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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 -
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 -
Biomedicine & Pharmacotherapy =... Jul 2022Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for...
Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for liver cancer. To investigated whether TPZ-loaded microspheres enhance the synergy between TPZ and TAE in liver cancer, we prepared TPZ-loaded CalliSpheres microspheres (CSMTPZs) and characterized their properties as a chemoembolization agent in vitro. Tumor hypoxia after TAE was detected in the rabbit VX2 model of liver cancer using a modified Clark-type microelectrode research system. CSMTPZ therapy was performed in the animal model. The plasma and tumor concentrations of TPZ and its metabolites were measured, and the efficacy and safety of CSMTPZ therapy were evaluated and compared with those of the conventional combination of intraarterial TPZ injection and embolization. The results showed that CSMTPZs displayed favorable in vitro properties including drug loading and release and microsphere size, shape, and surface profiles. TAE induced acute tumor hypoxia, but residual tumor cells responded to hypoxia through hypoxia-inducible factor 1α. CSMTPZ therapy improved TPZ delivery into tumor tissue with minimal systemic exposure. Accordingly, CSMTPZ therapy exhibited advantages in terms of hypoxia-selected cytotoxicity, tumor apoptosis and necrosis, animal survival, and safety over the conventional combination of TPZ and TAE. We revealed the improved synergistic anti-tumor effects of CSMTPZ therapy in the rabbit VX2 liver cancer model. Our data support the clinical evaluation of CSMTPZs in the treatment of hepatocellular carcinoma, and CSMTPZ administration might serve as a successful therapeutic strategy for this malignancy.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Embolization, Therapeutic; Hypoxia; Liver Neoplasms; Microspheres; Rabbits; Tirapazamine
PubMed: 35594702
DOI: 10.1016/j.biopha.2022.113123 -
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 -
Cancers May 2023Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor,... (Review)
Review
Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as well as a hypoxic tumor, due to the liver being a relatively hypoxic environment compared to other organs. Trans-arterial chemoembolization (TACE) and trans-arterial embolization (TAE) are locoregional therapies that are part of the treatment guidelines for HCC but can also exacerbate hypoxia in tumors, as seen with HIF-1α upregulation post-hepatic embolization. Hypoxia-activated prodrugs (HAPs) are a novel class of anticancer agent that are selectively activated under hypoxic conditions, potentially allowing for the targeted treatment of hypoxic HCC. Early studies targeting hypoxia show promising results; however, further research is needed to understand the effects of HAPs in combination with embolization in the treatment of HCC. This review aims to summarize current knowledge on the role of hypoxia and HIF-1α in HCC, as well as the potential of HAPs and liver-directed embolization.
PubMed: 37345074
DOI: 10.3390/cancers15102738 -
Frontiers in Oncology 2021Hypoxia is an important characteristic of most solid malignancies, and is closely related to tumor prognosis and therapeutic resistance. Hypoxia is one of the most...
Hypoxia is an important characteristic of most solid malignancies, and is closely related to tumor prognosis and therapeutic resistance. Hypoxia is one of the most important factors associated with resistance to conventional radiotherapy and chemotherapy. Therapies targeting tumor hypoxia have attracted considerable attention. Hypoxia-activated prodrugs (HAPs) are bioreductive drugs that are selectively activated under hypoxic conditions and that can accurately target the hypoxic regions of solid tumors. Both single-agent and combined use with other drugs have shown promising antitumor effects. In this review, we discuss the mechanism of action and the current preclinical and clinical progress of several of the most widely used HAPs, summarize their existing problems and shortcomings, and discuss future research prospects.
PubMed: 34395270
DOI: 10.3389/fonc.2021.700407 -
Cancer Chemotherapy and Pharmacology Mar 2016The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour... (Review)
Review
The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high-priority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia-activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (1) the ability of oxygen to either reverse or inhibit the activation process and (2) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.
Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Drug Delivery Systems; Drug Design; Humans; Neoplasms; Oxidoreductases; Oxygen; Prodrugs; Tumor Microenvironment
PubMed: 26811177
DOI: 10.1007/s00280-015-2920-7 -
MethodsX 2023Tirapazamine (TPZ), a hypoxia-selective cytotoxic agent, has proved to exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) against...
