pharmaceuticals Review Lung Cancer Management with Silibinin: A Historical and Translational Perspective Sara Verdura 1,2,† , Elisabet Cuyàs 1,2,†, Verónica Ruiz-Torres 3 , Vicente Micol 3 , Jorge Joven 4 , Joaquim Bosch-Barrera 2,5,6,* and Javier A. Menendez 1,2,* 1 Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain; [email protected] (S.V.); [email protected] (E.C.) 2 Metabolism and Cancer Group, Program against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007 Girona, Spain 3 Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE) and Instituto de Biología Molecular y Celular (IBMC), Universidad Miguel Hernández (UMH), 03202 Elche, Spain; [email protected] (V.R.-T.); [email protected] (V.M.) 4 Unitat de Recerca Biomèdica (URB-CRB), Hospital Universitari de Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, 43201 Reus, Spain; [email protected] 5 Medical Oncology, Catalan Institute of Oncology, Dr. Josep Trueta Hospital of Girona, 17007 Girona, Spain 6 Department of Medical Sciences, Faculty of Medicine, University of Girona (UdG), 17003 Girona, Spain * Correspondence: [email protected] (J.B.-B.); [email protected] (J.A.M.) † Both authors contributed equally to this work. Abstract: The flavonolignan silibinin, the major bioactive component of the silymarin extract of Silybum marianum (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights Citation: Verdura, S.; Cuyàs, E.; into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone Ruiz-Torres, V.; Micol, V.; Joven, J.; to metastasis. First, we summarize the evidence from chemically induced primary lung tumors Bosch-Barrera, J.; Menendez, J.A. Lung Cancer Management with supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and Silibinin: A Historical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits Translational Perspective. of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic Pharmaceuticals 2021, 14, 559. https:// and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by doi.org/10.3390/ph14060559 unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we Academic Editor: Thomas Efferth illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., KRAS/STK11 co-mutant tumors). Forthcoming studies should Received: 12 May 2021 take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel Accepted: 9 June 2021 lung cancer-preventive and therapeutic biomolecules. Published: 11 June 2021 Keywords: silibinin; silymarin; non-small cell lung cancer; EMT; metastasis; STAT3 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Phytochemicals are biologically active compounds synthesized by plants (Phyto means “plant” in Greek). The term, however, is generally employed for those influencing human Copyright: © 2021 by the authors. health. Flavonoids are a subclass of polyphenol phytochemicals that are commonly present Licensee MDPI, Basel, Switzerland. in fruits, vegetables, nuts, seeds, herbs, spices, stems, flowers, teas, and red wine [1,2]. This article is an open access article As they have existed in nature for millions of years, flavonoids have a long historical distributed under the terms and association with animal species throughout evolution, which likely explains their myriad conditions of the Creative Commons biochemical and pharmacological properties [3]. Although not without limitations, the Attribution (CC BY) license (https:// mutualistic relationship between plant flavonoids and animals, which is embraced in the creativecommons.org/licenses/by/ concept of xenohormesis [4,5], can be applied to human pathophysiology; in particular, the 4.0/). Pharmaceuticals 2021, 14, 559. https://doi.org/10.3390/ph14060559 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 18 Pharmaceuticals 2021, 14, 559 2 of 18 in particular, the various bioactivities of flavonoids (e.g., anti-inflammatory, antioxidant, antiallergic, hepatoprotective, antithrombotic, antiviral, and anticarcinogenic) in numer- ous biological systems. variousFlavonolignans bioactivities of are flavonoids a minor (e.g.,subclass anti-inflammatory, of flavonoids antioxidant,comprising antiallergic,a flavonoid hepato-moiety protective,and a lignan antithrombotic, (phenylpropanoid) antiviral, part. and They anticarcinogenic) were first isolated in numerous from the biologicalseeds of milk systems. this- tle (SilybumFlavonolignans