Cordani, Marco

Dando, Ilaria

Kumar, Suresh

Somoza, Álvaro

Tafani, Marco

English

Somoza, Álvaro

Catalogo dei prodotti della ricerca

Editorial: Novel Cancer TreatmentsBased on Autophagy ModulationMarco Cordani 1*, Álvaro Somoza1, Marco Tafani 2, Ilaria Dando3 and Suresh Kumar41IMDEA Nanociencia, Ciudad Universitaria de Cantoblanco, Madrid, Spain, 2Department of Experimental Medicine, SapienzaUniversity of Rome, Rome, Italy, 3Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry,University of Verona, Verona, Italy, 4Department of Molecular Genetics and Microbiology, University of New Mexico HealthSciences Center, Albuquerque, NM, United StatesKeywords: cancer treatment, autophagy, pharmacology, nanomedicine, chemoresistance, signalling pathwaysEditorial on the Research TopicNovel Cancer Treatments based on Autophagy ModulationAutophagy is an intracellular process in response to stimulus by which damaged organelles, proteinaggregates, or invading pathogens, are targeted from autophagic vesicles to lysosomes and theneliminated (Mizushima et al., 2011). Autophagy has been described to play a role in severalpathological conditions, including neurodegenerative disorders, infectious diseases, and cancer.The role of autophagy in cancer remains highly controversial, and it is likely reliant on the tumortype, the stage of neoplasia, the cellular context, as well as on the metabolic context in which the cellslie. Earliest reports suggested a role of autophagy against tumorigenesis favoring tumor cell death inan apoptotic-dependent or independent way (Levine and Yuan, 2005; Pattingre et al., 2005). In thisregard, uncontrolled autophagy can lead to excessive degradation of cellular constituents andorganelles required for the cells’ homeostasis, and its enhancement represent a valid therapeutictarget of many anticancer drugs. Hence, autophagy has been widely known as a tumor-suppressivemechanism and cancer cells with limited autophagy may suffer from increased oxidative stress, DNAdamage, and genomic instability, which lead to the acquisition of genome mutations that drivetumorigenesis (Mathew et al., 2007; Mathew et al., 2009). On the other hand, autophagy also plays aprotective role in cancer cells by removing damaged organelles or recycling misfoldedmacromolecules. Several studies report that autophagy tries to satisfy the high metabolicdemands of the proliferating tumor cells suffering stressful conditions, such as nutrientdeprivation, oxidative stress, hypoxia, or in response to therapy (Condo et al., 2005).Hence, the possibility to modulate autophagy may represent a useful therapeutic approach to treatdifferent types of cancer. In this regard, a variety of clinical trials based on autophagy modulators areongoing. For instance, in tumors with enhanced autophagy, which acts as a survival mechanism andchemoresistance, its inhibition can make them more prone to initiate cell death mechanisms. In thissense, there are a variety of examples showing that autophagy inhibitors, as 3-methyl-adenine (3-MA) or hydroxychloroquine (HCQ), when used in combination with anticancer drugs, may sensitizechemoresistant cells, thus leading to cancer cell death (Jain et al., 2013; Lee et al., 2015). However,excessive autophagy induction upon cytotoxic drug treatments or through the use of autophagyinducers, as mTOR inhibitors, may also lead to autophagic cell death (Bursch et al., 1996; Tian et al.,2019).On the other hand, recent advances in nanomedicine make it possible to fight cancer with effectivetherapeutic compounds, removing the obstacles encountered with traditional drugs. Interestingly,nanomaterials have been explored as potent modulators of autophagy through multiple mechanismsand have been exploited as therapeutic agents against cancer (Cordani and Somoza, 2019). For thisreason, autophagy modulation with chemotherapy drugs, including nanoparticle-based strategies,Edited and reviewed by:Olivier Feron,Université catholique de Louvain,Belgium*Correspondence:Marco Cordanimarco.cordani@imdea.orgSpecialty section:This article was submitted toPharmacology of Anti-Cancer Drugs,a section of the journalFrontiers in PharmacologyReceived: 07 January 2021Accepted: 01 March 2021Published: 16 April 2021Citation:Cordani M, Somoza Á, Tafani M,Dando I and Kumar S (2021) Editorial:Novel Cancer Treatments Based onAutophagy Modulation.Front. Pharmacol. 