Increased stiffness is usually associated with poor prognosis of breast tumor [[176], [177], [178], [179]]

Increased stiffness is usually associated with poor prognosis of breast tumor [[176], [177], [178], [179]]. components of TME?or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. In this review, we briefly summarize the recent improvements of small-molecule inhibitors that target TME for the tumor treatment. Introduction The tumor microenvironment (TME) is usually a hypoxic and acidic milieu constituted of cellular and noncellular components. The cellular component is composed of various stromal cells, including endothelial cells (ECs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs). The noncellular component includes nonsoluble or semisoluble substances, such as the extracellular matrix (ECM), and soluble substances, such as interstitial fluids, various cytokines and chemokines, growth factors, and metabolites [[1], [2], [3], [4], [5]]. TME is not only intrinsically immunosuppressive to protect tumor cells from immune surveillance? but also dynamically adaptive to accommodate rapid tumor growth and progression and to counter any stress and insult conditions, such as chemotherapy [6,7]. TME is an essential part of the tumor mass, which is important for tumor growth, progression, metastasis, and therapy resistance [4,6,8]. Therefore, targeting TME would be an efficient way for the treatment of cancer. Indeed, many strategies have been developed to target the TME. As small molecules can easily access TME than can penetrate into tumor cells, development of small-molecule inhibitors that specifically target TME is one of the rapidly growing areas in this field. Small-molecule inhibitors are compounds with a small size (500 Da). Compared with macromolecule agents, small-molecule inhibitors are more penetrative to the targets and usually can be engineered to be suitable for oral administration [[9], [10], [11], [12]]. Many small-molecule inhibitors have been successfully applied to treat a wide range of cancers, and much more are currently in either clinical trials or ongoing development. For example, sunitinib (Sutent), a multiple-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), oncogene ( em KIT /em ), receptor tyrosine kinase and platelet-derived growth factor receptor (PDGFR), has been approved as a potent antiangiogenesis drug and is applied to treat various tumors [9,13]. Recently, many small-molecule inhibitors have been developed to specifically or mainly target TME. These small molecules are designed to interrupt the specific features of TME, including the hypoxic, acidic, inflammatory milieu, as well as the abnormal ECM network in TME. Here, we briefly review the recent advances in the development of therapeutic small-molecule inhibitors that target TME. Targeting Hypoxia in the TME Hypoxia is one of the prominent features of TME. The rapid proliferation of cancer cells speeds up the consumption of oxygen, resulting in reduced oxygen level in solid tumor areas [14]. The disorganized vascular networks in tumor site that induce diffusion distance of oxygen also contribute to low oxygen level in TME [6,14,15]. In addition, tumor-associated and/or therapy-induced anemia causes a decreased O2 transport capacity of the blood, leading to hypoxia in tumor sites [16]. Hypoxia is associated with tumor metastasis, radiotherapy/chemotherapy resistance, and poor prognosis [15,17]. In hypoxic environment, tumor cells can use many mechanisms to survive, including shifting from aerobic to anaerobic metabolism, erythropoietin (EPO) production, deregulating DNA repair systems, recruiting the stromal components, as well as upregulating protooncogenes and hypoxia-inducible factor (HIF) 1 and HIF 2 [18,19]. For a detailed review of targeting hypoxia in cancer therapy, please refer to a recent publication by Wilson and Hay [20]. To exploit the unique feature of hypoxia in TME, the therapeutic agents are often designed as low-toxicity prodrugs in normoxia environment while selectively activated in hypoxic tumor areas (Figure?1). Papadopoulos et?al. [21] designed the hypoxia-activated prodrug AQ4N (banoxantrone) that is converted into AQ4, a potent inhibitor of topoisomerase II, in hypoxic areas. This prodrug is applied to treat advanced solid tumors such as bronchoalveolar lung cancer and ovarian cancer. Weiss et?al. [22] designed a hypoxia-activated prodrug TH-302 that is consisted of 2-nitroimidazole, a hypoxia trigger, and a brominated version of isophosphoramide mustard (Br-IPM). This prodrug remains intact in normal oxygen conditions and can be activated in severe hypoxic conditions ( 0.5% O2) to release Br-IPM, a DNA cross-linking agent. TH-302 shows antitumor activities in metastatic melanoma and small cell lung cancer (SCLC). Another hypoxic cell toxin is tirapazamine (TPZ), which preferentially shows cytotoxic activity to hypoxic cancer cells. The underlying mechanism is that TPZ forms a radical by adding an electron under the catalytic action SOD2 of various