marianum are (L.) a minorGaertn.), subclass an annual/biannual of flavonoids comprising plant of the a Asteraceae flavonoid family moiety flow- and aering lignan in (phenylpropanoid)July–August with characteristic part. They were reddish-purple first isolated from flowers. the seedsThe milk of milk thistle thistle is indig- (Sily- bumenous marianum to South(L.) Europe, Gaertn.), South an annual/biannual Russia, Asia Minor, plant and of the NorthAsteraceae Africa,family but has flowering also been in July–Augustnaturalized in with North characteristic and South reddish-purpleAmerica and in flowers. South Australia. The milk The thistle so-called is indigenous silymarin to Southextract Europe, of milk Souththistle, Russia, which Asia was Minor,classified and by North the World Africa, Health but has Organization also been naturalized as an offi- incial North medicine and South with Americahealth-promoting and in South properties Australia. in the The 1970s, so-called is obtained silymarin through extract oforganic milk thistle,solvent which extraction was classifiedand represents by the 1.5–3% World Healthof the dry Organization weight of the as an frui officialt. Silymarin medicine contains with health-promotinga mixture of flavonolignans properties inof themainly 1970s, four is obtainedisomers: throughsilibinin organic(or silybin), solvent isosilybin, extraction si- and represents 1.5–3% of the dry weight of the fruit. Silymarin contains a mixture of lychristin, and silydianin. There is also a minor fraction of polymeric and oxidized poly- flavonolignans of mainly four isomers: silibinin (or silybin), isosilybin, silychristin, and phenolic components [6–12], including two pairs of diastereomers––silibinin A/B and is- silydianin. There is also a minor fraction of polymeric and oxidized polyphenolic com- osilybin A/B. Silibinin is composed of a 1:1 mixture of silibinin A and B and comprises 50– ponents [6–12], including two pairs of diastereomers—-silibinin A/B and isosilybin A/B. 70% of the extract and 20–40% of the commonly used pharmaceutical preparations Silibinin is composed of a 1:1 mixture of silibinin A and B and comprises 50–70% of the [11,13,14]. Whereas the chemical composition of milk thistle fruits includes other flavo- extract and 20–40% of the commonly used pharmaceutical preparations [11,13,14]. Whereas noids (e.g., taxifolin, quercetin, kaempferol, apigenin), the highest concentration of si- the chemical composition of milk thistle fruits includes other flavonoids (e.g., taxifolin, lymarin corresponds to silibinin, which is considered the major bioactive component [15– quercetin, kaempferol, apigenin), the highest concentration of silymarin corresponds to 18]. silibinin, which is considered the major bioactive component [15–18]. Originally described as a cure for the venom of poisonous snakes, silibinin is the most Originally described as a cure for the venom of poisonous snakes, silibinin is the extensively studied flavonolignan and is currently clinically employed to treat ama- most extensively studied flavonolignan and is currently clinically employed to treat am- atoxin/toxin/AmanitaAmanita mushroommushroom poisoning poisoning or or lipotoxic lipotoxic injury injury in infatty fatty liver liver diseases. diseases. Here, Here, we wereview review the thehistorical historical context context of the of thedevelopmen developmentt of silibinin of silibinin research research in lung inlung cancer cancer (Fig- (Figureure 1). 1A). literatureA literature search search (silibinin (silibinin AND AND lung lung cancer) cancer) was wasinitially initially conducted conducted in the in elec- the electronictronic database database PubMed PubMed with with no date-range no date-range restriction. restriction. No Noqualit quality-assessmenty-assessment scale scale sys- systemstems were were used used to evaluate to evaluate the the collected collected stud studies.ies. Manuscripts Manuscripts were were screened screened by by checking check- ingthe thetitle title and and abstract abstract or reading or reading the thefull full text text to determine to determine their their inclusion. inclusion. In addition, In addition, we weprovide provide some some experimental experimental results results to illustra to illustratete how how we wemight might capitalize capitalize