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Science (New York, N.Y.) Jul 2022Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT)....
Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; DNA Methylation; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Dacarbazine; Drug Design; Drug Resistance, Neoplasm; Glioblastoma; Humans; Temozolomide; Tumor Suppressor Proteins
PubMed: 35901163
DOI: 10.1126/science.abn7570 -
Journal of Experimental & Clinical... Feb 2022Glioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction...
BACKGROUND
Glioblastoma (GB) is the most common and highly malignant brain tumor characterized by aggressive growth and resistance to alkylating chemotherapy. Autophagy induction is one of the hallmark effects of anti-GB therapies with temozolomide (TMZ). However, the non-classical form of autophagy, autophagy-based unconventional secretion, also called secretory autophagy and its role in regulating the sensitivity of GB to TMZ remains unclear. There is an urgent need to illuminate the mechanism and to develop novel therapeutic targets for GB.
METHODS
Cancer genome databases and paired-GB patient samples with or without TMZ treatment were used to assess the relationship between HMGB1 mRNA levels and overall patient survival. The relationship between HMGB1 protein level and TMZ sensitivity was measured by immunohistochemistry, ELISA, Western blot and qRT-PCR. GB cells were engineered to express a chimeric autophagic flux reporter protein consisting of mCherry, GFP and LC3B. The role of secretory autophagy in tumor microenvironment (TME) was analyzed by intracranial implantation of GL261 cells. Coimmunoprecipitation (Co-IP) and Western blotting were performed to test the RAGE-NFκB-NLRP3 inflammasome pathway.
RESULTS
The exocytosis of HMGB1 induced by TMZ in GB is dependent on the secretory autophagy. HMGB1 contributed to M1-like polarization of tumor associated macrophages (TAMs) and enhanced the sensitivity of GB cells to TMZ. Mechanistically, RAGE acted as a receptor for HMGB1 in TAMs and through RAGE-NFκB-NLRP3 inflammasome pathway, HMGB1 enhanced M1-like polarization of TAMs. Clinically, the elevated level of HMGB1 in sera may serve as a beneficial therapeutic-predictor for GB patients under TMZ treatment.
CONCLUSIONS
We demonstrated that enhanced secretory autophagy in GB facilitates M1-like polarization of TAMs to enhance TMZ sensitivity of GB cells. HMGB1 acts as a key regulator in the crosstalk between GB cells and tumor-suppressive M1-like TAMs in GB microenvironment and may be considered as an adjuvant for the chemotherapeutic agent TMZ.
Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Autophagy; Cell Line, Tumor; Glioblastoma; Humans; Macrophages; Male; Mice; Temozolomide; Tumor Microenvironment
PubMed: 35193644
DOI: 10.1186/s13046-022-02291-8 -
Theranostics 2022The concentration and duration of intracellular drugs have always been the key factors for determining the efficacy of the treatment. Efflux of chemotherapeutic drugs...
The concentration and duration of intracellular drugs have always been the key factors for determining the efficacy of the treatment. Efflux of chemotherapeutic drugs or anticancer agents is a major reason for multidrug resistance generation in cancer cells. The high expression of polymerase I and transcript release factor (PTRF) is correlated with a worse prognosis in glioma patients. However, the importance of PTRF on temozolomide (TMZ) resistance in glioblastoma (GBM) is poorly understood. TCGA data analysis, CGGA data analysis, transmission electron microscopy (TEM), scanning electron microscopy (SEM), clone formation, cell counting kit-8 (cck-8), western blot (WB), immunofluorescence (IF), immunohistochemistry (IHC) and flow cytometry assays were performed to investigate the underlying mechanism and effect of PTRF on TMZ-resistance in a variety of GBM cell lines and GBM patient-derived xenograft (PDX) models. Clone formation, WB, IF, IHC and flow cytometry assays were performed to examine the efficacy of sequential therapy of TMZ followed by CQ in GBM cells and PDX models. The prognosis of GBM patients treated with TMZ was negatively correlated with PTRF expression. Our results reveal that PTRF knockdown significantly decrease proliferation and increase apoptosis in GBM after TMZ treatment. Moreover, PTRF contribute to TMZ-resistance by increasing TMZ efflux through extracellular vesicles (EVs). Furthermore, our results demonstrate that sequential therapy of TMZ followed by CQ significantly promotes the TMZ efficacy against GBM by increasing intracellular TMZ concentration ([TMZ]i). This study highlights that PTRF can act as an independent biomarker to predict the prognosis of GBM patients after TMZ treatment and describes a new mechanism contributing to TMZ-resistance. In addition, this study may provide a novel idea for GBM therapy.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Vesicles; Glioblastoma; Humans; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 35673568
DOI: 10.7150/thno.71763 -
