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Volume 31, Issue 42
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Introduction

Although radiotherapy is one of the main cancer treatment modalities, exposing healthy organs/tissues to ionizing radiation during treatment and tumor resistance to ionizing radiation are the chief challenges of radiotherapy that can lead to different adverse effects. It was shown that the combined treatment of radiotherapy and natural bioactive compounds (such as silymarin/silibinin) can alleviate the ionizing radiation-induced adverse side effects and induce synergies between these therapeutic modalities. In the present review, the potential radiosensitization effects of silymarin/silibinin during cancer radiation exposure/radiotherapy were studied.

Methods

According to the PRISMA guideline, a systematic search was performed for the identification of relevant studies in different electronic databases of Google Scholar, PubMed, Web of Science, and Scopus up to October 2022. We screened 843 articles in accordance with a pre-defined set of inclusion and exclusion criteria. Seven studies were finally included in this systematic review.

Results

Compared to the control group, the cell survival/proliferation of cancer cells treated with ionizing radiation was considerably less, and silymarin/silibinin administration synergistically increased ionizing radiation-induced cytotoxicity. Furthermore, there was a decrease in the tumor volume, weight, and growth of ionizing radiation-treated mice as compared to the untreated groups, and these diminutions were predominant in those treated with radiotherapy plus silymarin/silibinin. Furthermore, the irradiation led to a set of biochemical and histopathological changes in tumoral cells/tissues, and the ionizing radiation-induced alterations were synergized following silymarin/silibinin administration (in most cases).

Conclusion

In most cases, silymarin/silibinin administration could sensitize the cancer cells to ionizing radiation through an increase of free radical formation, induction of DNA damage, increase of apoptosis, inhibition of angiogenesis and metastasis, However, suggesting the use of silymarin/silibinin during radiotherapeutic treatment of cancer patients requires further clinical studies.

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References

  1. FarhoodB. GerailyG. AlizadehA. Incidence and mortality of various cancers in Iran and compare to other countries: A review article.Iran. J. Public Health201847330931629845017
     [Google Scholar]
  2. MortezaeeK. NarmaniA. SalehiM. BagheriH. FarhoodB. Haghi-AminjanH. NajafiM. Synergic effects of nanoparticles-mediated hyperthermia in radiotherapy/chemotherapy of cancer.Life Sci.202126911902010.1016/j.lfs.2021.11902033450258
     [Google Scholar]
  3. 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]
  4. NajafiM. Hooshangi ShayestehM.R. MortezaeeK. FarhoodB. Haghi-AminjanH. The role of melatonin on doxorubicin-induced cardiotoxicity: A systematic review.Life Sci.202024111717310.1016/j.lfs.2019.11717331843530
     [Google Scholar]
  5. TalakeshT. TabatabaeeN. AtoofF. AliasgharzadehA. SarvizadeM. FarhoodB. Effect of nano-curcumin on radiotherapy-induced skin reaction in breast cancer patients: A randomized, triple-blind, placebo-controlled trial.Curr Radiopharm.2022154332340
     [Google Scholar]
  6. MortezaeeK. ParwaieW. MotevaseliE. Mirtavoos-MahyariH. MusaA.E. ShabeebD. EsmaelyF. NajafiM. FarhoodB. Targets for improving tumor response to radiotherapy.Int. Immunopharmacol.20197610584710.1016/j.intimp.2019.10584731466051
     [Google Scholar]
  7. FordE.C. TerezakisS. How safe is safe? Risk in radiotherapy.Int. J. Radiat. Oncol. Biol. Phys.201078232132210.1016/j.ijrobp.2010.04.04720832662
     [Google Scholar]
  8. BaskarR. LeeK.A. YeoR. YeohK.W. Cancer and radiation therapy: current advances and future directions.Int. J. Med. Sci.20129319319910.7150/ijms.363522408567
     [Google Scholar]
  9. MortezaeeK. NajafiM. FarhoodB. AhmadiA. ShabeebD. MusaA.E. Resveratrol as an adjuvant for normal tissues protection and tumor sensitization.Curr. Cancer Drug Targets202020213014510.2174/156800961966619101914353931738153
     [Google Scholar]
  10. FarhoodB. GerailyG. AbtahiS.M.M. A systematic review of clinical applications of polymer gel dosimeters in radiotherapy.Appl. Radiat. Isot.2019143475910.1016/j.apradiso.2018.08.01830390500
     [Google Scholar]
  11. BagheriH. Rabie MahdaviS. ShekarchiB. ManouchehriF. FarhoodB. Measurement of the contralateral breast photon and thermal neutron doses in breast cancer radiotherapy: A comparison between physical and dynamic wedges.Radiat. Prot. Dosimetry20181781738110.1093/rpd/ncx07628591863
     [Google Scholar]
  12. ModingE.J. KastanM.B. KirschD.G. Strategies for optimizing the response of cancer and normal tissues to radiation.Nat. Rev. Drug Discov.201312752654210.1038/nrd400323812271
     [Google Scholar]
  13. MortezaeeK. SalehiE. Mirtavoos-mahyariH. MotevaseliE. NajafiM. FarhoodB. RosengrenR.J. SahebkarA. Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy.J. Cell. Physiol.20192348125371255010.1002/jcp.2812230623450
     [Google Scholar]
  14. LiauwS.L. ConnellP.P. WeichselbaumR.R. New paradigms and future challenges in radiation oncology: An update of biological targets and technology.Sci. Transl. Med.20135173173sr210.1126/scitranslmed.300514823427246
     [Google Scholar]
  15. FarhoodB. GoradelN.H. MortezaeeK. KhanlarkhaniN. SalehiE. NashtaeiM.S. Mirtavoos-mahyariH. MotevaseliE. ShabeebD. MusaA.E. NajafiM. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization.Clin. Transl. Oncol.201921326827910.1007/s12094‑018‑1934‑030136132
     [Google Scholar]
  16. MortezaeeK. ShabeebD. MusaA.E. NajafiM. FarhoodB. Metformin as a radiation modifier; implications to normal tissue protection and tumor sensitization.Curr. Clin. Pharmacol.2019141415310.2174/157488471366618102514155930360725
     [Google Scholar]
  17. NarmaniA. FarhoodB. Haghi-AminjanH. MortezazadehT. AliasgharzadehA. MohseniM. NajafiM. AbbasiH. Gadolinium nanoparticles as diagnostic and therapeutic agents: Their delivery systems in magnetic resonance imaging and neutron capture therapy.J. Drug Deliv. Sci. Technol.20184445746610.1016/j.jddst.2018.01.011
     [Google Scholar]
  18. AlirezaG. BagherF. FarshidA.N. Histopathological evaluation of nanocurcumin for mitigation of radiation-induced small intestine injury.Curr Radiopharm.20221615763
     [Google Scholar]
  19. NajafiM. TaebS. FarhoodB. AminiP. NodooshanS.J. AshrafizadehM. AliasgharzadehA. VakiliZ. TavakoliS. AryafarT. MusaA.E. Imperatorin attenuates the proliferation of MCF-7 cells in combination with radiotherapy or hyperthermia.Curr. Radiopharm.202215323624110.2174/187447101566622031812220235306999
