Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Molecular Pharmacology
  4. Volume 17, Issue 1
  5. Article
Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
file format pdf download PDF
side by side viewer icon HTML

Abstract

Background:

While chemotherapy treatment demonstrates its initial effectiveness in eliminating the majority of the tumor cell population, nevertheless, most patients relapse and eventually succumb to the disease upon its recurrence. One promising approach is to explore novel, effective chemotherapeutic adjuvants to enhance the sensitivity of cancer cells to conventional chemotherapeutic agents. In the present study, we explored the effect of quercetin on the sensitivity of colorectal cancer (CRC) cells to conventional chemotherapeutic agent 5-fluorouracil (5-FU) and the molecular mechanisms.

Methods:

MTT assay, colony formation assay and Hoechst staining were performed to investigate the growth inhibition effect of quercetin alone or combined with 5-FU. The expression levels of apoptosis and autophagy-related proteins were assessed by western blotting. Intracellular ROS was detected using DCFH-DA. The change in the mitochondrial membrane potential was measured by a JC-1 probe. The effect of quercetin on mitochondrial morphology was examined using a mitochondrial-specific fluorescence probe, Mito-Tracker red.

Results:

The results demonstrated quercetin induced apoptosis and autophagy, as well as imbalanced ROS, decreased mitochondrial membrane potential, and Drp-1-mediated mitochondrial fission in CRC cells. Autophagy blockage with autophagy inhibitor chloroquine (CQ) enhanced quercetin-induced cytotoxicity, indicating that quercetin induced cytoprotective autophagy. Meanwhile, quercetin enhanced the sensitivity of CRC cells to 5-FU the induction of mitochondrial fragmentation, which could be further enhanced when the quercetin-induced protective autophagy was blocked by CQ.

Conclusions:

The findings of the study suggested that quercetin could enhance the sensitivity of CRC cells to conventional agent 5-FU by regulating autophagy and Drp-1-mediated mitochondrial fragmentation. Therefore, quercetin may act as a chemotherapeutic adjuvant. Moreover, the regulation of autophagic flux may be a potential therapeutic strategy for colorectal cancer.

© 2024 The Author(s). Published by Bentham Science Publisher.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Loading

Article metrics loading...

/content/journals/cmp/10.2174/0118761429283717231222104730
2024-03-12
2024-11-26

  • From This Site

    /content/journals/cmp/10.2174/0118761429283717231222104730
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmp/17/1/BMS-CMP-2023-240.html?itemId=/content/journals/cmp/10.2174/0118761429283717231222104730&mimeType=html&fmt=ahah

