DLD-1 xenograft tumour model
 
DNA fragmentation assay
 
Hoechst 33342 staining
 
inhibition
 
microtubule-associated protein 1 light chain 3
 
MTT assay
 
novel therapeutic strategies
 
promising strategy
 
protective mechanism
 
Tumour growth