     [Google Scholar]
  20. NodooshanS.J. AminiP. AshrafizadehM. TavakoliS. AryafarT. KhalafiL. MusaA.E. MahdaviS.R. NajafiM. AhmadiA. FarhoodB. Suberosin attenuates the proliferation of MCF-7 breast cancer cells in combination with radiotherapy or hyperthermia.Curr. Drug Res. Rev.202113214815310.2174/258997751266620122810452833371865
     [Google Scholar]
  21. FarhoodB. HassanzadehG. AminiP. ShabeebD. MusaA.E. KhodamoradiE. MohseniM. AliasgharzadehA. MoradiH. NajafiM. Mitigation of radiation-induced gastrointestinal system injury using resveratrol or alpha-lipoic acid: A pilot histopathological study.Antiinflamm. Antiallergy Agents Med. Chem.202019441342410.2174/187152301866619111112402831713500
     [Google Scholar]
  22. MotallebzadehE. TamehA.A. ZavarehS.A.T. FarhoodB. AliasgharzedehA. MohseniM. Neuroprotective effect of melatonin on radiation-induced oxidative stress and apoptosis in the brainstem of rats.J. Cell. Physiol.2020235118791879810.1002/jcp.2972232324264
     [Google Scholar]
  23. YahyapourR. AminiP. SaffarH. MotevaseliE. FarhoodB. PooladvandV. ShabeebD. MusaA.E. NajafiM. Protective effect of metformin, resveratrol and alpha-lipoic acid on radiation- induced pneumonitis and fibrosis: A histopathological study.Curr. Drug Res. Rev.201911211111710.2174/258997751166619101818075831875783
     [Google Scholar]
  24. KhezerlooD. MortezazadehT. FarhoodB. SheikhzadehP. SeyfizadehN. PezhmanL. The effect of date palm seed extract as a new potential radioprotector in gamma-irradiated mice.J. Cancer Res. Ther.201915351752110.4103/jcrt.JCRT_1341_1631169213
     [Google Scholar]
  25. AliasgharzadehA. FarhoodB. AminiP. SaffarH. MotevaseliE. RezapoorS. NouruziF. ShabeebD.H. Eleojo MusaA. MohseniM. MoradiH. NajafiM. Melatonin attenuates upregulation of Duox1 and Duox2 and protects against lung injury following chest irradiation in rats.Cell J.201921323624231210428
     [Google Scholar]
  26. AzmoonfarR. AminiP. SaffarH. RezapoorS. MotevaseliE. ChekiM. YahyapourR. farhoodB. NouruziF. KhodamoradiE. ShabeebD. Eleojo MusaA. NajafiM. Metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression.Adv. Pharm. Bull.20188469770410.15171/apb.2018.07830607342
     [Google Scholar]
  27. FarhoodB. AliasgharzadehA. AminiP. SaffarH. MotevaseliE. RezapoorS. NouruziF. ShabeebD. Eleojo MusaA. AshabiG. MohseniM. MoradiH. NajafiM. Radiation-induced dual oxidase upregulation in rat heart tissues: Protective effect of melatonin.Medicina201955731710.3390/medicina5507031731252673
     [Google Scholar]
  28. NajafiM. MotevaseliE. ShiraziA. GerailyG. RezaeyanA. NorouziF. RezapoorS. AbdollahiH. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications.Int. J. Radiat. Biol.201894433535610.1080/09553002.2018.144009229504497
     [Google Scholar]
  29. AllisonR. DickerA. Minimizing morbidity in radiation oncology: a special issue from future oncology.Future Oncol.201410152303230510.2217/fon.14.19525525839
     [Google Scholar]
  30. ArabzadehA. MortezazadehT. AryafarT. GharepapaghE. MajdaeenM. FarhoodB. Therapeutic potentials of resveratrol in combination with radiotherapy and chemotherapy during glioblastoma treatment: A mechanistic review.Cancer Cell Int.202121139110.1186/s12935‑021‑02099‑034289841
     [Google Scholar]
  31. SheikholeslamiS. KhodaverdianS. Dorri-GivM. Mohammad HosseiniS. SouriS. Abedi-FirouzjahR. ZamaniH. DastranjL. FarhoodB. The radioprotective effects of alpha-lipoic acid on radiotherapy-induced toxicities: A systematic review.Int. Immunopharmacol.20219610774110.1016/j.intimp.2021.10774133989970
     [Google Scholar]
  32. AminiP. NodooshanS.J. AshrafizadehM. EftekhariS-M. AryafarT. KhalafiL. MusaA.E. MahdaviS.R. NajafiM. FarhoodB. Resveratrol induces apoptosis and attenuates proliferation of MCF-7 cells in combination with radiation and hyperthermia.Curr. Mol. Med.202121214215010.2174/18755666MTA2pODE0z32436827
     [Google Scholar]
  33. AhmedR.F. MoussaR.A. EldemerdashR.S. ZakariaM.M. Abdel-GaberS.A. Ameliorative effects of silymarin on HCl-induced acute lung injury in rats; role of the Nrf-2/HO-1 pathway.Iran. J. Basic Med. Sci.201922121483149232133068
     [Google Scholar]
  34. ComelliM.C. MengsU. SchneiderC. ProsdocimiM. Toward the definition of the mechanism of action of silymarin: Activities related to cellular protection from toxic damage induced by chemotherapy.Integr. Cancer Ther.20076212012910.1177/153473540730234917548791
     [Google Scholar]
  35. de OliveiraD.R. TintinoS.R. BragaM.F. BoligonA.A. AthaydeM.L. CoutinhoH.D. de MenezesI.R. FachinettoR. In vitro antimicrobial and modulatory activity of the natural products silymarin and silibinin.BioMed Res. Int.2015201529279725866771
     [Google Scholar]
  36. FerenciP. Silymarin in the treatment of liver diseases: What is the clinical evidence?Clin. Liver Dis.20167181010.1002/cld.52231041017
     [Google Scholar]
  37. FerenciP. DragosicsB. DittrichH. FrankH. BendaL. LochsH. MerynS. BaseW. SchneiderB. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.J. Hepatol.19899110511310.1016/0168‑8278(89)90083‑42671116
     [Google Scholar]
  38. AbenavoliL. MilicN. Silymarin for liver disease.Liver Pathophysiology. MurielP. BostonAcademic Press201762163110.1016/B978‑0‑12‑804274‑8.00045‑X
     [Google Scholar]
  39. GazákR. WalterováD. KrenV. Silybin and silymarin--new and emerging applications in medicine.Curr. Med. Chem.200714331533810.2174/09298670777994115917305535
     [Google Scholar]
  40. TestinoG. LeoneS. AnsaldiF. BorroP. Silymarin and S-adenosyl-L-methionine (SAMe): Two promising pharmacological agents in case of chronic alcoholic hepathopathy. A review and a point of view.Minerva Gastroenterol. Dietol.201359434135624212353
     [Google Scholar]
  41. ZholobenkoA. ModrianskyM. Silymarin and its constituents in cardiac preconditioning.Fitoterapia20149712213210.1016/j.fitote.2014.05.01624879900
     [Google Scholar]
  42. Vargas-MendozaN. Madrigal-SantillánE. Morales-GonzálezA. Esquivel-SotoJ. Esquivel-ChirinoC. García-Luna Y González-RubioM. Gayosso-de-LucioJ.A. Morales-GonzálezJ.A. Hepatoprotective effect of silymarin.World J. Hepatol.20146314414910.4254/wjh.v6.i3.14424672644
     [Google Scholar]
  43. SuraiP. Silymarin as a natural antioxidant: An overview of the current evidence and perspectives.Antioxidants20154120424710.3390/antiox401020426785346
     [Google Scholar]
  44. GuzelS. SahinogullariZ.U. CanacankatanN. AntmenS.E. KibarD. Coskun YilmazB. Potential renoprotective effects of silymarin against vancomycin-induced nephrotoxicity in rats.Drug Chem. Toxicol.202043663063610.1080/01480545.2019.158420830862206
     [Google Scholar]
