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

Autor: Houcemeddine Othman, Ichrak Riahi-Chebbi, Meriam Haoues, Soumaya Souid, Makram Essafi, Habib Karoui, Alain Morel, Najet Srairi-Abid, Khadija Essafi-Benkhadir
Přispěvatelé: Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée aux Maladies Infectieuses (LR11IPT04), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of Tunis El Manar, Laboratoire des Venins et Biomolécules Thérapeutiques - Laboratory of Venoms and Therapeutic Biomolecules (LR11IPT08), Institut Pasteur de Tunis, Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by the Tunisian Ministry of Higher Education and Scientific Research (LR11IPT04/LR16IPT04) and the Institut Pasteur de Tunis (Collaborative Internal Project PCI_04_2012)., Dupuis, Christine, Université de Tunis - El Manar II, Université de Tunis El Manar (UTM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université Tunis El Manar (UTM)-Institut Pasteur de Tunis, Université Tunis El Manar (UTM), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cell Survival
Colorectal cancer
[SDV]Life Sciences [q-bio]
lcsh:Medicine
Antineoplastic Agents
Pharmacology
Article
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Phenols
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Cell Line
Tumor
medicine
Humans
Viability assay
Kaempferols
lcsh:Science
PI3K/AKT/mTOR pathway
Multidisciplinary
lcsh:R
Cell Cycle Checkpoints
Cell cycle
medicine.disease
3. Good health
030104 developmental biology
chemistry
Drug Resistance
Neoplasm
Apoptosis
Cell culture
[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie
Colonic Neoplasms
Cancer cell
[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
lcsh:Q
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Fluorouracil
Kaempferol
030217 neurology & neurosurgery
Zdroj: Scientific Reports
Scientific Reports, 2019, 9 (1), pp.195. ⟨10.1038/s41598-018-36808-z⟩
Scientific Reports, Nature Publishing Group, 2019, 9 (1), pp.195. ⟨10.1038/s41598-018-36808-z⟩
Scientific Reports, Vol 9, Iss 1, Pp 1-20 (2019)
Scientific Reports, Nature Publishing Group, 2019, 9 (1), ⟨10.1038/s41598-018-36808-z⟩
ISSN: 2045-2322
Popis: International audience; 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. Colorectal cancer (CRC) is one of the most frequently occurring malignancies worldwide 1. According to GLOBOCAN data, there were over 1.8 million new colorectal cancer cases and 881,000 deaths in 2018, accounting for about 1 in 10 cancer cases and deaths 2. Globally, colorectal cancer ranks third in terms of incidence but second in terms of mortality since 40-50% of patients develop metastatic disease (mCRC) 2,3. Although several chemotherapeutic agents have been identified to improve survival and quality of life of CRC patients 4 , 5-Fluorouracil (5-FU) remains recommended as the drug of a first choice after more than 30 years of clinical research 5. The antimetabolite drug elicits its cytotoxic effect mainly through inhibition of Thymidylate Synthase (TS), a key enzyme for catalyzing the novo synthesis of thymine 6. In CRC, 5-FU was used in monotherapy or in combination with oxaliplatin (Folfox), irinotecan (Folfiri), or irinotecan and bevacizumab (Folfiri-bevacizumab). Unfortunately, the adjuvant chemotherapeutic regimens rarely cure cancer and disease relapses from the drug-resistant cells 7. Thus, resistance, either intrinsic or acquired during the course of treatment, is a major challenge for cancer therapy 8. The development of chemoresistance can be attributed to a wide variety of mechanisms including drug influx and efflux, enhancement of drug inactivation and mutation of the drug target 9. Acquired 5-FU resistance
Databáze: OpenAIRE
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