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Science Advances Mar 2021Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired...
Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair-inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; DNA Repair; Humans; Hypoxia; Nanomedicine; Neoplasms; Tirapazamine
PubMed: 33771859
DOI: 10.1126/sciadv.abc5267 -
Scientific Reports Feb 2021Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to...
Tumor tissue contains a continuous distribution of static and dynamically changing oxygen environments with levels ranging from physiologically normal oxygen down to anoxia. However, in vitro studies are often performed under oxygen levels that are far higher than those found in vivo. A number of devices are available to alter the oxygen environment in cell culture, including designs from our laboratory. However, in our devices and most other designs, changing the media in order to feed or dose cells remains a disruptive factor in maintaining a consistent hypoxic environment. This report presents a novel 96-well plate design that recirculates the local oxygen environment to shield cells during media changes and facilitates toxicity studies of cells cultured under varying oxygen levels. The principle behind the design is presented and the response of human pancreatic cancer PANC-1 cells treated with tirapazamine and doxorubicin under eight different static or cycling oxygen levels was measured. As expected, tirapazamine is progressively more toxic as oxygen levels decrease but retains some toxicity as oxygen is cycled between hypoxic and normoxic levels. Doxorubicin sensitivity is largely unaffected by changing oxygen levels. This technology is ideal for assessing the effects of oxygen as a variable in toxicity screens.
Topics: Cell Culture Techniques; Cell Hypoxia; Cell Line, Tumor; Doxorubicin; High-Throughput Screening Assays; Humans; Neoplasms; Oxygen; Pancreatic Neoplasms; Tirapazamine; Toxicity Tests; Triazines; Tumor Microenvironment
PubMed: 33597640
DOI: 10.1038/s41598-021-83579-1 -
Acta Pharmaceutica Sinica. B Jan 2021Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of... (Review)
Review
Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.
PubMed: 33532180
DOI: 10.1016/j.apsb.2020.09.016 -
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 -
Journal of Thoracic Disease Oct 2020Systemic treatment in small cell lung carcinoma has been a challenge for oncologists for decades. The high propensity for recurrence is usually due to distant... (Review)
Review
Systemic treatment in small cell lung carcinoma has been a challenge for oncologists for decades. The high propensity for recurrence is usually due to distant metastasis, which makes systemic treatment an essential component of treatment in small cell lung carcinoma. The regimen of cisplatin and etoposide (established in the mid-1980's) concurrently with thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) remains the standard of care in limited stage disease. Despite numerous trials, this regimen has not been improved upon. The standard combination regimen of cisplatin and etoposide has been compared to alternative platinum-containing regimens with drugs like epirubicin, irinotecan, paclitaxel, topotecan, pemetrexed, amrubicin and belotecan. Non-platinum containing regimens like ifosfamide and etoposide have also been tested. Attempts to intensify therapy have included the addition of a third drug like paclitaxel, ifosfamide, tirapazamine, tamoxifen, and thalidomide. Maintenance therapy following induction with chemotherapy, vandetanib and interferon-alpha have also been attempted. Molecularly directed targeted therapies and immunotherapeutic agents are areas of active research. In this review, we discuss the various systemic therapy options in limited stage small cell lung carcinoma, from the historical regimens to the modern-day therapy and promising areas of research. We also discuss the role of growth factors, the optimal number of chemotherapy cycles, the use of prognostic and predictive factors, the optimal timing of chemotherapy and the treatment of special populations of patients including older patients, and patients with comorbidities.
PubMed: 33209466
DOI: 10.21037/jtd-2019-sclc-11 -
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 -
Oncotarget Sep 2020Metastatic melanoma cells overexpressing gap junctions were assayed for their ability to propagate cell death by a novel combination therapy that generates reactive...
Metastatic melanoma cells overexpressing gap junctions were assayed for their ability to propagate cell death by a novel combination therapy that generates reactive oxygen species (ROS) by both 1) non-thermal plasma (NTP) and 2) tirapazamine (TPZ) under hypoxic conditions. Results demonstrate additive-to-synergistic effects of combination therapy compared to each agent individually. NTP induces highly localized cell death in target areas whereas TPZ partially reduces viability over the total surface area. However, when high gap junction expression was induced in melanoma cells, effects of combination NTP+TPZ therapy was augmented, spreading cell death across the entire plate. Similarly, studies of human metastatic melanoma in a mouse tumor model demonstrate that the combined effect of NTP+TPZ causes a 90% reduction in tumor volume, specifically in the model expressing gap junctions. Treatment with NTP+TPZ increases gene expression in the apoptotic pathway and oxidative stress while decreasing genes related to cell migration. Immune response was also elicited through differential regulation of cytokines and chemokines, suggesting potential for this therapy to induce a cytotoxic immune response with fewer side effects than current therapies. Interestingly, the gap junction protein, Cx26 was upregulated following treatment with NTP+TPZ and these gap junctions were shown to maintain functionality during the onset of treatment. Therefore, we propose that gap junctions both increase the efficacy of NTP+TPZ and perpetuate a positive feedback mechanism of gap junction expression and tumoricidal activity. Our unique approach to ROS induction in tumor cells with NTP+TPZ shows potential as a novel cancer treatment.