  45. ZhuZ. SunG. Silymarin mitigates lung impairments in a rat model of acute respiratory distress syndrome.Inflammopharmacology201826374775410.1007/s10787‑017‑0407‑329098546
     [Google Scholar]
  46. SinghM. KadhimM.M. Turki JalilA. OudahS.K. AminovZ. AlsaikhanF. JawharZ.H. Ramírez-CoronelA.A. FarhoodB. A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity.Cancer Cell Int.20232318810.1186/s12935‑023‑02936‑437165384
     [Google Scholar]
  47. TalebA AhmadKA IhsanAU QuJ LinN HezamK Antioxidant effects and mechanism of silymarin in oxidative stress induced cardiovascular diseases.Biomed. Pharmacother.201810268969810.1016/j.biopha.2018.03.140
     [Google Scholar]
  48. FerrazA.C. AlmeidaL.T. da Silva CaetanoC.C. da Silva MenegattoM.B. Souza LimaR.L. de SennaJ.P.N. de Oliveira CardosoJ.M. PerucciL.O. TalvaniA. Geraldo de LimaW. de Mello SilvaB. Barbosa ReisA. de MagalhãesJ.C. Lopes de Brito MagalhãesC. Hepatoprotective, antioxidant, anti-inflammatory, and antiviral activities of silymarin against mayaro virus infection.Antiviral Res.202119410516810.1016/j.antiviral.2021.10516834437912
     [Google Scholar]
  49. Post-WhiteJ. LadasE.J. KellyK.M. Advances in the use of milk thistle (Silybum marianum).Integr. Cancer Ther.20076210410910.1177/153473540730163217548789
     [Google Scholar]
  50. HosseinabadiT. LorigooiniZ. TabarzadM. SalehiB. RodriguesC.F. MartinsN. Sharifi-RadJ. Silymarin antiproliferative and apoptotic effects: Insights into its clinical impact in various types of cancer.Phytother. Res.201933112849286110.1002/ptr.647031407422
     [Google Scholar]
  51. Abd EldaimM.A. BarakatE.R. AlkafafyM. ElazizS.A.A. Antioxidant and anti-apoptotic prophylactic effect of silymarin against lead-induced hepatorenal toxicity in rats.Environ. Sci. Pollut. Res. Int.20212841579975800610.1007/s11356‑021‑14722‑834100211
     [Google Scholar]
  52. BarrosT.M.B. LimaA.P.B. AlmeidaT.C. da SilvaG.N. Inhibition of urinary bladder cancer cell proliferation by silibinin.Environ. Mol. Mutagen.202061444545510.1002/em.2236332078183
     [Google Scholar]
  53. YuH.C. ChenL.J. ChengK.C. LiY.X. YehC.H. ChengJ.T. Silymarin inhibits cervical cancer cell through an increase of phosphatase and tensin homolog.Phytother. Res.201226570971510.1002/ptr.361822016029
     [Google Scholar]
  54. WuT. LiuW. GuoW. ZhuX. Silymarin suppressed lung cancer growth in mice via inhibiting myeloid-derived suppressor cells.Biomed. Pharmacother.20168146046710.1016/j.biopha.2016.04.03927261626
     [Google Scholar]
  55. KimS.H. ChooG.S. YooE.S. WooJ.S. LeeJ.H. HanS.H. JungS.H. KimH.J. JungJ.Y. Silymarin inhibits proliferation of human breast cancer cells via regulation of the MAPK signaling pathway and induction of apoptosis.Oncol. Lett.202121649210.3892/ol.2021.1275333968208
     [Google Scholar]
  56. FéherJ. LengyelG. Silymarin in the prevention and treatment of liver diseases and primary liver cancer.Curr. Pharm. Biotechnol.201213121021710.2174/13892011279886881821466434
     [Google Scholar]
  57. KoltaiT. FliegelL. Role of silymarin in cancer treatment: Facts, hypotheses, and questions.J. Evid. Based Integr. Med.2022272515690x211068826
     [Google Scholar]
  58. SinghR.P. AgarwalR. Flavonoid antioxidant silymarin and skin cancer.Antioxid. Redox Signal.20024465566310.1089/1523086026022016612230878
     [Google Scholar]
  59. ZhuW. ZhangJ.S. YoungC.Y. Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP.Carcinogenesis20012291399140310.1093/carcin/22.9.139911532861
     [Google Scholar]
  60. MoherD LiberatiA TetzlaffJ AltmanDG Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.Ann. Intern. Med.200915142649, w64
     [Google Scholar]
  61. NambiarD.K. RajamaniP. DeepG. JainA.K. AgarwalR. SinghR.P. Silibinin preferentially radiosensitizes prostate cancer by inhibiting DNA repair signaling.Mol. Cancer Ther.201514122722273410.1158/1535‑7163.MCT‑15‑034826516160
     [Google Scholar]
  62. NambiarD.K. RajamaniP. SinghR.P. Silibinin attenuates ionizing radiation-induced pro-angiogenic response and EMT in prostate cancer cells.Biochem. Biophys. Res. Commun.2015456126226810.1016/j.bbrc.2014.11.06925446081
     [Google Scholar]
  63. LalM. GuptaD. Studies on radiation sensitization efficacy by silymarin in colon carcinoma cells.Discoveries201641e5610.15190/d.2016.332309577
     [Google Scholar]
  64. Prack Mc CormickB. LangleY. BelgoroskyD. VanzulliS. BalarinoN. SandesE. EijánA.M. Flavonoid silybin improves the response to radiotherapy in invasive bladder cancer.J. Cell. Biochem.201811975402541210.1002/jcb.2669329363820
     [Google Scholar]
  65. BilgicE. TuncelN. KocaT. Radio-sensitivity on MCF-7 cells of silver nanoparticles synthesized by Silybum marianum.Inorgan Nano-Met Chem202119
     [Google Scholar]
  66. RajputM. MishraD. KumarK. SinghR.P. Silibinin radiosensitizes egf receptor-knockdown prostate cancer cells by attenuating DNA repair pathways.J. Cancer Prev.202227317018110.15430/JCP.2022.27.3.17036258717
     [Google Scholar]
  67. LalM. Ahmad KhanS. GuptaD. Silymarin mediates apoptosis through activation of jnk/erk signaling pathway in human colon carcinoma cells in response to ( 60 Co) gamma radiation.Acta Scientific Cancer Biology202266011310.31080/ASCB.2022.06.0388
     [Google Scholar]
  68. LatacelaG.A. RamaiahP. PatraI. JalilA.T. GuptaR. MadaminovF.A. Shaker ShafikS. Al-GazallyM.E. AnsariM.J. KandeelM. MustafaY.F. FarhoodB. The radioprotective potentials of silymarin/silibinin against radiotherapy- induced toxicities: A systematic review of clinical and experimental studies.Curr. Med. Chem.202330333775379710.2174/092986733066622112415533936424777
     [Google Scholar]
  69. GhodousiM. KarbasforooshanH. ArabiL. ElyasiS. Silymarin as a preventive or therapeutic measure for chemotherapy and radiotherapy-induced adverse reactions: A comprehensive review of preclinical and clinical data.Eur. J. Clin. Pharmacol.2023791153810.1007/s00228‑022‑03434‑836450892
     [Google Scholar]
  70. RamadanL.A. RoushdyH.M. Abu SennaG.M. AminN.E. El-DeshwO.A. Radioprotective effect of silymarin against radiation induced hepatotoxicity.Pharmacol. Res.200245644745410.1006/phrs.2002.099012162944
     [Google Scholar]
  71. TiwariP. KumarA. AliM. MishraK.P. Radioprotection of plasmid and cellular DNA and Swiss mice by silibinin.Mutat. Res. Genet. Toxicol. Environ. Mutagen.20106951-2556010.1016/j.mrgentox.2009.11.00719945544
     [Google Scholar]
  72. Becker-SchiebeM. MengsU. SchaeferM. BulittaM. HoffmannW. Topical use of a silymarin-based preparation to prevent radiodermatitis : Results of a prospective study in breast cancer patients.Strahlenther. Onkol.2011187848549110.1007/s00066‑011‑2204‑z21786113
     [Google Scholar]
