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Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors

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Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors International Journal of Molecular Sciences Review Combination of Anti-Cancer Drugs with Molecular Chaperone Inhibitors Maxim Shevtsov 1,2,3,4,5,6,* , Gabriele Multhoff 1 , Elena Mikhaylova 2, Atsushi Shibata 7 , Irina Guzhova 2 and Boris Margulis 2,* 1 Center for Translational Cancer Research, TUM (TranslaTUM), Technische Universität München (TUM), Klinikum rechts der Isar, Radiation Immuno Oncology, Einsteinstr. 25, 81675 Munich, Germany; gabriele.multhoff@tum.de 2 Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky Ave., 4, St. Petersburg 194064, Russia; [email protected] (E.M.); [email protected] (I.G.) 3 Department of Biotechnology Pavlov First Saint Petersburg State Medical University, L’va Tolstogo str., 6/8, St. Petersburg 197022, Russia 4 Almazov National Medical Research Centre, Polenov Russian Scientific Research Institute of Neurosurgery, Mayakovskogo str., 12, St. Petersburg 191014, Russia 5 Department of Biomedical Cell Technologies Far Eastern Federal University, Russky Island, Vladivostok 690000, Russia 6 National Center for Neurosurgery, Turan Ave., 34/1, Nur-Sultan 010000, Kazakhstan 7 Signal Transduction Program, Gunma University Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Gunma 371-8511, Japan; [email protected] * Correspondence: [email protected] (M.S.); [email protected] (B.M.) Received: 31 August 2019; Accepted: 22 October 2019; Published: 24 October 2019 Abstract: Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology. Keywords: heat shock protein inhibitors; molecular chaperones; HSP90; HSP70; HSP27; concurrent therapy; cancer therapy 1. Overview on Combinational Anti-Cancer Therapies In the last decade, progress in the development of anti-tumor therapies has been achieved, especially with respect to specifically targeting anti-tumor drugs that aim to interfere with molecular mechanisms that are responsible for tumor growth. However, traditional chemotherapeutic agents such as cisplatin, etoposide, 5-fluorouracil and their derivatives as well as ionizing radiation, are still widely applied to cure cancer. Both strategies can exert harmful effects on normal cells and may cause serious changes in the tumor microenvironment, which makes it difficult to predict outcome of these approaches. To improve tumor control, combinatorial therapies that target a wide range of tumorigenic functions including extensive cell growth, motility, proteostasis, apoptosis, autophagy and others are presently under investigation (see Figure1). The concurrent administration of several drugs that are Int. J. Mol. Sci. 2019, 20, 5284; doi:10.3390/ijms20215284 www.mdpi.com/journal/ijms Version August 31, 2019 submitted to Int. J. Mol. Sci. 2 of 22 44 Int.are J.presently Mol. Sci. 2019 under, 20, 5284 investigation (see Figure 1). The concurrent administration of several drugs2 that of 22 45 are targeting different cellular drivers of tumor cell viability and propagation is often advantageous 46 targetingover monotherapeutic different cellular approach drivers ofes tumorbecause cell viabilitythey might and propagationact synergistically is often. advantageous Furthermore, over in 47 monotherapeuticcombinatorial therapies approaches, reduce becaused dose theys of might the individual act synergistically. drugs c Furthermore,an be applied in and combinatorial therefore, 48 therapies,unfavorable reduced side effects doses ofcan the be individual avoided [1,2] drugs. Currently, can be applied bioinformatic and therefore, models unfavorable have been side designed effects 49 canthat bemight avoided predict [1,2 ].synergistic Currently, effects bioinformatic of novel models drug combinations have been designed [3–5]. thatCombinatorial might predict formulations synergistic 50 ecouldffects ofalso novel exert drug beneficial combinations effects [3 in–5 ].therapy Combinatorial-resistan formulationst tumor cells could by down also exert-regulating beneficial different effects 51 inmetabolic therapy-resistant factors, which tumor are cells induced by down-regulating by i.e., hypoxia, different oxidative metabolic or factors,reductive which stress are. inducedThirdly, 52 bycombinat i.e., hypoxia,orial therap oxidativeies may or reductivereduce tumor stress. recurrence Thirdly, combinatorialby suppression therapies of survival may mechanisms reduce tumor in 53 recurrenceresistant tumor by suppression cells after first of survival-line therapy mechanisms [6]. The relevance in resistant of tumor combinational cells after therap first-lineies in therapy oncology [6]. 