intracellular reductases. This TPZ radical is highly reactive and can lead to DNA single- or double-strand.Some immune cells in TME, for instance TAMs?and myeloid-derived suppressor cells (MDSCs), are tumor-promotive, while the immune activity of other cells, for instance CD8+ cells of TILs, is suppressed in TME [5,59,60]. TME or the components of TME?or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. In this review, we briefly summarize the recent advances of small-molecule inhibitors that target TME for the tumor treatment. Introduction The tumor microenvironment (TME) is a hypoxic and acidic milieu constituted of cellular and noncellular components. The cellular component is composed of various stromal cells, including endothelial cells (ECs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs). The noncellular component includes nonsoluble or semisoluble substances, such as the extracellular matrix (ECM), and soluble substances, such as interstitial fluids, numerous cytokines and chemokines, growth factors, and metabolites [[1], [2], [3], [4], [5]]. TME isn’t just intrinsically immunosuppressive to protect tumor cells from immune monitoring?but also dynamically adaptive to accommodate rapid tumor growth and progression and to counter any stress and insult conditions, such as chemotherapy [6,7]. TME is an essential part of the tumor mass, which is definitely important for tumor growth, progression, metastasis, and therapy resistance [4,6,8]. Consequently, focusing on TME would be an efficient way for the treatment of cancer. Indeed, many strategies have been developed to target the TME. As small molecules can easily access TME than can penetrate into tumor cells, development of small-molecule inhibitors that specifically target TME is one of the rapidly growing areas with this field. Small-molecule inhibitors are compounds with a small size (500 Da). Compared with macromolecule providers, small-molecule inhibitors are more penetrative to the focuses on and usually can be engineered to be suitable for oral administration [[9], [10], [11], [12]]. Many small-molecule inhibitors have been successfully applied to treat a wide range of cancers, and much more are currently in either medical tests or ongoing development. For example, sunitinib (Sutent), a multiple-tyrosine kinase inhibitor of vascular endothelial growth element receptor (VEGFR), oncogene ( em KIT /em ), receptor tyrosine kinase and platelet-derived growth element receptor (PDGFR), has been approved like a potent antiangiogenesis drug and is applied to treat numerous tumors [9,13]. Recently, many small-molecule inhibitors have been developed to specifically or mainly target TME. These small molecules are designed to interrupt the specific features of TME, including the hypoxic, acidic, inflammatory milieu, as well as the irregular ECM network in TME. Here, we briefly review the recent advances in the development of restorative small-molecule inhibitors that target TME. Focusing on Hypoxia in the TME Hypoxia is one of the prominent features of TME. The quick proliferation of malignancy cells speeds up the consumption of oxygen, resulting in reduced oxygen level in solid tumor areas [14]. The disorganized vascular networks in tumor site that induce diffusion range of oxygen also contribute to low oxygen level in TME [6,14,15]. In addition, tumor-associated and/or therapy-induced anemia causes a decreased O2 transport capacity of the blood, leading to hypoxia in tumor sites [16]. Hypoxia is definitely associated with tumor metastasis, radiotherapy/chemotherapy resistance, and poor prognosis [15,17]. In hypoxic environment, tumor cells can use many mechanisms to survive, including shifting from aerobic to anaerobic rate of metabolism, erythropoietin (EPO) production, deregulating DNA restoration systems, recruiting the stromal parts, as well as upregulating protooncogenes and hypoxia-inducible element (HIF) 1 and HIF 2 [18,19]. For a detailed review of focusing on hypoxia in malignancy therapy, please refer to a recent publication by Wilson and Hay [20]. To exploit the unique feature of hypoxia in TME, the restorative agents are often designed as low-toxicity prodrugs in normoxia environment while selectively triggered in hypoxic tumor areas (Number?1). Papadopoulos et?al. [21] designed the hypoxia-activated prodrug AQ4N (banoxantrone) that is converted into AQ4, a potent inhibitor of topoisomerase II, in hypoxic areas. This prodrug is definitely applied to treat advanced solid tumors such as bronchoalveolar lung malignancy and ovarian malignancy. Weiss et?al. [22] designed a hypoxia-activated prodrug TH-302 that is consisted of 2-nitroimidazole, a hypoxia result in, and a brominated version of isophosphoramide mustard (Br-IPM). This prodrug remains intact in normal oxygen conditions and may be triggered in severe hypoxic conditions ( 0.5% O2) to release Br-IPM, a DNA cross-linking agent. TH-302 shows antitumor activities in metastatic melanoma and small cell lung malignancy (SCLC). Another hypoxic cell toxin is definitely