  73. SonY. LeeH.J. RhoJ.K. ChungS.Y. LeeC.G. YangK. KimS.H. LeeM. ShinI.S. KimJ.S. The ameliorative effect of silibinin against radiation-induced lung injury: Protection of normal tissue without decreasing therapeutic efficacy in lung cancer.BMC Pulm. Med.20151516810.1186/s12890‑015‑0055‑626143275
     [Google Scholar]
  74. AdhikariM. AroraR. The flavonolignan-silymarin protects enzymatic, hematological, and immune system against γ-radiation-induced toxicity.Environ. Toxicol.201631664165410.1002/tox.2207625411116
     [Google Scholar]
  75. KimJ.S. HanN.K. KimS.H. LeeH.J. Silibinin attenuates radiation-induced intestinal fibrosis and reverses epithelial-to-mesenchymal transition.Oncotarget2017841693866939710.18632/oncotarget.2062429050211
     [Google Scholar]
  76. ElyasiS. HosseiniS. Niazi MoghadamM.R. AledavoodS.A. KarimiG. Effect of oral silymarin administration on prevention of radiotherapy induced mucositis: A randomized, double-blinded, placebo-controlled clinical trial.Phytother. Res.201630111879188510.1002/ptr.570427555604
     [Google Scholar]
  77. FatehiD. MohammadiM. ShekarchiB. ShabaniA. SeifyM. RostamzadehA. Radioprotective effects of Silymarin on the sperm parameters of NMRI mice irradiated with γ-rays.J. Photochem. Photobiol. B201817848949510.1016/j.jphotobiol.2017.12.00429232573
     [Google Scholar]
  78. KarbasforooshanH. HosseiniS. ElyasiS. Fani PakdelA. KarimiG. Topical silymarin administration for prevention of acute radiodermatitis in breast cancer patients: A randomized, double-blind, placebo-controlled clinical trial.Phytother. Res.201933237938610.1002/ptr.623130479044
     [Google Scholar]
  79. MohamedM.A.E.H. MohammedH.S. MostafaS.A. IbrahimM.T. Protective effects of Saraca indica L. leaves extract (family Fabaceae) against gamma irradiation induced injury in the kidney of female albino rats.Environ. Toxicol.202136450651910.1002/tox.2305633166054
     [Google Scholar]
  80. DheerajA. TailorD. SinghS.P. SinghR.P. Anticancer attributes of silibinin: Chemo-and radiosensitization of cancer.Role of Nutraceuticals in Cancer Chemosensitization.Elsevier2018199220
     [Google Scholar]
  81. WangJ. WangH. QianH. Biological effects of radiation on cancer cells.Mil. Med. Res.2018512010.1186/s40779‑018‑0167‑429958545
     [Google Scholar]
  82. AshrafizadehM. FarhoodB. Eleojo MusaA. TaebS. NajafiM. The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives.Int. Immunopharmacol.20208710680710.1016/j.intimp.2020.10680732683299
     [Google Scholar]
  83. IliakisG. WangY. GuanJ. WangH. DNA damage checkpoint control in cells exposed to ionizing radiation.Oncogene200322375834584710.1038/sj.onc.120668212947390
     [Google Scholar]
  84. PriseK.M. SchettinoG. FolkardM. HeldK.D. New insights on cell death from radiation exposure.Lancet Oncol.20056752052810.1016/S1470‑2045(05)70246‑115992701
     [Google Scholar]
  85. LeeS.Y. JeongE.K. JuM.K. JeonH.M. KimM.Y. KimC.H. ParkH.G. HanS.I. KangH.S. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation.Mol. Cancer20171611010.1186/s12943‑016‑0577‑428137309
     [Google Scholar]
  86. CheungC.W. VeseyD.A. NicolD.L. JohnsonD.W. Silibinin inhibits renal cell carcinoma via mechanisms that are independent of insulin-like growth factor-binding protein 3.BJU Int.200799245446010.1111/j.1464‑410X.2007.06571.x17313429
     [Google Scholar]
  87. BhatiaN. ZhaoJ. WolfD.M. AgarwalR. Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: Comparison with silymarin.Cancer Lett.19991471-2778410.1016/S0304‑3835(99)00276‑110660092
     [Google Scholar]
  88. CuiH. LiT.L. GuoH.F. WangJ.L. XueP. ZhangY. FanJ.H. LiZ.P. GaoY.J. Silymarin-mediated regulation of the cell cycle and DNA damage response exerts antitumor activity in human hepatocellular carcinoma.Oncol. Lett.201815188589229399153
     [Google Scholar]
  89. YurtcuE. İşeriÖ.D. SahinF.I. Genotoxic and cytotoxic effects of doxorubicin and silymarin on human hepatocellular carcinoma cells.Hum. Exp. Toxicol.201433121269127610.1177/096032711452945324677352
     [Google Scholar]
  90. DeepG. SinghR.P. AgarwalC. KrollD.J. AgarwalR. Silymarin and silibinin cause G1 and G2–M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: A comparison of flavanone silibinin with flavanolignan mixture silymarin.Oncogene20062571053106910.1038/sj.onc.120914616205633
     [Google Scholar]
  91. AshrafizadehM. TaebS. Haghi-AminjanH. AfrashiS. MoloudiK. MusaA.E. NajafiM. FarhoodB. Resveratrol as an enhancer of apoptosis in cancer: A mechanistic review.Anticancer. Agents Med. Chem.202121172327233610.2174/187152062066620102016034833081687
     [Google Scholar]
  92. MortezaeeK. NajafiM. FarhoodB. AhmadiA. PotesY. ShabeebD. MusaA.E. Modulation of apoptosis by melatonin for improving cancer treatment efficiency: An updated review.Life Sci.201922822824110.1016/j.lfs.2019.05.00931077716
     [Google Scholar]
  93. JangJ.S. KimK.M. KangK.H. ChoiJ.E. LeeW.K. KimC.H. KangY.M. KamS. KimI.S. JunJ.E. JungT.H. ParkJ.Y. Polymorphisms in the survivin gene and the risk of lung cancer.Lung Cancer2008601313910.1016/j.lungcan.2007.09.00817961802
     [Google Scholar]
  94. Akbari-KordkheyliV Abbaszadeh-GoudarziK Nejati-LaskokalayehM ZarpouS Khonakdar-TarsiA The protective effects of silymarin on ischemia-reperfusion injuries: A mechanistic review.Iran J Basic Med Sci.2019229968
     [Google Scholar]
  95. FischerT.W. ZmijewskiM.A. WortsmanJ. SlominskiA. Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes.J. Pineal Res.200844439740710.1111/j.1600‑079X.2007.00542.x18086147
     [Google Scholar]
  96. MoutabianH. MajdaeenM. Ghahramani-AslR. YadollahiM. GharepapaghE. AtaeiG. FalahatpourZ. BagheriH. FarhoodB. A systematic review of the therapeutic effects of resveratrol in combination with 5-fluorouracil during colorectal cancer treatment: with a special focus on the oxidant, apoptotic, and anti-inflammatory activities.Cancer Cell Int.202222114210.1186/s12935‑022‑02561‑735366874
     [Google Scholar]
  97. WuX-Y. ZhaiJ. HuanX-K. XuW-W. TianJ. FarhoodB. A systematic review of the therapeutic potential of resveratrol during colorectal cancer chemotherapy.Mini Rev. Med. Chem.202236173048
     [Google Scholar]
  98. SantivasiW.L. XiaF. Ionizing radiation-induced DNA damage, response, and repair.Antioxid. Redox Signal.201421225125910.1089/ars.2013.566824180216
     [Google Scholar]
  99. SurovaO. ZhivotovskyB. Various modes of cell death induced by DNA damage.Oncogene201332333789379710.1038/onc.2012.55623208502
     [Google Scholar]
  100. GudkovA.V. KomarovaE.A. The role of p53 in determining sensitivity to radiotherapy.Nat. Rev. Cancer20033211712910.1038/nrc99212563311
     [Google Scholar]
  101. FeiP. El-DeiryW.S. P53 and radiation responses.Oncogene200322375774578310.1038/sj.onc.120667712947385
     [Google Scholar]
