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International Journal of Molecular... Apr 20233-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and other heteroaromatic -oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities....
3-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and other heteroaromatic -oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities. Their action is attributed to the enzymatic single-electron reduction to free radicals that initiate the prooxidant processes. In order to clarify the mechanisms of aerobic mammalian cytotoxicity of ArN→O, we derived a TPZ-resistant subline of murine hepatoma MH22a cells (resistance index, 5.64). The quantitative proteomic of wild-type and TPZ-resistant cells revealed 5818 proteins, of which 237 were up- and 184 down-regulated. The expression of the antioxidant enzymes aldehyde- and alcohol dehydrogenases, carbonyl reductases, catalase, and glutathione reductase was increased 1.6-5.2 times, whereas the changes in the expression of glutathione peroxidase, superoxide dismutase, thioredoxin reductase, and peroxiredoxins were less pronounced. The expression of xenobiotics conjugating glutathione-S-transferases was increased by 1.6-2.6 times. On the other hand, the expression of NADPH:cytochrome P450 reductase was responsible for the single-electron reduction in TPZ and for the 2.1-fold decrease. These data support the fact that the main mechanism of action of TPZ under aerobic conditions is oxidative stress. The unchanged expression of intranuclear antioxidant proteins peroxiredoxin, glutaredoxin, and glutathione peroxidase, and a modest increase in the expression of DNA damage repair proteins, tend to support non-site-specific but not intranuclear oxidative stress as a main factor of TPZ aerobic cytotoxicity.
Topics: Animals; Mice; Tirapazamine; Triazines; Antineoplastic Agents; Antioxidants; Carcinoma, Hepatocellular; Proteomics; Oxidation-Reduction; Liver Neoplasms; Glutathione Peroxidase; Mammals
PubMed: 37047836
DOI: 10.3390/ijms24076863 -
Journal of Controlled Release :... Nov 2022Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor...
Photodynamic therapy (PDT) can produce a large amount of reactive oxygen species (ROS) in the radiation field to kill tumor cells. However, the sustainable anti-tumor efficacy of PDT is limited due to the hypoxic microenvironment of tumor. In this study, classic PDT agent indocyanine green (ICG) and hypoxia-activated chemotherapeutic drug tirapazamine (TPZ) were loaded on mesoporous polydopamine (PDA) to construct PDA@ICG-TPZ nanoparticles (PIT). Then, PIT was camouflaged with cyclic arginine-glycine-aspartate (cRGD) modified tumor cell membranes to obtain the engineered membrane-coated nanoreactor (cRGD-mPIT). The nanoreactor cRGD-mPIT could achieve the dual-targeting ability via tumor cell membrane mediated homologous targeting and cRGD mediated active targeting. With the enhanced tumor-targeting and penetrating delivery system, PIT could efficiently accumulate in hypoxic tumor cells and the loaded drugs were quickly released in response to near-infrared (NIR) laser. The nanoreactor might produce cytotoxic ROS under NIR and further enhance hypoxia within tumor to activate TPZ, which efficiently inhibited hypoxic tumor by synergistic photodynamic-chemotherapy. Mechanically, hypoxia-inhibitory factor-1α (HIF-1α) was down-regulated by the synergistic therapy. Accordingly, the cRGD-mPIT nanoreactor with sustainable and cascade anti-tumor effects and satisfied biosafety might be a promising strategy in hypoxic tumor therapy.
Topics: Humans; Reactive Oxygen Species; Biomimetics; Tirapazamine; Photochemotherapy; Neoplasms; Indocyanine Green; Hypoxia; Nanoparticles; Nanotechnology; Cell Line, Tumor; Photosensitizing Agents; Tumor Microenvironment
PubMed: 36122895
DOI: 10.1016/j.jconrel.2022.09.020 -
International Journal of Molecular... Nov 2020Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to...
Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and ferredoxin:NADP oxidoreductase (FNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and FNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O ( 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and FNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic oxides.
Topics: Aerobiosis; Animals; Anti-Bacterial Agents; Antioxidants; Antiprotozoal Agents; Cell Line, Tumor; Cell Survival; Cyclic N-Oxides; Dicumarol; Enzyme Assays; Enzyme Inhibitors; Ferredoxin-NADP Reductase; HCT116 Cells; Hepatocytes; Humans; Kinetics; Mice; NAD(P)H Dehydrogenase (Quinone); NADPH-Ferrihemoprotein Reductase; Oxidation-Reduction; Plasmodium falciparum; Protozoan Proteins; Rats; Tirapazamine
PubMed: 33228195
DOI: 10.3390/ijms21228754 -
Technology in Cancer Research &... 2022The tumor microenvironment is complex and changeable, so the design of a nano-delivery system for the tumor microenvironment has attracted wide attention. Based on this,...
The tumor microenvironment is complex and changeable, so the design of a nano-delivery system for the tumor microenvironment has attracted wide attention. Based on this, we designed an intelligent nano-reactor for the characteristics of acidic pH and hypoxia in the tumor microenvironment. Firstly, the silver nano-balls were synthesized by the biological template method, which exhibited a good photothermal conversion efficiency and can realize the photothermal treatment of tumor sites. Subsequently, the hypoxic prodrug tirapazamine (TPZ) and polydopamine (PDA) for chemotherapy were self-assembled. After PDA arrived at the tumor site (pH 5.5) from the normal physiological environment (pH 7.4), the hypoxic prodrug TPZ was released in pH response by PDA. Subsequently, TPZ selectively induced obvious cell damage under tumor hypoxia stimulation but had no toxic effect on normal cells under normal oxygen. In addition, the nano-converter was loaded with iRGD on the surface, which enhanced the targeted delivery of the nano-reactor to achieve a highly effective antitumor effect. The nano-reactor was capable of combining photothermal/chemotherapy therapy. Importantly, it can selectively kill tumor cells without damaging normal cells based on the characteristics of the tumor microenvironment, with high bio-safety and clinical transformation potential.