Tirapazamine (TPZ), a hypoxia-selective cytotoxic agent, has proved to exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) against liver cancer. This advances TPZ to transcatheter therapies for liver cancer, particularly in combination with drug-eluting microspheres. We describe methods for preparing and characterizing TPZ-loaded CalliSpheres microspheres (CSMTPZs) with regard to their properties as a chemoembolization agent, which includes 1) preparation of CSMTPZs and determination of drug loading level, 2) determination of TPZ release, 3) assessment of CSMTPZ size and appearance, and 4) determination of TPZ pharmacokinetics and intratumoral drug concentration . These methods can be adapted for further clinical I trial.•This is to our knowledge the first methods for preparing and characterizing tirapazamine-loaded microspheres with regard to their properties as a chemoembolization agent•Detailed protocols for preparation of CSMTPZs, determination of drug loading level, determination of TPZ release, assessment of CSMTPZ size and appearance, and determination of TPZ pharmacokinetics and intratumoral drug concentration•Adaptable to experiments on other animal models and clinical trials.
PubMed: 37168773
DOI: 10.1016/j.mex.2023.102188 -
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 -
Microbiology Spectrum Aug 2023Pseudomonas aeruginosa is the most common pathogen infecting cystic fibrosis (CF) lungs, causing acute and chronic infections. Intrinsic and acquired antibiotic...
Repurposing High-Throughput Screening Identifies Unconventional Drugs with Antibacterial and Antibiofilm Activities against Pseudomonas aeruginosa under Experimental Conditions Relevant to Cystic Fibrosis.
Pseudomonas aeruginosa is the most common pathogen infecting cystic fibrosis (CF) lungs, causing acute and chronic infections. Intrinsic and acquired antibiotic resistance allow P. aeruginosa to colonize and persist despite antibiotic treatment, making new therapeutic approaches necessary. Combining high-throughput screening and drug repurposing is an effective way to develop new therapeutic uses for drugs. This study screened a drug library of 3,386 drugs, mostly FDA approved, to identify antimicrobials against P. aeruginosa under physicochemical conditions relevant to CF-infected lungs. Based on the antibacterial activity, assessed spectrophotometrically against the prototype RP73 strain and 10 other CF virulent strains, and the toxic potential evaluated toward CF IB3-1 bronchial epithelial cells, five potential hits were selected for further analysis: the anti-inflammatory and antioxidant ebselen, the anticancer drugs tirapazamine, carmofur, and 5-fluorouracil, and the antifungal tavaborole. A time-kill assay showed that ebselen has the potential to cause rapid and dose-dependent bactericidal activity. The antibiofilm activity was evaluated by viable cell count and crystal violet assays, revealing carmofur and 5-fluorouracil as the most active drugs in preventing biofilm formation regardless of the concentration. In contrast, tirapazamine and tavaborole were the only drugs actively dispersing preformed biofilms. Tavaborole was the most active drug against CF pathogens other than P. aeruginosa, especially against Burkholderia cepacia and Acinetobacter baumannii, while carmofur, ebselen, and tirapazamine were particularly active against Staphylococcus aureus and B. cepacia. Electron microscopy and propidium iodide uptake assay revealed that ebselen, carmofur, and tirapazamine significantly damage cell membranes, with leakage and cytoplasm loss, by increasing membrane permeability. Antibiotic resistance makes it urgent to design new strategies for treating pulmonary infections in CF patients. The repurposing approach accelerates drug discovery and development, as the drugs' general pharmacological, pharmacokinetic, and toxicological properties are already well known. In the present study, for the first time, a high-throughput compound library screening was performed under experimental conditions relevant to CF-infected lungs. Among 3,386 drugs screened, the clinically used drugs from outside infection treatment ebselen, tirapazamine, carmofur, 5-fluorouracil, and tavaborole showed, although to different extents, anti-P. aeruginosa activity against planktonic and biofilm cells and broad-spectrum activity against other CF pathogens at concentrations not toxic to bronchial epithelial cells. The mode-of-action studies revealed ebselen, carmofur, and tirapazamine targeted the cell membrane, increasing its permeability with subsequent cell lysis. These drugs are strong candidates for repurposing for treating CF lung P. aeruginosa infections.
Topics: Humans; Pseudomonas aeruginosa; Cystic Fibrosis; High-Throughput Screening Assays; Drug Repositioning; Tirapazamine; Anti-Bacterial Agents; Fluorouracil; Biofilms; Pseudomonas Infections
PubMed: 37306577
DOI: 10.1128/spectrum.00352-23