  102. AdhyaAK SrinivasanR PatelFD Radiation therapy induced changes in apoptosis and its major regulatory proteins, Bcl-2, Bcl-XL, and Bax, in locally advanced invasive squamous cell carcinoma of the cervix.Int. J. Gynecol. Pathol.2006253281287
     [Google Scholar]
  103. SakakuraC. SweeneyE.A. ShirahamaT. IgarashiY. HakomoriS. NakataniH. TsujimotoH. ImanishiT. OhgakiM. OhyamaT. YamazakiJ. HagiwaraA. YamaguchiT. SawaiK. TakahashiT. Overexpression of bax sensitizes human breast cancer MCF-7 cells to radiation-induced apoptosis.Int. J. Cancer199667110110510.1002/(SICI)1097‑0215(19960703)67:1<101::AID‑IJC17>3.0.CO;2‑H8690508
     [Google Scholar]
  104. JänickeR.U. SprengartM.L. WatiM.R. PorterA.G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis.J. Biol. Chem.1998273169357936010.1074/jbc.273.16.93579545256
     [Google Scholar]
  105. GondoH.K. The effect of spirulina on apoptosis through the caspase-3 pathway in a Preeclamptic Wistar rat model.J. Nat. Sci. Biol. Med.2021123280284
     [Google Scholar]
  106. YardımA. KucuklerS. ÖzdemirS. ÇomaklıS. CaglayanC. KandemirF.M. ÇelikH. Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats.Gene202176914523910.1016/j.gene.2020.14523933069805
     [Google Scholar]
  107. SuC. Survivin in survival of hepatocellular carcinoma.Cancer Lett.2016379218419010.1016/j.canlet.2015.06.01626118774
     [Google Scholar]
  108. RödelF. HoffmannJ. DistelL. HerrmannM. NoisternigT. PapadopoulosT. SauerR. RödelC. Survivin as a radioresistance factor, and prognostic and therapeutic target for radiotherapy in rectal cancer.Cancer Res.200565114881488710.1158/0008‑5472.CAN‑04‑302815930309
     [Google Scholar]
  109. MobahatM. NarendranA. RiabowolK. Survivin as a preferential target for cancer therapy.Int. J. Mol. Sci.20141522494251610.3390/ijms1502249424531137
     [Google Scholar]
  110. VaidM. SinghT. PrasadR. KatiyarS.K. Silymarin inhibits melanoma cell growth both in vitro and in vivo by targeting cell cycle regulators, angiogenic biomarkers and induction of apoptosis.Mol. Carcinog.201554111328133910.1002/mc.2220825174976
     [Google Scholar]
  111. FanL. MaY. LiuY. ZhengD. HuangG. Silymarin induces cell cycle arrest and apoptosis in ovarian cancer cells.Eur. J. Pharmacol.2014743798810.1016/j.ejphar.2014.09.01925242120
     [Google Scholar]
  112. KimK.W. ChoiC.H. KimT.H. KwonC.H. WooJ.S. KimY.K. Silibinin inhibits glioma cell proliferation via Ca2+/ROS/MAPK-dependent mechanism in vitro and glioma tumor growth in vivo.Neurochem. Res.20093481479149010.1007/s11064‑009‑9935‑619263218
     [Google Scholar]
  113. SinghR.P. RainaK. SharmaG. AgarwalR. Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice.Clin. Cancer Res.200814237773778010.1158/1078‑0432.CCR‑08‑130919047104
     [Google Scholar]
  114. WangY.X. CaiH. JiangG. ZhouT.B. WuH. Silibinin inhibits proliferation, induces apoptosis and causes cell cycle arrest in human gastric cancer MGC803 cells via STAT3 pathway inhibition.Asian Pac. J. Cancer Prev.201415166791679810.7314/APJCP.2014.15.16.679125169527
     [Google Scholar]
  115. WonD.H. KimL.H. JangB. YangI.H. KwonH.J. JinB. OhS.H. KangJ.H. HongS.D. ShinJ.A. ChoS.D. In vitro and in vivo anti-cancer activity of silymarin on oral cancer.Tumour Biol.201840510.1177/101042831877617029764340
     [Google Scholar]
  116. NambiarD. PrajapatiV. AgarwalR. SinghR.P. In vitro and in vivo anticancer efficacy of silibinin against human pancreatic cancer BxPC-3 and PANC-1 cells.Cancer Lett.2013334110911710.1016/j.canlet.2012.09.00423022268
     [Google Scholar]
  117. WangY. YuanA.J. WuY.J. WuL.M. ZhangL. Silymarin in cancer therapy: Mechanisms of action, protective roles in chemotherapy-induced toxicity, and nanoformulations.J. Funct. Foods202310010538410.1016/j.jff.2022.105384
     [Google Scholar]
  118. MashhadiA.B.M. MashhadiA.B.M. GolmohammadS. Overview of Silibinin anti-tumor effects.J. Herb. Med.20202310037510.1016/j.hermed.2020.100375
     [Google Scholar]
  119. ShiW HouX BaoX HouW JiangX MaL Mechanism and protection of radiotherapy induced sensorineural hearing loss for head and neck cancer.Biomed Res Int.20212021354870610.1155/2021/3548706
     [Google Scholar]
  120. BrownL. BenchimolS. The involvement of MAPK signaling pathways in determining the cellular response to p53 activation: cell cycle arrest or apoptosis.J. Biol. Chem.200628173832384010.1074/jbc.M50795120016330547
     [Google Scholar]
  121. HariyantiT. MargianaR. Al-GazallyM.E. PatraI. Lateef Al-AwsiG.R. HameedN. KayumovaD. AnsariM.J. Torres-CriolloL.M. MustafaY.F. Abedi-FirouzjahR. FarhoodB. The protective effects of silymarin on the reproductive toxicity: A comprehensive review.Curr. Med. Chem.202330394421444910.2174/092986733066623013011533236717999
     [Google Scholar]
  122. HoxhajG. ManningB.D. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism.Nat. Rev. Cancer2020202748810.1038/s41568‑019‑0216‑731686003
     [Google Scholar]
  123. LiH.F. KimJ.S. WaldmanT. Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells.Radiat. Oncol.2009414310.1186/1748‑717X‑4‑4319828040
     [Google Scholar]
  124. HeinA.L. OuelletteM.M. YanY. Radiation-induced signaling pathways that promote cancer cell survival (Review).Int. J. Oncol.20144551813181910.3892/ijo.2014.261425174607
     [Google Scholar]
  125. MaramponF. CiccarelliC. ZaniB.M. Biological rationale for targeting MEK/ERK pathways in anti-cancer therapy and to potentiate tumour responses to radiation.Int. J. Mol. Sci.20192010253010.3390/ijms2010253031126017
     [Google Scholar]
  126. LeeK.B. KimK-R. HuhT-L. LeeY.M. Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways.Int. J. Oncol.20083361247125619020758
     [Google Scholar]
  127. ChoiE.S. OhS. JangB. YuH.J. ShinJ.A. ChoN.P. YangI.H. WonD.H. KwonH.J. HongS.D. ChoS.D. Silymarin and its active component silibinin act as novel therapeutic alternatives for salivary gland cancer by targeting the ERK1/2-Bim signaling cascade.Cell Oncol.201740323524610.1007/s13402‑017‑0318‑828401485
     [Google Scholar]
  128. SinghR.P. DhanalakshmiS. MohanS. AgarwalC. AgarwalR. Silibinin inhibits UVB- and epidermal growth factor–induced mitogenic and cell survival signaling involving activator protein-1 and nuclear factor-κB in mouse epidermal JB6 cells.Mol. Cancer Ther.2006551145115310.1158/1535‑7163.MCT‑05‑047816731746
     [Google Scholar]
  129. BowmanT. GarciaR. TurksonJ. JoveR. STATs in oncogenesis.Oncogene200019212474248810.1038/sj.onc.120352710851046
     [Google Scholar]
  130. BrombergJ.F. Activation of STAT proteins and growth control.BioEssays200123216116910.1002/1521‑1878(200102)23:2<161::AID‑BIES1023>3.0.CO;2‑011169589
     [Google Scholar]
  131. BrombergJ. Stat proteins and oncogenesis.J. Clin. Invest.200210991139114210.1172/JCI021561711994401
