S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation.
Laura MoscaMartina PaganoLuigi BorzacchielloLuigi MeleAnnapina RussoGiulia RussoGiovanna CacciapuotiMarina PorcelliPublished in: International journal of molecular sciences (2021)
Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.
Keyphrases
- poor prognosis
- signaling pathway
- long non coding rna
- induced apoptosis
- pi k akt
- oxidative stress
- lps induced
- endothelial cells
- cell cycle arrest
- nuclear factor
- cell death
- drug induced
- cell proliferation
- endoplasmic reticulum stress
- induced pluripotent stem cells
- high glucose
- cell therapy
- stem cells
- early stage
- squamous cell carcinoma
- inflammatory response
- immune response
- papillary thyroid
- big data
- emergency department
- mesenchymal stem cells
- binding protein
- adverse drug
- cancer stem cells
- artificial intelligence
- deep learning
- replacement therapy
- lymph node metastasis
- stress induced