tirapazamine (TPZ), which preferentially shows cytotoxic activity to hypoxic.To exploit the unique feature of hypoxia in TME, the therapeutic providers are often designed mainly because low-toxicity prodrugs in normoxia environment while selectively activated in hypoxic tumor areas (Number?1). cellular and noncellular parts. The cellular component is composed of numerous stromal cells, including endothelial cells (ECs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs). The noncellular component includes nonsoluble or semisoluble substances, such as the extracellular matrix (ECM), and soluble substances, such as interstitial fluids, numerous cytokines and chemokines, growth factors, and metabolites [[1], [2], [3], [4], [5]]. TME isn’t just intrinsically immunosuppressive to protect tumor cells from immune monitoring?but also dynamically adaptive to accommodate rapid tumor growth and progression and to counter any stress and insult conditions, such as chemotherapy [6,7]. TME is an essential part of the tumor mass, which is definitely important for tumor growth, progression, metastasis, and therapy resistance [4,6,8]. Consequently, focusing on TME would be an efficient way for the treatment of cancer. Indeed, many strategies have been developed to target the TME. As small molecules can easily access TME than can penetrate into tumor cells, development of small-molecule inhibitors that specifically target TME is one of the rapidly growing areas with this field. Small-molecule inhibitors are compounds with a small size (500 Da). Compared with macromolecule providers, small-molecule inhibitors are more penetrative to the focuses on and usually can be engineered to be suitable for oral administration [[9], [10], [11], [12]]. Many small-molecule inhibitors have been successfully applied to treat a wide range of cancers, and much more are currently in either clinical trials or ongoing development. For example, sunitinib (Sutent), a multiple-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), oncogene ( em KIT /em ), receptor tyrosine kinase and platelet-derived growth factor receptor (PDGFR), has been approved as a potent antiangiogenesis drug and is applied to treat numerous tumors [9,13]. Recently, many small-molecule inhibitors have been developed to specifically or mainly target TME. These small molecules are designed to interrupt the specific features of TME, including the hypoxic, acidic, inflammatory milieu, as well as the abnormal ECM network in TME. Here, we briefly review the recent advances in the development of therapeutic small-molecule inhibitors that target TME. Targeting Hypoxia in the TME Hypoxia is one of the prominent features of TME. The quick proliferation of malignancy cells speeds up the consumption of oxygen, resulting in reduced AGK2 oxygen level in solid tumor areas [14]. The disorganized vascular networks in tumor site that induce diffusion distance of oxygen also contribute to low oxygen level in TME [6,14,15]. In addition, tumor-associated and/or therapy-induced anemia causes a decreased O2 transport capacity of the blood, leading to hypoxia in tumor sites [16]. Hypoxia is usually associated with tumor metastasis, radiotherapy/chemotherapy resistance, and poor prognosis [15,17]. In hypoxic environment, tumor cells can use many mechanisms to survive, including shifting from aerobic to anaerobic metabolism, erythropoietin (EPO) production, deregulating DNA repair systems, recruiting the stromal components, as well as upregulating protooncogenes AGK2 and hypoxia-inducible factor (HIF) 1 and HIF 2 [18,19]. For a detailed review of targeting hypoxia in malignancy therapy, please refer to a recent publication by Wilson and Hay [20]. To exploit the unique feature of hypoxia in TME, the therapeutic agents are often designed as low-toxicity prodrugs in normoxia environment while selectively activated in hypoxic tumor areas (Physique?1). Papadopoulos et?al. [21] designed the hypoxia-activated prodrug AQ4N (banoxantrone) that is converted into AQ4, a potent inhibitor of topoisomerase II, in hypoxic areas. This prodrug is usually applied to treat advanced solid tumors such as bronchoalveolar lung malignancy and ovarian malignancy. Weiss et?al. [22] designed a hypoxia-activated prodrug TH-302 that is consisted of 2-nitroimidazole, a hypoxia trigger, and a brominated version of isophosphoramide mustard (Br-IPM). This prodrug remains intact in normal oxygen conditions and can be activated in severe hypoxic conditions ( 0.5% O2) to release Br-IPM, a DNA cross-linking agent. TH-302 shows antitumor activities in metastatic melanoma and small cell lung malignancy (SCLC). Another hypoxic cell toxin is usually tirapazamine (TPZ), which preferentially shows cytotoxic activity to hypoxic malignancy cells. The underlying mechanism is usually that TPZ forms a radical by adding an electron under the catalytic action of various intracellular reductases. This TPZ radical is usually highly reactive and can lead to DNA single- or double-strand.For instance, modifying a small-molecule