Topics: Cell Line, Tumor; Humans; Nanoparticles; Neoplasms; Prodrugs; Tirapazamine; Tumor Microenvironment
PubMed: 35712964
DOI: 10.1177/15330338221095670 -
Cancers Aug 2021Hypoxia is a key characteristic of the tumor microenvironment, too rarely considered during drug development due to the lack of a user-friendly method to culture...
Hypoxia is a key characteristic of the tumor microenvironment, too rarely considered during drug development due to the lack of a user-friendly method to culture naturally hypoxic 3D tumor models. In this study, we used soft lithography to engineer a microfluidic platform allowing the culture of up to 240 naturally hypoxic tumor spheroids within an 80 mm by 82.5 mm chip. These jumbo spheroids on a chip are the largest to date (>750 µm), and express gold-standard hypoxic protein CAIX at their core only, a feature absent from smaller spheroids of the same cell lines. Using histopathology, we investigated response to combined radiotherapy (RT) and hypoxic prodrug Tirapazamine (TPZ) on our jumbo spheroids produced using two sarcoma cell lines (STS117 and SK-LMS-1). Our results demonstrate that TPZ preferentially targets the hypoxic core (STS117: = 0.0009; SK-LMS-1: = 0.0038), but the spheroids' hypoxic core harbored as much DNA damage 24 h after irradiation as normoxic spheroid cells. These results validate our microfluidic device and jumbo spheroids as potent fundamental and pre-clinical tools for the study of hypoxia and its effects on treatment response.
PubMed: 34439199
DOI: 10.3390/cancers13164046 -
Acta Pharmaceutica Sinica. B Aug 2020Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the... (Review)
Review
Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.
PubMed: 32963938
DOI: 10.1016/j.apsb.2020.01.004 -
Journal of Nanobiotechnology Jan 2022Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton...
BACKGROUND
Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.
RESULTS
In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.
CONCLUSIONS
The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Dendrimers; Mice; Nanostructures; Tirapazamine; Tumor Microenvironment
PubMed: 35062953
DOI: 10.1186/s12951-022-01247-6 -
Acta Pharmaceutica Sinica. B Apr 2022Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great...
Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great clinical significance, yet remain a major challenge. Photodynamic therapy (PDT) realizes potent ablation efficacy under precise manipulation of laser irradiation. In this study, we constructed theranostic nanoprobes (NPs), which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging. The NPs were formulated from human serum albumin (HSA) conjugated with a high affinity-peptide targeting osteopontin (OPN) and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine (TPZ). After intravenous injection into atherosclerotic mice, the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery. Under the visible guidance of fluorescence and MR dual-model imaging, the precise near-infrared (NIR) laser irradiation generated massive reactive oxygen species (ROS), which resulted in efficient plaque ablation and amplified hypoxia within VASPs. In response to the elevated hypoxia, the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages. After therapeutic administration of the NPs for 2 weeks, the plaque area and the degree of carotid artery stenosis were markedly reduced. Furthermore, the formulated NPs displayed excellent biocompatibility. In conclusion, the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.
PubMed: 35847489
DOI: 10.1016/j.apsb.2021.12.020 -
Journal of Molecular Modeling May 2021Tirapazamine (TP) has been shown to enhance the cytotoxic effects of ionizing radiation in hypoxic cells, thus making it a candidate for a radiosensitizer. This...
Tirapazamine (TP) has been shown to enhance the cytotoxic effects of ionizing radiation in hypoxic cells, thus making it a candidate for a radiosensitizer. This selective behavior is often directly linked to the abundance of O. In this paper, we study the electronic properties of TP in vacuum, micro-hydrated from one up to three molecules of water and embedded in a continuum of water. We discuss electron affinities, charge distribution, and bond dissociation energies of TP, and find that these properties do not change significantly upon hydration. In agreement with its large electron affinity, and bond breaking triggered by electron attachment requires energies higher than 2.5 eV, ruling out the direct formation of bioactive TP radicals. Our results suggest, therefore, that the selective behavior of TP cannot be explained by a one-electron reduction from a neighboring O molecule. Alternatively, we propose that TP's hypoxic selectivity could be a consequence of O scavenging hydrogen radicals.
Topics: Models, Chemical; Models, Molecular; Radiation-Sensitizing Agents; Tirapazamine
PubMed: 34021836
DOI: 10.1007/s00894-021-04771-8 -
International Journal of Molecular... Sep 2019Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is...
Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN→O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase/adrenodoxin (ADR/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR/ADX-catalyzed single-electron reduction, the reactivity of ArN→O ( = 9) increased with their single-electron reduction midpoint potential (), and correlated with the reactivity of quinones. NQO1 reduced ArN→O at low rates with concomitant superoxide production. The cytotoxicity of ArN→O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their , being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 α-naphthoflavone, isoniazid and miconazole statistically significantly ( < 0.02) decreased the toxicity of ArN→O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN→O is higher than that of quinones. This is partly attributed to ArN→O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN→O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia.
Topics: Antineoplastic Agents; Biomarkers; Humans; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); NADP; Oxidants; Oxidation-Reduction; Reactive Oxygen Species; Tirapazamine
PubMed: 31533349
DOI: 10.3390/ijms20184602