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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 -
Angewandte Chemie (International Ed. in... Sep 2020Tirapazamine (TPZ) has been tested in clinical trials on radio-chemotherapy due to its potential highly selective toxicity towards hypoxic tumor cells. It was suggested...
Tirapazamine (TPZ) has been tested in clinical trials on radio-chemotherapy due to its potential highly selective toxicity towards hypoxic tumor cells. It was suggested that either the hydroxyl radical or benzotriazinyl radical may form as bioactive radical after the initial reduction of TPZ in solution. In the present work, we studied low-energy electron attachment to TPZ in the gas phase and investigated the decomposition of the formed TPZ anion by mass spectrometry. We observed the formation of the (TPZ-OH) anion accompanied by the dissociation of the hydroxyl radical as by far the most abundant reaction pathway upon attachment of a low-energy electron. Quantum chemical calculations suggest that NH pyramidalization is the key reaction coordinate for the reaction dynamics upon electron attachment. We propose an OH roaming mechanism for other reaction channels observed, in competition with the OH dissociation.
PubMed: 32543771
DOI: 10.1002/anie.202006675 -
Journal of Nanobiotechnology Sep 2021Hypoxia is a characteristic of solid tumors that can lead to tumor angiogenesis and early metastasis, and addressing hypoxia presents tremendous challenges. In this...
BACKGROUND
Hypoxia is a characteristic of solid tumors that can lead to tumor angiogenesis and early metastasis, and addressing hypoxia presents tremendous challenges. In this work, a nanomedicine based on oxygen-absorbing perfluorotributylamine (PFA) and the bioreductive prodrug tirapazamine (TPZ) was prepared by using a polydopamine (PDA)-coated UiO-66 metal organic framework (MOF) as the drug carrier.
RESULTS
The results showed that TPZ/PFA@UiO-66@PDA nanoparticles significantly enhanced hypoxia, induced cell apoptosis in vitro through the oxygen-dependent HIF-1α pathway and decreased oxygen levels in vivo after intratumoral injection. In addition, our study demonstrated that TPZ/PFA@UiO-66@PDA nanoparticles can accumulate in the tumor region after tail vein injection and effectively inhibit tumor growth when combined with photothermal therapy (PTT). TPZ/PFA@UiO-66@PDA nanoparticles increased HIF-1α expression while did not promote the expression of CD31 in vivo during the experiment.
CONCLUSIONS
By using TPZ and PFA and the enhanced permeability and retention effect of nanoparticles, TPZ/PFA@UiO-66@PDA can target tumor tissues, enhance hypoxia in the tumor microenvironment, and activate TPZ. Combined with PTT, the growth of osteosarcoma xenografts can be effectively inhibited.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Fluorocarbons; Humans; Indoles; Male; Metal-Organic Frameworks; Mice; Mice, Nude; Nanoparticles; Osteosarcoma; Phthalic Acids; Polymers; Tirapazamine; Tumor Hypoxia
PubMed: 34592996
DOI: 10.1186/s12951-021-01013-0 -
Cancer Research Sep 2002Tirapazamine (TPZ), a hypoxia-selective cytotoxin, has demonstrated activity in cancer clinical trials. Under hypoxic conditions, TPZ is reduced to a radical that leads...
Tirapazamine (TPZ), a hypoxia-selective cytotoxin, has demonstrated activity in cancer clinical trials. Under hypoxic conditions, TPZ is reduced to a radical that leads to DNA double-strand breaks (DSBs), single-strand breaks, and base damage. A previous finding of an association of the DSBs with protein led us to investigate the involvement of topoisomerase II (topo II) in their formation. Nuclear extracts from human lung cancer cells treated with either the topo II poison etoposide or TPZ under hypoxic conditions had markedly reduced topo II activity as judged by an inability to convert kinetoplast DNA from the catenated to the decatenated form. Because topo II poisons, such as etoposide, cause DNA DSBs, we hypothesized that pretreatment of cells with merbarone or aclarubicin, known catalytic inhibitors of topo II, would abrogate DNA DSBs caused by topo II. Cells pretreated with these catalytic inhibitors abrogated both DNA DSBs and cell kill induced by etoposide or by TPZ. Etoposide- and TPZ-mediated DSBs were also greatly reduced in a small cell lung cancer cell line with low levels of nuclear topo IIalpha. We also showed that topo IIalpha becomes covalently bound to DNA after TPZ treatment under hypoxic conditions, and that the cleavable complexes formed by TPZ are more stable over time than those formed by etoposide. Taken together, these data suggest that TPZ exerts its cytotoxic effect at least in part through poisoning topo II. Because TPZ is activated only under hypoxic conditions, which are characteristic of solid tumors, these data implicate TPZ as a tumor-specific topo II poison.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Hypoxia; DNA Damage; DNA Topoisomerases, Type II; DNA, Neoplasm; Enzyme Inhibitors; Etoposide; HeLa Cells; Humans; Lung Neoplasms; Tirapazamine; Topoisomerase II Inhibitors; Triazines
PubMed: 12234992
DOI: No ID Found -
Molecular Cancer Therapeutics Mar 2014Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer....
Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1α (HIF-1α) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1α expression by decreasing HIF-1α protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1α protein, decreased the HIF-1α transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1α is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1α is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers.
Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Mice; Tirapazamine; Topoisomerase I Inhibitors; Triazines; Xenograft Model Antitumor Assays
PubMed: 24362462
DOI: 10.1158/1535-7163.MCT-13-0490 -
Oxidative Medicine and Cellular... 2012Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug,...
Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug, passes the same red-ox transformation as DOX. The aim of the study was to evaluate an effect of tirapazamine on oxidative stress, contractile protein level, and cardiomyocyte necrosis in rats administered doxorubicin. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses, 5 (5TP) and 10 mg/kg (10TP), while doxorubicin was administered in dose 1.8 mg/kg (DOX). Subsequent two groups received both drugs simultaneously (5TP+DOX and 10TP+DOX). Tirapazamine reduced heart lipid peroxidation and normalised RyR2 protein level altered by doxorubicin. There were no significant changes in GSH/GSSG ratio, total glutathione, cTnI, AST, and SERCA2 level between DOX and TP+DOX groups. Cardiomyocyte necrosis was observed in groups 10TP and 10TP+DOX.
Topics: Animals; Aspartate Aminotransferases; Biomarkers; Blotting, Western; Calcium; DNA; Doxorubicin; Drug Interactions; Eosinophilia; Male; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Oxidative Stress; Proteins; Rats; Rats, Wistar; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tirapazamine; Triazines; Troponin I
PubMed: 22666522
DOI: 10.1155/2012/890826 -
Journal of Materials Chemistry. B Jul 2021For cancer treatment, the traditional monotherapy has the problems of low drug utilization rate, poor efficacy and easy recurrence of the cancer. Herein, nanoparticles...
For cancer treatment, the traditional monotherapy has the problems of low drug utilization rate, poor efficacy and easy recurrence of the cancer. Herein, nanoparticles (NPs) based on a novel semiconducting molecule (ITTC) are developed with excellent photostability, high photothermal conversion efficiency and good 1O2 generation ability. The chemotherapy of the hypoxia-activated prodrug tirapazamine (TPZ) was improved accordingly after oxygen consumption by the photodynamic therapy of ITTC NPs. Additionally, the metabolic process of ITTC NPs in vivo could be monitored in real time for fluorescence imaging guided phototherapy, which presented great passive targeting ability to the tumor site. Remarkably, both in vitro and in vivo experiments demonstrated that the combination of ITTC NPs and TPZ presented excellent synergistic tumor ablation through photothermal therapy, photodynamic therapy and hypoxia-activated chemotherapy with great potential for clinical applications in the future.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Humans; Hypoxia; Injections, Intraperitoneal; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Nanoparticles; Neoplasms, Experimental; Optical Imaging; Photosensitizing Agents; Semiconductors; Tirapazamine
PubMed: 34231629
DOI: 10.1039/d1tb00659b -
British Journal of Cancer Jun 1998Human solid tumours are composed of a significant proportion of hypoxic cells, i.e. cells with oxygen levels lower than those of normal tissues. Tumour hypoxic cells... (Review)
Review
Human solid tumours are composed of a significant proportion of hypoxic cells, i.e. cells with oxygen levels lower than those of normal tissues. Tumour hypoxic cells have been shown to have a negative impact on the response of solid tumours to radiation therapy and chemotherapy. However, these low cellular oxygen levels can be exploited by a drug that is specifically activated to a cytotoxic metabolite at these low levels. Tirapazamine is a novel bioreductive agent with selective cytotoxicity to hypoxic tumour cells, irrespective of their p53 status or apoptotic response, and acts synergistically with cisplatin. This potentiation is dependent on an interaction that can only take place in a hypoxic environment, resulting in a significant sensitization of the cells to cisplatin cell killing, with no increase in the systemic toxicity of cisplatin. Thus, the low cellular oxygen levels common in solid tumours can be turned from disadvantage to advantage using the hypoxia-selective cytotoxic drug tirapazamine.