12:650559.doi: 10.3389/fphar.2021.650559Frontiers in Pharmacology | www.frontiersin.org April 2021 | Volume 12 | Article 6505591EDITORIALpublished: 16 April 2021doi: 10.3389/fphar.2021.650559would acquire clinical relevance in the near future, as acomplementary therapy for the treatment of cancers.This Research Topic gathers original research and reviewpapers on novel drugs and nanomaterials in cancer treatmentbased on autophagy modulation and the related molecularmechanisms of action ranging from basic research to moreapplied translational and clinical studies. The 17 acceptedarticles consist of 9 Original Research articles and 8 Reviewsor Mini-Reviews, demonstrating that inhibition or enhancementof the autophagy pathway may serve as an effective tool tocounteract cancer.Some of the research articles published describe the anticancerproprieties, both in vivo and in vitro, of several natural substancesby modulating signaling pathways regulating autophagy invarious tumors, thus representing great candidates for furthertherapeutic applications. Wang et al. showed that Sotetsuflavone,a naturally derived and occurring flavonoid, induced autophagyin lung cancer blocking PI3K/Akt/mTOR signaling pathway invivo and in vitro, was able to increase the levels of pro-apoptoticmarkers, as cytochrome C or cleaved-caspase 3, and to reduce theexpression of cyclin D1 and CDK4, thus blocking cell cycle in theG0/G1 phases. Tsai et al. reported that 6-Gingerol, a naturalphenol found in ginger, inhibits lung cancer cell growth viasuppression of USP14 expression and enhances autophagy-dependent ferroptosis, revealing the therapeutic efficacy of 6-Gingerol in A549 and its possible mechanism of action.Natural compounds derived from herbal medicines have beenextensively studied for their anticancer proprieties throughmodulation of signaling pathways leading to tumor cell deathin various cancer types. In this context, Wu et colleagues showedthat honokiol and magnolol, two compounds derived bymagnolia bark extract, display therapeutic potential causingcell cycle arrest, induction of caspase 3-dependent apoptosis,and autophagy in high-grade urothelial carcinoma. Chen et al.explored the anti-breast cancer potential of ethanol crude extractsfrom Brucea javanica seed (BJE). Their data showed that BJEcould inhibit breast cancer cell proliferation and induceapoptosis, together with the inhibition of autophagy, asdemonstrated by the reduction of several autophagy-relatedmarkers and the increase of mTOR phosphorylation. Gaoet al. revealed the molecular mechanisms through, whichMoracin N (MAN), a secondary metabolite extracted from theleaves of Morus alba L, inhibited cell proliferation and inducedapoptosis in lung cancer cells. Interestingly, they found thatMANtreatment dysregulated mitochondrial function and enhancedautophagy flux, concomitantly to the inhibition of mTORsignaling pathway in a time- and dose-dependent manner.Defects in autophagy lead to the accumulation of impairedmitochondria, which are a potential source of ROS that lead toDNA damage and genomic instability. In this regard, Chicoteet al. reported that autophagy inhibitor 3-methyladeninedisplayed cytotoxicity in mouse fibroblasts and correlates withmassive DNA damage, suggesting that in growing conditions,autophagy acts as a protective mechanism to diminish theintrinsic cytotoxicity of 3-methyladenine.Recently, it has been shown that platinum compounds exertlong-term effects, including autophagy activation in rat B50neuroblastoma cells (Grimaldi et al., 2019). However, althoughcancer therapy based on platinum compounds display a potentanticancer effect, it also causes many side effects that limit itsapplicability. In this regard, Zhang et al. showed here that drug-induced platinum accumulation might also interfere withimmune cells and, thus, increase the risk of immune toxicityin cancer patients.However, due to their ability to elicit autophagy, metal-basedcompounds remain attractive agents for anticancer applications.Here, Chen et al. showed that nickel complex NiPT, aproteasomal inhibitor, was able to induce autophagy bydysregulating AMPK/mTOR signaling pathways in bothcultured tumor cell lines and cancer cells derived from acutemyeloid leukemia human