PubMed: 32973969
DOI: 10.18632/oncotarget.27732 -
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 -
APL Bioengineering Sep 2020Hepatocellular carcinoma (HCC) is an intractable cancer with a high mortality rate. Transarterial chemoembolization (TACE), a non-curative method, is the first line...
Hepatocellular carcinoma (HCC) is an intractable cancer with a high mortality rate. Transarterial chemoembolization (TACE), a non-curative method, is the first line therapy for intermediate stage patients. This effectively extends patient survival but requires a complicated intraarterial catheterization procedure and is poorly suited to repeated administration. Here, we investigate gas chemoembolization, a less invasive, more easily administered transient occlusion method that circumvents these limitations. We examined the efficacy of repeated embolization combined with systemically administered doxorubicin, the most common chemotherapeutic in TACE, or tirapazamine, a hypoxia-activated cytotoxic agent, in an ectopic xenograft model of HCC. Emboli were generated using acoustic droplet vaporization, the noninvasive focused ultrasound-mediated conversion of intravenously administered perfluorocarbon microdroplets into microbubbles. Gas embolization alone significantly reduced the Ki67 index and tumor viability (11.6 ± 6.71% non-necrotic vs 100% in control; p < 0.01) after 3 treatments, as assessed by histological analysis. Mice treated for three weeks exhibited significant tumor regression compared to control (23.8 ± 5.37% of initial volume vs 427 ± 49.7% in controls, p < 0.01), irrespective of the chosen chemotherapeutic agent. However, an additional three weeks of monitoring post-treatment elucidated a significant difference in the tumor recurrence rate, with combined gas embolization and doxorubicin resulting in the best treatment outcomes (60% complete regression). While doxorubicin administration resulted in significant cardiotoxicity (p < 0.01), it strongly interacted with the droplet shells, reducing the systemic dose by 11.4%. Overall, gas chemoembolization shows promise as a developmental therapy and merits further study in more complex tumor models.
PubMed: 32923844
DOI: 10.1063/5.0005329 -
Theranostics 2020Nanoscale vehicles responsive to abnormal variation in tumor environment are promising for use in targeted delivery of therapeutic drugs specifically to tumor sites....
Nanoscale vehicles responsive to abnormal variation in tumor environment are promising for use in targeted delivery of therapeutic drugs specifically to tumor sites. Herein, we report the design and fabrication of self-accelerating HO-responsive plasmonic gold nanovesicles (GVs) encapsulated with tirapazamine (TPZ) and glucose oxidase (GOx) for synergistic chemo/starving therapy of cancers. Gold nanoparticles were modified with HO-responsive amphiphilic block copolymer PEG--PABE by ligand exchange. The TPZ and GOx loaded GVs (TG-GVs) were prepared through the self-assembly of PEG--PABE -grafted nanoparticles together with TPZ and GOx by solvent displacement method. In response to HO in tumor, the TG-GVs dissociate to release the payloads that are, otherwise, retained inside the vesicles for days without noticeable leakage. The released GOx enzymes catalyze the oxidation of glucose by oxygen in the tumor tissue to enhance the degree of hypoxia that subsequently triggers the reduction of hypoxia-activated pro-drug TPZ into highly toxic free radicals. The HO generated in the GOx-catalyzed reaction also accelerate the dissociation of vesicles and hence the release rate of the cargoes in tumors. The drug-loaded GVs exhibit superior tumor inhibition efficacy in 4T1 tumor-bearing mice owing to the synergistic effect of chemo/starvation therapy, in addition to their use as contrast agents for computed tomography imaging of tumors. This nanoplatform may find application in managing tumors deeply trapped in viscera or other important tissues that are not compatible with external stimulus (e.g. light).
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Drug Synergism; Female; Glucose Oxidase; Gold; Humans; Hydrogen Peroxide; Metal Nanoparticles; Mice; Tirapazamine; Tomography, X-Ray Computed; Tumor Hypoxia; Xenograft Model Antitumor Assays
PubMed: 32754272
DOI: 10.7150/thno.45392