     [Google Scholar]
  132. Epling-BurnetteP.K. LiuJ.H. Catlett-FalconeR. TurksonJ. OshiroM. KothapalliR. LiY. WangJ.M. Yang-YenH.F. KarrasJ. JoveR. LoughranT.P.Jr Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression.J. Clin. Invest.2001107335136210.1172/JCI994011160159
     [Google Scholar]
  133. YuH. JoveR. The STATs of cancer — new molecular targets come of age.Nat. Rev. Cancer2004429710510.1038/nrc127514964307
     [Google Scholar]
  134. ParkS.Y. LeeC.J. ChoiJ.H. KimJ.H. KimJ.W. KimJ.Y. NamJ.S. The JAK2/STAT3/CCND2 Axis promotes colorectal cancer stem cell persistence and radioresistance.J. Exp. Clin. Cancer Res.201938139910.1186/s13046‑019‑1405‑731511084
     [Google Scholar]
  135. LuL. DongJ. WangL. XiaQ. ZhangD. KimH. YinT. FanS. ShenQ. Activation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide.Oncogene201837395292530410.1038/s41388‑018‑0340‑y29855616
     [Google Scholar]
  136. LiF. GaoL. WangZ. DongB. YanT. JiangQ. ChenX. Radiation enhances the invasion abilities of pulmonary adenocarcinoma cells via STAT3.Mol. Med. Rep.2013761883188810.3892/mmr.2013.144123620191
     [Google Scholar]
  137. Singh-GuptaV. ZhangH. BanerjeeS. KongD. RaffoulJ.J. SarkarF.H. HillmanG.G. Radiation-induced HIF-1α cell survival pathway is inhibited by soy isoflavones in prostate cancer cells.Int. J. Cancer200912471675168410.1002/ijc.2401519101986
     [Google Scholar]
  138. WangX. ZhangX. QiuC. YangN. STAT3 contributes to radioresistance in cancer.Front. Oncol.202010112010.3389/fonc.2020.0112032733808
     [Google Scholar]
  139. GaurP. BoseD. SamuelS. EllisL.M. Eds.; Targeting tumor angiogenesis.Seminars in oncology.Elsevier2009
     [Google Scholar]
  140. KanthouC. TozerG. Targeting the vasculature of tumours: Combining VEGF pathway inhibitors with radiotherapy.Br. J. Radiol.20199210932018040530160184
     [Google Scholar]
  141. BachtiaryB. SelzerE. KnockeT.H. PötterR. ObermairA. Serum VEGF levels in patients undergoing primary radiotherapy for cervical cancer: impact on progression-free survival.Cancer Lett.2002179219720310.1016/S0304‑3835(01)00872‑211888674
     [Google Scholar]
  142. ChenHH SuW-C ChouC-Y GuoH-R HoS-Y QueJ Increased expression of nitric oxide synthase and cyclooxygenase-2 is associated with poor survival in cervical cancer treated with radiotherapy.Int. J. Radiat. Oncol Biol. Phys.2005634109310010.1016/j.ijrobp.2005.03.062
     [Google Scholar]
  143. SolbergTD NearmanJ MullinsJ LiS Baranowska-KortylewiczJ Correlation between tumor growth delay and expression of cancer and host VEGF, VEGFR2, and osteopontin in response to radiotherapy.Int. J. Radiat. Oncol. Biol. Phys.2008723918926
     [Google Scholar]
  144. KleibeukerE.A. GriffioenA.W. VerheulH.M. SlotmanB.J. ThijssenV.L. Combining angiogenesis inhibition and radiotherapy: A double-edged sword.Drug Resist. Updat.201215317318210.1016/j.drup.2012.04.00222561672
     [Google Scholar]
  145. SonveauxP. BrouetA. HavauxX. GrégoireV. DessyC. BalligandJ-L. FeronO. Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway: Implications for tumor radiotherapy.Cancer Res.20036351012101912615716
     [Google Scholar]
  146. DeepG. GangarS.C. RajamanickamS. RainaK. GuM. AgarwalC. OberliesN.H. AgarwalR. Angiopreventive efficacy of pure flavonolignans from milk thistle extract against prostate cancer: Targeting VEGF-VEGFR signaling.PLoS One201274e3463010.1371/journal.pone.003463022514647
     [Google Scholar]
  147. DeepG. RainaK. SinghR.P. OberliesN.H. KrollD.J. AgarwalR. Isosilibinin inhibits advanced human prostate cancer growth in athymic nude mice: Comparison with silymarin and silibinin.Int. J. Cancer2008123122750275810.1002/ijc.2387918798272
     [Google Scholar]
  148. SinghR.P. SharmaG. DhanalakshmiS. AgarwalC. AgarwalR. Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis.Cancer Epidemiol. Biomarkers Prev.200312993393914504208
     [Google Scholar]
  149. TyagiA. AgarwalC. Dwyer-NieldL.D. SinghR.P. MalkinsonA.M. AgarwalR. Silibinin modulates TNF-α and IFN-γ mediated signaling to regulate COX2 and iNOS expression in tumorigenic mouse lung epithelial LM2 cells.Mol. Carcinog.2012511083284210.1002/mc.2085121882257
     [Google Scholar]
  150. SinghR.P. DeepG. ChittezhathM. KaurM. Dwyer-NieldL.D. MalkinsonA.M. AgarwalR. Effect of silibinin on the growth and progression of primary lung tumors in mice.J. Natl. Cancer Inst.2006981284685510.1093/jnci/djj23116788158
     [Google Scholar]
  151. RamasamyK. Dwyer-NieldL.D. SerkovaN.J. HasebroockK.M. TyagiA. RainaK. SinghR.P. MalkinsonA.M. AgarwalR. Silibinin prevents lung tumorigenesis in wild-type but not in iNOS-/- mice: potential of real-time micro-CT in lung cancer chemoprevention studies.Clin. Cancer Res.201117475376110.1158/1078‑0432.CCR‑10‑229021148748
     [Google Scholar]
  152. YangS.H. LinJ.K. ChenW.S. ChiuJ.H. Anti-angiogenic effect of silymarin on colon cancer lovo cell line.J. Surg. Res.2003113113313810.1016/S0022‑4804(03)00229‑412943822
     [Google Scholar]
  153. García-MaceiraP. MateoJ. Silibinin inhibits hypoxia-inducible factor-1α and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy.Oncogene200928331332410.1038/onc.2008.39818978810
     [Google Scholar]
  154. MiyazawaM. YasudaM. MiyazawaM. OganeN. KatohT. YanoM. HirasawaT. MikamiM. IshimotoH. Hypoxia-inducible factor-1α suppression in ovarian clear-cell carcinoma cells by silibinin administration.Anticancer Res.202040126791679810.21873/anticanres.1470233288572
     [Google Scholar]
  155. TsaiJ.H. YangJ. Epithelial–mesenchymal plasticity in carcinoma metastasis.Genes Dev.201327202192220610.1101/gad.225334.11324142872
     [Google Scholar]
  156. WeberG.F. Why does cancer therapy lack effective anti-metastasis drugs?Cancer Lett.2013328220721110.1016/j.canlet.2012.09.02523059758
     [Google Scholar]
  157. QuailD.F. JoyceJ.A. Microenvironmental regulation of tumor progression and metastasis.Nat. Med.201319111423143710.1038/nm.339424202395
     [Google Scholar]
  158. WuM. WangG. HuW. YaoY. YuX.F. Emerging roles and therapeutic value of exosomes in cancer metastasis.Mol. Cancer20191815310.1186/s12943‑019‑0964‑830925925
     [Google Scholar]
  159. BakirB. ChiarellaA.M. PitarresiJ.R. RustgiA.K. EMT, MET, plasticity, and tumor metastasis.Trends Cell Biol.2020301076477610.1016/j.tcb.2020.07.00332800658
     [Google Scholar]
  160. CraeneB.D. BerxG. Regulatory networks defining EMT during cancer initiation and progression.Nat. Rev. Cancer20131329711010.1038/nrc344723344542
     [Google Scholar]
  161. LamouilleS. XuJ. DerynckR. Molecular mechanisms of epithelial–mesenchymal transition.Nat. Rev. Mol. Cell Biol.201415317819610.1038/nrm375824556840
     [Google Scholar]