patients. Interestingly, they found thatNiPT leads to apoptosis in lung cancer cells if it is concomitantlyused together with autophagy inhibitors, suggesting that NiPT-induced autophagy protects cancer cells from death.The Research Topic also counts with several well-structuredreview articles that summarize studies describing novel drugs andnanomaterials in cancer treatment based on autophagymodulation and the related molecular mechanisms.In recent years, several nanocarriers have been developed andinvestigated to improve the solubility, bioavailability, controlledrelease of therapeutics, and increase their cytotoxic effect oncancer cells. Sharma et al. highlighted that the use ofnanoparticles for the delivery of miRNA-34a in cancer cellsmight inhibit critical autophagy-related pathways, thussensitizing cancer cells to traditional chemotherapy drugs. Onthe other side, Condello et al. focused on the most effectiveliposomal formulations for the simultaneous transport ofchemotherapeutics and autophagy inhibitors to controlpharmacokinetics and targeting, thus reducing the adverseeffects of drugs.Alkylphosphocholine (APC) derivatives represent a novelclass of antineoplastic agents that inhibit the serine–threoninekinase Akt, which acts as the primary regulator of cell survival.Berger et colleagues focused their attention on the capability ofsuch structures to induce autophagy by inhibiting the Akt/mTORcascade when administered as monotherapy or in combinationwith other drugs.The cytoprotective role that autophagy plays under certainconditions during cancer therapy is well assumed, and manystudies have been addressed to reduce protective autophagy toovercome drug resistance in the clinical practice. Liu et al.discussed the advantages of combining agents that inducecytoprotective autophagy with autophagy inhibitors as acancer therapeutic approach in clinical application. Hence, theexploitation of appropriate autophagy might cooperate withtraditional anticancer drugs to overcome drug resistance.Iron-dependent ferroptosis is a type of cell death discovered inrecent years, which is driven by lipid peroxidation and, recently, ithas been linked with various kinds of diseases, including cancer.Lin et al. elegantly described the relationship between ferroptosisand autophagy and focused their interest on small moleculesinducing ferroptosis, which have been observed to lead to a robustinhibitory effect on tumor growth and enhance the sensitivity tochemotherapeutic drugs. The tripartite motif family of proteinsFrontiers in Pharmacology | www.frontiersin.org April 2021 | Volume 12 | Article 6505592Cordani et al. Editorial: Autophagy Modulation for CancerTherapy(TRIMs) has emerged as a critical regulator of the autophagyprocess, and their dysregulation is strongly connected tooncogenesis or cancer progression. The review of Mandellet al. covers how the actions of TRIM proteins intersect withand orchestrate autophagy, thus contributing to cancerprogression and the possibility of targeting TRIM-directedautophagy in cancer therapy.Recently, the interest in metabolic therapy for cancer hasbeen renewed, particularly in amino acid deprivation byenzymes. In this context, L-asparaginase was approved forthe treatment of acute lymphoblastic leukemia by the U.S.Food and Drug Administration (Truelove et al., 2013).Importantly, the combination of amino acid degradingenzymes and autophagy regulators has been demonstratedto show synergistic anticancer effects in preclinical andclinical studies (Song et al., 2015). In this sense, Wang et al.highlighted recent advances of several potential anticancerenzymes and the concomitant employment of autophagymodulators with amino acid degrading enzymes as potentialcancer therapeutic approaches.Recent studies have elucidated that autophagy, in addition tolead severe metabolic changes and chemoresistance also plays arole in regulating the immune system, and increasing attentionhas been focused on the potential applications of autophagymodulation for tumor immunotherapy. In this regard, Limand Murthy summarized their current understanding of howautophagy drives tumor progression and chemoresistance viaimmunosuppression and they resumed an increasing set ofpharmacologically actionable targets in the autophagypathway, which may serve for novel cancer immunotherapies.In conclusion, this collection of Review and Original Researcharticles critically summarizes the current understanding of howautophagy modulation could be exploited for cancer treatment.We believe that these advances will inspire basic and clinicalscientists working in related fields to investigate molecularmechanisms and translational studies further.