S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation
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 ident...
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/17/9286 |
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| author | Laura Mosca Martina Pagano Luigi Borzacchiello Luigi Mele Annapina Russo Giulia Russo Giovanna Cacciapuoti Marina Porcelli |
| author_facet | Laura Mosca Martina Pagano Luigi Borzacchiello Luigi Mele Annapina Russo Giulia Russo Giovanna Cacciapuoti Marina Porcelli |
| author_sort | Laura Mosca |
| collection | DOAJ |
| description | 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 116<sup>p53+/+</sup> 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. |
| first_indexed | 2024-03-10T08:10:58Z |
| format | Article |
| id | doaj.art-994134f1ec4f47cd90cdf89007948182 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:10:58Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-994134f1ec4f47cd90cdf890079481822023-11-22T10:41:24ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012217928610.3390/ijms22179286S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB ActivationLaura Mosca0Martina Pagano1Luigi Borzacchiello2Luigi Mele3Annapina Russo4Giulia Russo5Giovanna Cacciapuoti6Marina Porcelli7Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 7, 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 7, 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 7, 80138 Naples, ItalyDepartment of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via Luciano Armanni 5, 80138 Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 7, 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio 7, 80138 Naples, ItalyColorectal 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 116<sup>p53+/+</sup> 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.https://www.mdpi.com/1422-0067/22/17/9286S-Adenosylmethioninecolorectal cancer5-Fluorouracilmultidrug resistanceP-glycoproteincombination therapy |
| spellingShingle | Laura Mosca Martina Pagano Luigi Borzacchiello Luigi Mele Annapina Russo Giulia Russo Giovanna Cacciapuoti Marina Porcelli S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation International Journal of Molecular Sciences S-Adenosylmethionine colorectal cancer 5-Fluorouracil multidrug resistance P-glycoprotein combination therapy |
| title | S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation |
| title_full | S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation |
| title_fullStr | S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation |
| title_full_unstemmed | S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation |
| title_short | S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation |
| title_sort | s adenosylmethionine increases the sensitivity of human colorectal cancer cells to 5 fluorouracil by inhibiting p glycoprotein expression and nf κb activation |
| topic | S-Adenosylmethionine colorectal cancer 5-Fluorouracil multidrug resistance P-glycoprotein combination therapy |
| url | https://www.mdpi.com/1422-0067/22/17/9286 |
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