References

  1. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202171320924910.3322/caac.2166033538338
     [Google Scholar]
  2. SiegelR.L. MillerK.D. Goding SauerA. FedewaS.A. ButterlyL.F. AndersonJ.C. CercekA. SmithR.A. JemalA. Colorectal cancer statistics, 2020.CA Cancer J. Clin.202070314516410.3322/caac.2160132133645
     [Google Scholar]
  3. Fortea-SanchisC. Forcadell-ComesE. Martínez-RamosD. Escrig-SosJ. Modelling the probability of erroneous negative lymph node staging in patients with colon cancer.Cancer Commun.201939111010.1186/s40880‑019‑0377‑531171042
     [Google Scholar]
  4. AdamR. de GramontA. FiguerasJ. KokudoN. KunstlingerF. LoyerE. PostonG. RougierP. Rubbia-BrandtL. SobreroA. TehC. TejparS. Van CutsemE. VautheyJ.N. PåhlmanL. of the EGOSLIM (Expert Group on OncoSurgery management of LIver Metastases) group Managing synchronous liver metastases from colorectal cancer: A multidisciplinary international consensus.Cancer Treat. Rev.201541972974110.1016/j.ctrv.2015.06.00626417845
     [Google Scholar]
  5. BlondyS. DavidV. VerdierM. MathonnetM. PerraudA. ChristouN. 5-fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes.Cancer Sci.202011193142315410.1111/cas.1453232536012
     [Google Scholar]
  6. RaufA. ImranM. KhanI.A. ur-RehmanM. GilaniS.A. MehmoodZ. MubarakM.S. Anticancer potential of quercetin: A comprehensive review.Phytother. Res.201832112109213010.1002/ptr.615530039547
     [Google Scholar]
  7. TangS.M. DengX.T. ZhouJ. LiQ.P. GeX.X. MiaoL. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects.Biomed. Pharmacother.202012110960410.1016/j.biopha.2019.10960431733570
     [Google Scholar]
  8. WangK. LiuR. LiJ. MaoJ. LeiY. WuJ. ZengJ. ZhangT. WuH. ChenL. HuangC. WeiY. Quercetin induces protective autophagy in gastric cancer cells: Involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling.Autophagy20117996697810.4161/auto.7.9.1586321610320
     [Google Scholar]
  9. KasiriN. RahmatiM. AhmadiL. EskandariN. MotedayyenH. Therapeutic potential of quercetin on human breast cancer in different dimensions.Inflammopharmacology2020281396210.1007/s10787‑019‑00660‑y31754939
     [Google Scholar]
  10. Ghafouri-FardS. ShabestariF.A. VaeziS. AbakA. ShooreiH. KarimiA. TaheriM. BasiriA. Emerging impact of quercetin in the treatment of prostate cancer.Biomed. Pharmacother.202113811154810.1016/j.biopha.2021.11154834311541
     [Google Scholar]
  11. DasP. GhoshS. AshashainyV. NayakB. Augmentation of anti-proliferative efficacy of quercetin encapsulated chitosan nanoparticles by induction of cell death via mitochondrial membrane permeabilization in oral cancer.Int. J. Biol. Macromol.202325012615110.1016/j.ijbiomac.2023.12615137544568
     [Google Scholar]
  12. SabziniM. PourmadadiM. YazdianF. Khadiv-ParsiP. RashediH. Development of chitosan/halloysite/graphitic-carbon nitride nanovehicle for targeted delivery of quercetin to enhance its limitation in cancer therapy: An in vitro cytotoxicity against MCF-7 cells.Int. J. Biol. Macromol.202322615917110.1016/j.ijbiomac.2022.11.18936435458
     [Google Scholar]
  13. Y L, W G, Y Y ZQuercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer.Apoptosis : an international journal on programmed cell death2017224544557
     [Google Scholar]
  14. LanC-Y. ChenS-Y. KuoC-W. LuC.C. YenG.C. Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells.J. Food Drug Anal.201927488789631590760
     [Google Scholar]
  15. ChoiJ.S. PiaoY.J. KangK.W. Effects of quercetin on the bioavailability of doxorubicin in rats: Role of CYP3A4 and P-gp inhibition by quercetin.Arch. Pharm. Res.201134460761310.1007/s12272‑011‑0411‑x21544726
     [Google Scholar]
  16. LeiC.S. HouY.C. PaiM.H. LinM.T. YehS.L. Effects of quercetin combined with anticancer drugs on metastasis-associated factors of gastric cancer cells: in vitro and in vivo studies.J. Nutr. Biochem.20185110511310.1016/j.jnutbio.2017.09.01129125991
     [Google Scholar]
  17. FossoE. LeoM. MuccilloL. MandroneV.M. Di MeoM.C. MolinarioA. VarricchioE. SabatinoL. Quercetin’s dual mode of action to counteract the Sp1-miR-27a axis in colorectal cancer cells.Antioxidants2023128154710.3390/antiox1208154737627542
     [Google Scholar]
  18. TangZ. WangL. ChenY. ZhengX. WangR. LiuB. ZhangS. WangH. Quercetin reverses 5-fluorouracil resistance in colon cancer cells by modulating the NRF2/HO-1 pathway.Eur. J. Histochem.2023673371910.4081/ejh.2023.371937548240
     [Google Scholar]
  19. JiangJ. ZhangL. ChenH. LeiY. ZhangT. WangY. JinP. LanJ. ZhouL. HuangZ. LiB. LiuY. GaoW. XieK. ZhouL. NiceE.C. PengY. CaoY. WeiY. WangK. HuangC. Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma.Autophagy202016110612210.1080/15548627.2019.159875230909789
     [Google Scholar]
  20. QunL YuS ZihaoL Non-coding RNAs as new autophagy regulators in cancer progression.BBA - Molecular Basis of Disease,202218681166293
     [Google Scholar]
  21. LiX. HeS. MaB. Autophagy and autophagy-related proteins in cancer.Mol. Cancer20201911210.1186/s12943‑020‑1138‑431969156
     [Google Scholar]