inhibitor with tumor-selective ligands (such as folate, transferrin, peptides) and PEGylation will improve target specificity, while integrating this inhibitor into nanoparticle delivery systems will increase the delivery efficiency. tumor-associated macrophages (TAMs). The noncellular component includes nonsoluble or semisoluble substances, such as the extracellular matrix (ECM), and soluble substances, such as interstitial fluids, numerous cytokines and chemokines, growth factors, and metabolites [[1], [2], [3], [4], [5]]. TME is not only intrinsically immunosuppressive to protect tumor cells from immune surveillance?but also dynamically adaptive to accommodate rapid tumor growth and progression and to counter any stress and insult conditions, such as chemotherapy [6,7]. TME is an essential part of the tumor mass, which is usually important for tumor growth, progression, metastasis, and therapy resistance [4,6,8]. Therefore, targeting TME would be an efficient way for the treatment of cancer. Indeed, many strategies have been developed to target the TME. As small molecules can easily access TME than can penetrate into tumor cells, development of small-molecule inhibitors that specifically target TME is one of the rapidly growing areas in this field. Small-molecule inhibitors are compounds with a small size (500 Da). Compared with macromolecule brokers, small-molecule inhibitors are more penetrative to the targets and usually can be engineered to be suitable for oral administration [[9], [10], [11], [12]]. Many small-molecule inhibitors have been successfully applied to treat a wide range of cancers, and much more are currently in either clinical trials or ongoing development. For example, sunitinib (Sutent), a multiple-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), oncogene ( em KIT /em AGK2 ), receptor tyrosine kinase and platelet-derived growth factor receptor (PDGFR), has been approved as a potent antiangiogenesis drug and is applied to treat numerous tumors [9,13]. Recently, many small-molecule inhibitors have been developed to specifically or mainly target TME. These little molecules are made to interrupt the precise top features of TME, like the hypoxic, acidic, inflammatory milieu, aswell as the unusual ECM network in TME. Right here, we briefly review the latest advances in the introduction of healing small-molecule inhibitors that focus on TME. Concentrating on Hypoxia in the TME Hypoxia is among the prominent top features of TME. The fast proliferation of tumor cells boosts the intake of air, resulting in decreased air level in solid tumor areas [14]. The disorganized vascular systems in tumor site that creates diffusion length of air also donate to low air level in TME [6,14,15]. Furthermore, tumor-associated and/or therapy-induced anemia causes a reduced O2 transport capability from the blood, resulting in hypoxia in tumor sites [16]. Hypoxia is certainly connected with tumor metastasis, radiotherapy/chemotherapy level of resistance, and poor prognosis [15,17]. In hypoxic environment, tumor cells may use many systems to survive, including moving from aerobic to anaerobic fat burning capacity, erythropoietin (EPO) creation, deregulating DNA fix systems, recruiting the stromal elements, aswell as upregulating protooncogenes and hypoxia-inducible aspect (HIF) 1 and HIF 2 [18,19]. For an in depth review of concentrating on hypoxia in tumor therapy, please make reference to a recently available publication by Wilson and Hay [20]. To exploit the initial feature of hypoxia in TME, the healing agents tend to be designed as low-toxicity prodrugs in normoxia environment while selectively turned on in hypoxic tumor areas (Body?1). Papadopoulos et?al. [21] designed the hypoxia-activated prodrug AQ4N (banoxantrone) that’s changed into AQ4, a powerful inhibitor of topoisomerase II, in hypoxic areas. This prodrug is certainly applied to deal with advanced solid tumors such as for example bronchoalveolar lung tumor and ovarian tumor. Weiss et?al. [22] designed a hypoxia-activated prodrug TH-302 that’s contains 2-nitroimidazole, a hypoxia cause, and a brominated edition of isophosphoramide mustard (Br-IPM). This prodrug continues to be intact in regular air conditions and will be turned on in serious hypoxic circumstances ( 0.5% O2) release a Br-IPM, a DNA cross-linking agent. TH-302 displays antitumor actions in metastatic melanoma and little cell lung tumor (SCLC). Another hypoxic cell toxin is certainly tirapazamine (TPZ), which preferentially displays cytotoxic activity to hypoxic tumor cells. The root mechanism is certainly that TPZ forms a radical with the addition of an electron beneath the catalytic actions of varied intracellular reductases. This TPZ radical is certainly highly reactive and will result in DNA one- or double-strand breaks in hypoxic environment. Nevertheless, under aerobic circumstances, the TPZ radical is certainly back-oxidized into its non-toxic parent, and its own cytotoxicity is certainly decreased [15,23]. Another technique is certainly.