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.FUNDINGThis work was supported by the Spanish Ministry of Economyand Competitiveness (SAF 2017-87305-R) and by Fondi diAteneo 2019 (Sapienza University). IMDEA Nanocienciaacknowledges support from the ’Severo Ochoa’ Programme forCentres of Excellence in R&D (MINECO, Grant SEV-2016-0686).REFERENCESBursch, W., Ellinger, A., Kienzl, H., Török, L., Pandey, S., Sikorska, M., et al. (1996).Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 inhuman mammary carcinoma cells (MCF-7) in culture: the role of autophagy.Carcinogenesis 17, 1595–1607. doi:10.1093/carcin/17.8.1595Cordani, M., and Somoza, Á. (2019). Targeting autophagy using metallicnanoparticles: a promising strategy for cancer treatment. Cell. Mol. Life Sci.76, 1215–1242. doi:10.1007/s00018-018-2973-yGrimaldi, M., Bo, V. D., Ferrari, B., Roda, E., De Luca, F., Veneroni, P., et al.(2019). Long-term effects after treatment with platinum compounds,cisplatin and [Pt(O,O′-acac)(γ-acac)(DMS)]: autophagy activation in ratB50 neuroblastoma cells. Toxicol. Appl. Pharmacol. 364, 1–11. doi:10.1016/j.taap.2018.12.005Jain, K., Paranandi, K. S., Sridharan, S., and Basu, A. (2013). Autophagy in breastcancer and its implications for therapy. Am. J. Cancer Res. 3, 251–265.Kondo, Y., Kanzawa, T., Sawaya, R., and Kondo, S. (2005). The role of autophagy incancer development and response to therapy. Nat. Rev. Cancer 5, 726–734.doi:10.1038/nrc1692Lee, H. O., Mustafa, A., Hudes, G. R., and Kruger, W. D. (2015).Hydroxychloroquine destabilizes phospho-S6 in human renal carcinomacells. PLoS One. 10, e0131464. doi:10.1371/journal.pone.0131464Levine, B., and Yuan, J. (2005). Autophagy in cell death: an innocent convict?J. Clin. Invest. 115, 2679–2688. doi:10.1172/JCI26390Mathew, R., Karp, C. M., Beaudoin, B., Vuong, N., Chen, G., Chen, H.-Y., et al.(2009). Autophagy suppresses tumorigenesis through elimination of p62. Cell137, 1062–1075. doi:10.1016/j.cell.2009.03.048Mathew, R., Kongara, S., Beaudoin, B., Karp, C. M., Bray, K., Degenhardt, K.,et al. (2007). Autophagy suppresses tumor progression by limitingchromosomal instability. Genes Development 21, 1367–1381. doi:10.1101/gad.1545107Mizushima, N., Yoshimori, T., and Ohsumi, Y. (2011). The role of atg proteins inautophagosome formation. Annu. Rev. Cel Dev. Biol. 27, 107–132. doi:10.1146/annurev-cellbio-092910-154005Pattingre, S., Tassa, A., Qu, X., Garuti, R., Liang, X. H., Mizushima, N., et al. (2005).Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122,927–939. doi:10.1016/j.cell.2005.07.002Song, P., Ye, L., Fan, J., Li, Y., Zeng, X., Wang, Z., et al. (2015). Asparaginaseinduces apoptosis and cytoprotective autophagy in chronic myeloid leukemiacells. Oncotarget 6, 3861–3873. doi:10.18632/oncotarget.2869Tian, T., Li, X., and Zhang, J. (2019). mTOR signaling in cancer and mTORinhibitors in solid tumor targeting therapy. Ijms 20, 755. doi:10.3390/ijms20030755Truelove, E., Fielding, A. K., and Hunt, B. J. (2013). The coagulopathy andthrombotic risk associated with L-asparaginase treatment in adults withacute lymphoblastic leukaemia. Leukemia 27, 553–559. doi:10.1038/leu.2012.290Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2021 Cordani, Somoza, Tafani, Dando and Kumar. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and that theoriginal publication in this journal is cited, in accordance with accepted academicpractice. No use, distribution or reproduction is permitted which does not complywith these terms.Frontiers in Pharmacology | www.frontiersin.org April 2021 | Volume 12 | Article 6505593Cordani et al. Editorial: Autophagy Modulation for CancerTherapy

Editorial: Novel cancer treatments based on autophagy modulation

https://iris.univr.it/bitstream/11562/1043022/1/fphar-12-650559.pdf

Editorial: Novel cancer treatments based on autophagy modulation

Abstract

Similar works

Full text

Available Versions

Catalogo dei prodotti della ricerca