  22. GewirtzD.A. The four faces of autophagy: Implications for cancer therapy.Cancer Res.201474364765110.1158/0008‑5472.CAN‑13‑296624459182
     [Google Scholar]
  23. RahB. AminH. YousufK. KhanS. JamwalG. MukherjeeD. GoswamiA. A novel MMP-2 inhibitor 3-azidowithaferin A (3-azidoWA) abrogates cancer cell invasion and angiogenesis by modulating extracellular Par-4.PLoS One201279e4403910.1371/journal.pone.004403922962598
     [Google Scholar]
  24. ZengJ. LiM. XuJ.Y. XiaoH. YangX. FanJ.X. WuK. ChenS. Aberrant ROS mediate cell cycle and motility in colorectal cancer cells through an oncogenic CXCL14 signaling pathway.Front. Pharmacol.20211276401510.3389/fphar.2021.76401534744744
     [Google Scholar]
  25. WardA.B. MirH. KapurN. GalesD.N. CarriereP.P. SinghS. Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways.World J. Surg. Oncol.201816110810.1186/s12957‑018‑1400‑z29898731
     [Google Scholar]
  26. ModestD.P. PantS. Sartore-BianchiA. Treatment sequencing in metastatic colorectal cancer.Eur. J. Cancer2019109708310.1016/j.ejca.2018.12.01930690295
     [Google Scholar]
  27. VodenkovaS. BuchlerT. CervenaK. VeskrnovaV. VodickaP. VymetalkovaV. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future.Pharmacol. Ther.202020610744710.1016/j.pharmthera.2019.10744731756363
     [Google Scholar]
  28. AbduS. JuaidN. AminA. MoulayM. MiledN. Effects of sorafenib and quercetin alone or in combination in treating hepatocellular carcinoma: In vitro and in vivo approaches.Molecules20222722808210.3390/molecules2722808236432184
     [Google Scholar]
  29. ZhangX. GuoQ. ChenJ. ChenZ. Quercetin enhances cisplatin sensitivity of human osteosarcoma cells by modulating microRNA-217-KRAS Axis.Mol. Cells201538763864210.14348/molcells.2015.003726062553
     [Google Scholar]
  30. RoshanazadehM. Babaahmadi RezaeiH. RashidiM. Quercetin synergistically potentiates the anti-metastatic effect of 5-fluorouracil on the MDA-MB-231 breast cancer cell line.Iran. J. Basic Med. Sci.202124792893434712423
     [Google Scholar]
  31. LevyJ.M.M. TowersC.G. ThorburnA. Targeting autophagy in cancer.Nat. Rev. Cancer201717952854210.1038/nrc.2017.5328751651
     [Google Scholar]
  32. WuB. ZengW. OuyangW. XuQ. ChenJ. WangB. ZhangX. Quercetin induced NUPR1-dependent autophagic cell death by disturbing reactive oxygen species homeostasis in osteosarcoma cells.J. Clin. Biochem. Nutr.202067213714510.3164/jcbn.19‑12133041510
     [Google Scholar]
  33. YuT. GuoF. YuY. SunT. MaD. HanJ. QianY. KryczekI. SunD. NagarshethN. ChenY. ChenH. HongJ. ZouW. FangJ.Y. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy.Cell20171703548563.e1610.1016/j.cell.2017.07.00828753429
     [Google Scholar]
  34. XuW. WeiQ. HanM. ZhouB. WangH. ZhangJ. WangQ. SunJ. FengL. WangS. YeY. WangX. ZhouJ. JinH. CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer.Int. J. Biol. Sci.20181491054106610.7150/ijbs.2534929989092
     [Google Scholar]
  35. HuW. ZhengW. DuJ. TianZ. ZhaoY. ZhaoP. LiJ. TIPE2 sensitizes breast cancer cells to paclitaxel by suppressing drug-induced autophagy and cancer stem cell properties.Hum. Cell20233641485150010.1007/s13577‑023‑00900‑y36964413
     [Google Scholar]
  36. WestermannB. Mitochondrial fusion and fission in cell life and death.Nat. Rev. Mol. Cell Biol.2010111287288410.1038/nrm301321102612
     [Google Scholar]
  37. ZhouL. ZhangQ. ZhangP. SunL. PengC. YuanZ. ChengJ. c-Abl-mediated Drp1 phosphorylation promotes oxidative stress-induced mitochondrial fragmentation and neuronal cell death.Cell Death Dis.2017810e311710.1038/cddis.2017.52429022905
     [Google Scholar]
  38. RehmanJ. ZhangH.J. TothP.T. ZhangY. MarsboomG. HongZ. SalgiaR. HusainA.N. WietholtC. ArcherS.L. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer.FASEB J.20122652175218610.1096/fj.11‑19654322321727
     [Google Scholar]
  39. ZhaoJ. ZhangJ. YuM. XieY. HuangY. WolffD.W. AbelP.W. TuY. Mitochondrial dynamics regulates migration and invasion of breast cancer cells.Oncogene201332404814482410.1038/onc.2012.49423128392
     [Google Scholar]
  40. Inoue-YamauchiA. OdaH. Depletion of mitochondrial fission factor DRP1 causes increased apoptosis in human colon cancer cells.Biochem. Biophys. Res. Commun.20124211818510.1016/j.bbrc.2012.03.11822487795
     [Google Scholar]
  41. SinghA. KukretiR. SasoL. KukretiS. Oxidative stress: A key modulator in neurodegenerative diseases.Molecules2019248158310.3390/molecules2408158331013638
     [Google Scholar]
/content/journals/cmp/10.2174/0118761429283717231222104730
Loading
Quercetin Enhances 5-fluorouracil Sensitivity by Regulating the Autophagic Flux and Inducing Drp-1 Mediated Mitochondrial Fragmentation in Colorectal Cancer Cells
Curr Mol Pharmacol 17, e18761429283717 (2024); https://doi.org/10.2174/0118761429283717231222104730
/content/journals/cmp/10.2174/0118761429283717231222104730
/content/journals/cmp/10.2174/0118761429283717231222104730
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): Autophagic flux; Autophagy; Chemotheraphy; Colorectal cancer; Mitochondrial fragmentation; Quercetin

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test