Topics: Antineoplastic Agents; Cell Hypoxia; Cisplatin; Genes, p53; Humans; Mutation; Neoplasms; Tirapazamine; Triazines
PubMed: 9647614
DOI: 10.1038/bjc.1998.430 -
Molecules (Basel, Switzerland) Oct 2020Hypoxia is an adverse prognostic feature of solid cancers that may be overcome with hypoxia-activated prodrugs (HAPs). Tirapazamine (TPZ) is a HAP which has undergone...
Hypoxia is an adverse prognostic feature of solid cancers that may be overcome with hypoxia-activated prodrugs (HAPs). Tirapazamine (TPZ) is a HAP which has undergone extensive clinical evaluation in this context and stimulated development of optimized analogues. However the subcellular localization of the oxidoreductases responsible for mediating TPZ-dependent DNA damage remains unclear. Some studies conclude only nuclear-localized oxidoreductases can give rise to radical-mediated DNA damage and thus cytotoxicity, whereas others identify a broader role for endoplasmic reticulum and cytosolic oxidoreductases, indicating the subcellular location of TPZ radical formation is not a critical requirement for DNA damage. To explore this question in intact cells we engineered MDA-231 breast cancer cells to express the TPZ reductase human NADPH: cytochrome P450 oxidoreductase (POR) harboring various subcellular localization sequences to guide this flavoenzyme to the nucleus, endoplasmic reticulum, cytosol or inner surface of the plasma membrane. We show that all POR variants are functional, with differences in rates of metabolism reflecting enzyme expression levels rather than intracellular TPZ concentration gradients. Under anoxic conditions, POR expression in all subcellular compartments increased the sensitivity of the cells to TPZ, but with a fall in cytotoxicity per unit of metabolism (termed 'metabolic efficiency') when POR is expressed further from the nucleus. However, under aerobic conditions a much larger increase in cytotoxicity was observed when POR was directed to the nucleus, indicating very high metabolic efficiency. Consequently, nuclear metabolism results in collapse of hypoxic selectivity of TPZ, which was further magnified to the point of reversing O dependence (oxic > hypoxic sensitivity) by employing a DNA-affinic TPZ analogue. This aerobic hypersensitivity phenotype was partially rescued by cellular copper depletion, suggesting the possible involvement of Fenton-like chemistry in generating short-range effects mediated by the hydroxyl radical. In addition, the data suggest that under aerobic conditions reoxidation strictly limits the TPZ radical diffusion range resulting in site-specific cytotoxicity. Collectively these novel findings challenge the purported role of intra-nuclear reductases in orchestrating the hypoxia selectivity of TPZ.
Topics: Antineoplastic Agents; Cell Engineering; Cell Hypoxia; Cell Line, Tumor; Cell Membrane; Cell Nucleus; Cell Survival; Copper; DNA Damage; Humans; Hypoxia; Models, Biological; NADPH-Ferrihemoprotein Reductase; Oxygen; Prodrugs; Tirapazamine
PubMed: 33105798
DOI: 10.3390/molecules25214888 -
Biomolecules Oct 2021Tumour hypoxia is significantly correlated with patient survival and treatment outcomes. At the molecular level, hypoxia is a major driving factor for tumour progression... (Review)
Review
Tumour hypoxia is significantly correlated with patient survival and treatment outcomes. At the molecular level, hypoxia is a major driving factor for tumour progression and aggressiveness. Despite the accumulative scientific and clinical efforts to target hypoxia, there is still a need to find specific treatments for tumour hypoxia. In this review, we discuss a variety of approaches to alter the low oxygen tumour microenvironment or hypoxia pathways including carbogen breathing, hyperthermia, hypoxia-activated prodrugs, tumour metabolism and hypoxia-inducible factor (HIF) inhibitors. The recent advances in technology and biological understanding reveal the importance of revisiting old therapeutic regimens and repurposing their uses clinically.
Topics: Animals; Humans; Prodrugs; Tumor Hypoxia
PubMed: 34827602
DOI: 10.3390/biom11111604