  162. Wild-BodeC. WellerM. RimnerA. DichgansJ. WickW. Sublethal irradiation promotes migration and invasiveness of glioma cells: Implications for radiotherapy of human glioblastoma.Cancer Res.20016162744275011289157
     [Google Scholar]
  163. KawamotoA. YokoeT. TanakaK. SaigusaS. ToiyamaY. YasudaH. InoueY. MikiC. KusunokiM. Radiation induces epithelial-mesenchymal transition in colorectal cancer cells.Oncol. Rep.2012271515721971767
     [Google Scholar]
  164. ZhangX. LiX. ZhangN. YangQ. MoranM.S. Low doses ionizing radiation enhances the invasiveness of breast cancer cells by inducing epithelial–mesenchymal transition.Biochem. Biophys. Res. Commun.2011412118819210.1016/j.bbrc.2011.07.07421810413
     [Google Scholar]
  165. LiT. ZengZ-C. WangL. QiuS-J. ZhouJ-W. ZhiX-T. YuH-H. TangZ-Y. Radiation enhances long-term metastasis potential of residual hepatocellular carcinoma in nude mice through TMPRSS4-induced epithelial–mesenchymal transition.Cancer Gene Ther.201118961762610.1038/cgt.2011.2921637307
     [Google Scholar]
  166. VaidM. PrasadR. SunQ. KatiyarS.K. Silymarin targets β-catenin signaling in blocking migration/invasion of human melanoma cells.PLoS One201167e2300010.1371/journal.pone.002300021829575
     [Google Scholar]
  167. ChuS.C. ChiouH.L. ChenP.N. YangS.F. HsiehY.S. Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2.Mol. Carcinog.200440314314910.1002/mc.20018
     [Google Scholar]
  168. SinghT. PrasadR. KatiyarS.K. Therapeutic intervention of silymarin on the migration of non-small cell lung cancer cells is associated with the axis of multiple molecular targets including class 1 HDACs, ZEB1 expression, and restoration of miR-203 and E-cadherin expression.Am. J. Cancer Res.2016661287130127429844
     [Google Scholar]
  169. KimD.H. ParkS.J. LeeS.Y. YoonH.S. ParkC.M. Silymarin attenuates invasion and migration through the regulation of epithelial-mesenchymal transition in Huh7 cells.Korean J Clin Lab Sci201850333734410.15324/kjcls.2018.50.3.337
     [Google Scholar]
  170. RainaK. RajamanickamS. SinghR.P. DeepG. ChittezhathM. AgarwalR. Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model.Cancer Res.200868166822683010.1158/0008‑5472.CAN‑08‑133218701508
     [Google Scholar]
  171. TingH.J. DeepG. JainA.K. CimicA. SirintrapunJ. RomeroL.M. CramerS.D. AgarwalC. AgarwalR. Silibinin prevents prostate cancer cell-mediated differentiation of naïve fibroblasts into cancer-associated fibroblast phenotype by targeting TGF β2.Mol. Carcinog.201554973074110.1002/mc.2213524615813
     [Google Scholar]
  172. WuK. NingZ. ZengJ. FanJ. ZhouJ. ZhangT. ZhangL. ChenY. GaoY. WangB. GuoP. LiL. WangX. HeD. Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial–mesenchymal transition and stemness.Cell. Signal.201325122625263310.1016/j.cellsig.2013.08.02824012496
     [Google Scholar]
  173. SameriS. SaidijamM. BahreiniF. NajafiR. Cancer chemopreventive activities of silibinin on colorectal cancer through regulation of E-cadherin/β-catenin pathway.Nutr. Cancer20217381389139910.1080/01635581.2020.180076432748663
     [Google Scholar]
  174. SoleimaniV. DelghandiP.S. MoallemS.A. KarimiG. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review.Phytother. Res.20193361627163810.1002/ptr.636131069872
     [Google Scholar]
  175. BijakM. Silybin, a major bioactive component of milk thistle (Silybum marianum L. Gaernt.)—chemistry, bioavailability, and metabolism.Molecules20172211194210.3390/molecules2211194229125572
     [Google Scholar]
  176. GillessenA. SchmidtH.H.J. Silymarin as supportive treatment in liver diseases: A narrative review.Adv. Ther.20203741279130110.1007/s12325‑020‑01251‑y32065376
     [Google Scholar]
  177. AmawiH. HusseinN.A. KarthikeyanC. ManivannanE. WisnerA. WilliamsF.E. SamuelT. TrivediP. AshbyC.R.Jr TiwariA.K. HM015k, a novel silybin derivative, multi-targets metastatic ovarian cancer cells and is safe in zebrafish toxicity studies.Front. Pharmacol.2017849810.3389/fphar.2017.0049828824426
     [Google Scholar]
  178. KosinaP. KrenV. GebhardtR. GrambalF. UlrichováJ. WalterováD. Antioxidant properties of silybin glycosides.Phytother. Res.200216S1S33S3910.1002/ptr.79611933137
     [Google Scholar]
  179. DobiasováS. ŘehořováK. KučerováD. BiedermannD. KáňováK. PetráskováL. Multidrug resistance modulation activity of silybin derivatives and their anti-inflammatory potential.Antioxidants20209545510.3390/antiox9050455
     [Google Scholar]
  180. SimánekV. KubischJ. SedmeraP. HaladaP. GazákR. SkottováN. KrenV. Chemoenzymatic preparation of oligoglycosides of silybin, the flavonolignan from Silybum marianum.Heterocycles200154290191510.3987/COM‑00‑S(I)89
     [Google Scholar]
  181. ŠkottováN. ŠVageraZ. VečeřaR. UrbánekK. JegorovA. ŠimánekV. Pharmacokinetic study of iodine-labeled silibinins in rat.Pharmacol. Res.200144324725310.1006/phrs.2001.085411529693
     [Google Scholar]
  182. PlíškováM. VondráčekJ. KřenV. GažákR. SedmeraP. WalterováD. PsotováJ. ŠimánekV. MachalaM. Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation.Toxicology20052151-2808910.1016/j.tox.2005.06.02016076518
     [Google Scholar]
  183. RoubalováL. Dinkova-KostovaA.T. BiedermannD. KřenV. UlrichováJ. VrbaJ. Flavonolignan 2,3-dehydrosilydianin activates Nrf2 and upregulates NAD(P)H:quinone oxidoreductase 1 in Hepa1c1c7 cells.Fitoterapia201711911512010.1016/j.fitote.2017.04.01228450126
     [Google Scholar]
  184. PyszkováM. BilerM. BiedermannD. ValentováK. KuzmaM. VrbaJ. UlrichováJ. SokolováR. MojovićM. Popović-BijelićA. KubalaM. TrouillasP. KřenV. VacekJ. Flavonolignan 2,3-dehydroderivatives: Preparation, antiradical and cytoprotective activity.Free Radic. Biol. Med.20169011412510.1016/j.freeradbiomed.2015.11.01426582372
     [Google Scholar]
  185. YangL.X. HuangK.X. LiH.B. GongJ.X. WangF. FengY.B. TaoQ.F. WuY.H. LiX.K. WuX.M. ZengS. SpencerS. ZhaoY. QuJ. Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives.J. Med. Chem.200952237732775210.1021/jm900735p19673490
     [Google Scholar]
  186. MizunoM. MoriK. TsuchiyaK. TakakiT. MisawaT. DemizuY. ShibanumaM. FukuharaK. Design, synthesis, and biological activity of conformationally restricted analogues of silibinin.ACS Omega2020536231642317410.1021/acsomega.0c0293632954167
     [Google Scholar]
  187. ZarrelliA. RomanucciV. TuccilloC. FedericoA. LoguercioC. GravanteR. Di FabioG. New silibinin glyco-conjugates: Synthesis and evaluation of antioxidant properties.Bioorg. Med. Chem. Lett.201424225147514910.1016/j.bmcl.2014.10.02325442301
     [Google Scholar]
  188. VueB. ZhangS. ZhangX. ParisisK. ZhangQ. ZhengS. WangG. ChenQ.H. Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations.Eur. J. Med. Chem.2016109364610.1016/j.ejmech.2015.12.04126748997
     [Google Scholar]