54 Theis documented relevance of by combinational a large number therapies of clinical in oncologytrials which is documented are registered by at a largeclinical numbertrials.gov of clinicaland by 55 trials2548 references which are which registered appear at clinicaltrials.govwhen the two terms and “combination by 2548 references therapy” which and appear “cancer, when metasta the twosis” 56 termsare entered “combination. therapy” and “cancer, metastasis” are entered. 57 Figure 1. Currently used drugs, physico-chemical factors, molecular devices and vectors, which are 58 Figure 1. Currently used drugs, physico-chemical factors, molecular devices and vectors, which are presently tested in combinatorial treatment approaches of cancer. 59 presently tested in combinatorial treatment approaches of cancer. Drugs target polypeptides, protein modifications like phosphorylation, proteolysis or acetylation, 60 Drugs target polypeptides, protein modifications like phosphorylation, proteolysis or nucleic acids (i.e., RNA and DNA), lipids, and cancer metabolites and thereby impact on mitochondria, 61 acetylation, nucleic acids (i.e., RNA and DNA), lipids, and cancer metabolites and thereby impact on membranes, nucleus, ER and many other subcellular targets (Figure1). By damaging multiple 62 mitochondria, membranes, nucleus, ER and many other subcellular targets (Figure 1). By damaging cellular functions via combinatorial therapies alternative cell death mechanisms such as senescence or 63 multiple cellular functions via combinatorial therapies alternative cell death mechanisms such as autophagy can be induced or occasionally a conversion to a more resistant, stem-like phenotype can 64 senescence or autophagy can be induced or occasionally a conversion to a more resistant, stem-like occur [7,8]. The search for a successful combinatorial therapy may start with a better understanding of 65 phenotype can occur [7,8]. The search for a successful combinatorial therapy may start with a better molecular mechanisms of a drug hitting a certain target. Connectivity Map is a platform designed 66 understanding of molecular mechanisms of a drug hitting a certain target. Connectivity Map is a to provide information on signaling pathways induced by a certain drug [9]. Another powerful 67 platform designed to provide information on signaling pathways induced by a certain drug [9]. tool revealing clinically tested drug combinations is SynTarget which is based on 15 large-scale gene 68 Another powerful tool revealing clinically tested drug combinations is SynTarget which is based on expression data sets covering eight different cancer types. 69 15 large-scale gene expression data sets covering eight different cancer types. The list of components of therapeutic combinations includes chemicals (small molecules), proteins, 70 The list of components of therapeutic combinations includes chemicals (small molecules), particularly antibodies, physico-chemical interventions like radiation or hyperthermia, photodynamic 71 proteins, particularly antibodies, physico-chemical interventions like radiation or hyperthermia, treatment, anti-cancer vaccines and some other agents (Figure1; Table1). Since therapies should 72 photodynamic treatment, anti-cancer vaccines and some other agents (Figure 1; Table 1). Since specifically target tumor cells and not the surrounding normal tissue, special constructs are designed 73 therapies should specifically target tumor cells and not the surrounding normal tissue, special for a targeted delivery of the drug. Some of those vehicles are based on nanoparticles composed of a 74 constructs are designed for a targeted delivery of the drug. Some of those vehicles are based on magnetic or silicone core and specific peptides (aptamers) or antibodies that are directed against cell 75 nanoparticles composed of a magnetic or silicone core and specific peptides (aptamers) or antibodies surface molecules on cancer cells. A brief overview on anti-cancer therapies indicates that a specific 76 that are directed against cell surface molecules on cancer cells. A brief overview on anti-cancer spectrum of drugs is necessary to cure certain types of cancer. For instance, for the optimal treatment of 77 therapies indicates that a specific
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