The Phenolic compound Kaempferol overcomes 5-fluorouracil resistance in human resistant LS174 colon cancer cells

• Published in: Scientific reports 2019-01, Vol.9 (1), p.195-195, Article 195
• Main Authors: Riahi-Chebbi, Ichrak, Souid, Soumaya, Othman, Houcemeddine, Haoues, Meriam, Karoui, Habib, Morel, Alain, Srairi-Abid, Najet, Essafi, Makram, Essafi-Benkhadir, Khadija
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/2; 13/21; 13/31; 13/95; 38; 5-Fluorouracil; 631/67/1504/1885/1393; 692/699/67/1504/1885/1393; 96; AKT protein; Antineoplastic Agents - pharmacology; Apoptosis; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Colorectal cancer; Drug resistance; Drug Resistance, Neoplasm - drug effects; Fluorouracil - pharmacology; Human health and pathology; Humanities and Social Sciences; Humans; Infectious diseases; Kaempferol; Kaempferols - pharmacology; Life Sciences; MAP kinase; multidisciplinary; NF-κB protein; Phenolic compounds; Phenols; Phenols - pharmacology; Reactive oxygen species; Santé publique et épidémiologie; Science; Science (multidisciplinary); Stat3 protein; Structure-Activity Relationship
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-36808-z

Resistance to 5-Fluorouracil chemotherapy is a major cause of therapeutic failure in colon cancer cure. Development of combined therapies constitutes an effective strategy to inhibit cancer cells and prevent the emergence of drug resistance. For this purpose, we investigated the anti-tumoral effect of thirteen phenolic compounds, from the Tunisian quince Cydonia oblonga Miller, alone or combined to 5-FU, on the human 5-FU-resistant LS174-R colon cancer cells in comparison to parental cells. Our results showed that only Kaempferol was able to chemo-sensitize 5-FU-resistant LS174-R cells. This phenolic compound combined with 5-FU exerted synergistic inhibitory effect on cell viability. This combination enhanced the apoptosis and induced cell cycle arrest of both chemo-resistant and sensitive cells through impacting the expression levels of different cellular effectors. Kaempferol also blocked the production of reactive oxygen species (ROS) and modulated the expression of JAK/STAT3, MAPK, PI3K/AKT and NF-κB. In silico docking analysis suggested that the potent anti-tumoral effect of Kaempferol, compared to its two analogs (Kaempferol 3-O-glucoside and Kampferol 3-O-rutinoside), can be explained by the absence of glucosyl groups. Overall, our data propose Kaempferol as a potential chemotherapeutic agent to be used alone or in combination with 5-FU to overcome colon cancer drug resistance.