  189. Rajnochová SvobodováA. GabrielováE. UlrichováJ. ZálešákB. BiedermannD. VostálováJ. A pilot study of the UVA-photoprotective potential of dehydrosilybin, isosilybin, silychristin, and silydianin on human dermal fibroblasts.Arch. Dermatol. Res.2019311647749010.1007/s00403‑019‑01928‑731079190
     [Google Scholar]
  190. DrouetS. DoussotJ. GarrosL. MathironD. BassardS. Favre-RéguillonA. MoliniéR. LainéÉ. HanoC. Selective synthesis of 3-O-Palmitoyl-Silybin, a New-to-Nature flavonolignan with increased protective action against oxidative damages in lipophilic media.Molecules20182310259410.3390/molecules2310259430309022
     [Google Scholar]
  191. ChenX. ZengerK. LuppA. KlingB. HeilmannJ. FleckC. KrausB. DeckerM. Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo.J. Med. Chem.201255115231524210.1021/jm300246n22624880
     [Google Scholar]
  192. TilleyC. DeepG. AgarwalC. WempeM.F. BiedermannD. ValentováK. KrenV. AgarwalR. Silibinin and its 2,3-dehydro-derivative inhibit basal cell carcinoma growth via suppression of mitogenic signaling and transcription factors activation.Mol. Carcinog.201655131410.1002/mc.2225325492239
     [Google Scholar]
  193. Di CostanzoA. AngelicoR. Formulation strategies for enhancing the bioavailability of silymarin: The dtate of the art.Molecules20192411215510.3390/molecules2411215531181687
     [Google Scholar]
  194. HeJ. HouS. LuW. ZhuL. FengJ. Preparation, pharmacokinetics and body distribution of silymarin-loaded solid lipid nanoparticles after oral administration.J. Biomed. Nanotechnol.20073219520210.1166/jbn.2007.024
     [Google Scholar]
  195. YousafA.M. MalikU.R. ShahzadY. MahmoodT. HussainT. Silymarin-laden PVP-PEG polymeric composite for enhanced aqueous solubility and dissolution rate: Preparation and in vitro characterization.J. Pharm. Anal.201991343910.1016/j.jpha.2018.09.00330740255
     [Google Scholar]
  196. IbrahimA.H. RosqvistE. SmåttJ.H. IbrahimH.M. IsmaelH.R. AfounaM.I. SamyA.M. RosenholmJ.M. Formulation and optimization of lyophilized nanosuspension tablets to improve the physicochemical properties and provide immediate release of silymarin.Int. J. Pharm.201956321722710.1016/j.ijpharm.2019.03.06430946894
     [Google Scholar]
  197. LiangJ. LiuY. LiuJ. LiZ. FanQ. JiangZ. YanF. WangZ. HuangP. FengN. Chitosan-functionalized lipid-polymer hybrid nanoparticles for oral delivery of silymarin and enhanced lipid-lowering effect in NAFLD.J. Nanobiotechnology20181616410.1186/s12951‑018‑0391‑930176941
     [Google Scholar]
  198. YangG. ZhaoY. FengN. ZhangY. LiuY. DangB. Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids.Asian J. Pharm. Sci.201510319420210.1016/j.ajps.2014.12.001
     [Google Scholar]
  199. NasrS.S. NasraM.M.A. HazzahH.A. AbdallahO.Y. Mesoporous silica nanoparticles, a safe option for silymarin delivery: Preparation, characterization, and in vivo evaluation.Drug Deliv. Transl. Res.20199596897910.1007/s13346‑019‑00640‑331001719
     [Google Scholar]
  200. NagiA. IqbalB. KumarS. SharmaS. AliJ. BabootaS. Quality by design based silymarin nanoemulsion for enhancement of oral bioavailability.J. Drug Deliv. Sci. Technol.201740354410.1016/j.jddst.2017.05.019
     [Google Scholar]
  201. PiazziniV. RossetiC. BigagliE. LuceriC. BiliaA. BergonziM. Prediction of permeation and cellular transport of Silybum marianum extract formulated in a nanoemulsion by using PAMPA and Caco-2 cell models.Planta Med.20178314/151184119310.1055/s‑0043‑11005228472840
     [Google Scholar]
  202. WooJ.S. KimT.S. ParkJ.H. ChiS.C. Formulation and biopharmaceutical evaluation of silymarin using SMEDDS.Arch. Pharm. Res.2007301828910.1007/BF0297778217328246
     [Google Scholar]
  203. El-FarM. SalahN. EssamA. Abd El-AzimA.O. El-SherbinyI.M. Silymarin nanoformulation as potential anticancer agent in experimental Ehrlich ascites carcinoma-bearing animals.Nanomedicine201813151865185810.2217/nnm‑2017‑039430136915
     [Google Scholar]
  204. NguyenM.H. YuH. DongB. HadinotoK. A supersaturating delivery system of silibinin exhibiting high payload achieved by amorphous nano-complexation with chitosan.Eur. J. Pharm. Sci.20168916317110.1016/j.ejps.2016.04.03627140843
     [Google Scholar]
  205. TakkeA. ShendeP. Nanotherapeutic silibinin: An insight of phytomedicine in healthcare reformation.Nanomedicine20192110205710.1016/j.nano.2019.10205731340181
     [Google Scholar]
  206. TanJ.M. KarthivashanG. ArulselvanP. FakuraziS. HusseinM.Z. Characterization and in vitro sustained release of silibinin from pH responsive carbon nanotube-based drug delivery system.J. Nanomater.201420141
     [Google Scholar]
  207. AdhikariM. AroraR. Nano-silymarin provides protection against γ-radiation-induced oxidative stress in cultured human embryonic kidney cells.Mutat. Res. Genet. Toxicol. Environ. Mutagen.201579211110.1016/j.mrgentox.2015.08.00626433256
     [Google Scholar]
  208. AzadpourM. FarajollahiM.M. DariushnejadH. VarziA.M. VarezardiA. BaratiM. Effects of synthetic silymarin-PLGA nanoparticles on M2 polarization and inflammatory cytokines in LPS-treated murine peritoneal macrophages.Iran. J. Basic Med. Sci.202124101446145435096304
     [Google Scholar]
  209. MombeiniM. SakiG. KhorsandiL. BavarsadN. Effects of silymarin-loaded nanoparticles on HT-29 human colon cancer cells.Medicina.2018541110.3390/medicina5401000130344232
     [Google Scholar]
  210. HosseiniS. RezaeiS. MoghaddamM.R.N. ElyasiS. KarimiG. Evaluation of oral nano-silymarin formulation efficacy on prevention of radiotherapy induced mucositis: A randomized, double-blinded, placebo-controlled clinical trial.PharmaNutrition20211510025310.1016/j.phanu.2021.100253
     [Google Scholar]
  211. GhalehkhondabiV. SoleymaniM. FazlaliA. Folate-targeted nanomicelles containing silibinin as an active drug delivery system for liver cancer therapy.J. Drug Deliv. Sci. Technol.20216110215710.1016/j.jddst.2020.102157
     [Google Scholar]
  212. RipoliM. AngelicoR. SaccoP. CeglieA. MangiaA. Phytoliposome-based silibinin delivery system as a promising strategy to prevent hepatitis c virus infection.J. Biomed. Nanotechnol.201612477078010.1166/jbn.2016.216127301203
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673248404231006052436
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The Radiosensitizing Potentials of Silymarin/Silibinin in Cancer: A Systematic Review
Curr. Med. Chem. 31, 6992 (2024); https://doi.org/10.2174/0109298673248404231006052436
/content/journals/cmc/10.2174/0109298673248404231006052436
/content/journals/cmc/10.2174/0109298673248404231006052436
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  • Article Type:     Review Article
Keyword(s): Cancer; radiosensitization; radiotherapy; silibinin; silymarin; systematic review

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