International Journal of Molecular... Jun 2022Glioblastoma is a fatal brain tumor with a bleak prognosis. The use of chemotherapy, primarily the alkylating agent temozolomide, coupled with radiation and surgical... (Review)
Review
Glioblastoma is a fatal brain tumor with a bleak prognosis. The use of chemotherapy, primarily the alkylating agent temozolomide, coupled with radiation and surgical resection, has provided some benefit. Despite this multipronged approach, average patient survival rarely extends beyond 18 months. Challenges to glioblastoma treatment include the identification of functional pharmacologic targets as well as identifying drugs that can cross the blood-brain barrier. To address these challenges, current research efforts are examining metabolic differences between normal and tumor cells that could be targeted. Among the metabolic differences examined to date, the apparent addiction to exogenous methionine by glioblastoma tumors is a critical factor that is not well understood and may serve as an effective therapeutic target. Others have proposed this property could be exploited by methionine dietary restriction or other approaches to reduce methionine availability. However, methionine links the tumor microenvironment with cell metabolism, epigenetic regulation, and even mitosis. Therefore methionine depletion could result in complex and potentially undesirable responses, such as aneuploidy and the aberrant expression of genes that drive tumor progression. If methionine manipulation is to be a therapeutic strategy for glioblastoma patients, it is essential that we enhance our understanding of the role of methionine in the tumor microenvironment.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Epigenesis, Genetic; Glioblastoma; Humans; Methionine; Temozolomide; Tumor Microenvironment
PubMed: 35806160
DOI: 10.3390/ijms23137156 -
Molecules (Basel, Switzerland) Sep 2022DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA... (Review)
Review
DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA through different mechanisms with the aid of their unique scaffold and highly active functional groups. Therefore, the biosynthesis of these natural products has been extensively studied, especially the construction of their pharmacophores. Meanwhile, their producing strains have evolved corresponding self-resistance strategies to protect themselves. To further promote the functional characterization of their biosynthetic pathways and lay the foundation for the discovery and rational design of DNA alkylating agents, we summarize herein the progress of research into DNA-alkylating antitumor natural products, including their biosynthesis, modes of action, and auto-resistance mechanisms.
Topics: Alkylating Agents; Biological Products; Biosynthetic Pathways; DNA
PubMed: 36234921
DOI: 10.3390/molecules27196387 -
Journal of Hematology & Oncology Nov 2020The outcomes of multiple myeloma (MM) have been improved significantly with the therapies incorporating proteasome inhibitors (PI), immunomodulatory drugs, monoclonal... (Review)
Review
The outcomes of multiple myeloma (MM) have been improved significantly with the therapies incorporating proteasome inhibitors (PI), immunomodulatory drugs, monoclonal antibodies (MoAb) and stem cell transplantation. However, relapsed and refractory MM (RRMM) remains a major challenge. Novel agents and regimens are under active clinical development. These include new PIs such as ixazomib, marizomib, and oprozomib; new MoAbs such as isatuximab and MOR202; novel epigenetic agent ricolinostat and novel cytokines such as siltuximab. Recently, the first XPO-1 inhibitor, selinexor, was approved for RRMM. BCMA-targeted BiTE, antibody-drug conjugates and CAR-T cells have the potential to revolutionize the therapy for RRMM. In this review, we summarized the latest clinical development of these novel agents and regimens.
Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Immunotherapy, Adoptive; Multiple Myeloma; Proteasome Inhibitors
PubMed: 33168044
DOI: 10.1186/s13045-020-00980-5 -
Neurologia Medico-chirurgica 2015Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly... (Review)
Review
Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly diagnosed GBM. One of the main reasons accounting for the dismal prognosis is attributed to lack of active therapeutic regimens at recurrence. Since TMZ is the most active cytotoxic agent against GBM, and the standard dosing of TMZ has shown favorable safety profile in clinical trials, re-challenge with TMZ in increased dose density schedules for recurrent tumors that have evaded from prior standard TMZ therapy appears to be a rational approach and has been intensively exploited. A number of phase II clinical trials using different alternating scheduling of dose-dense TMZ (ddTMZ) have shown superior efficacy over the standard TMZ or historical controls with other alkylating agents including nitrosoureas and procarbazine. One ddTMZ schedule, consisting of a 21-days on/7-days off regimen was applied to newly-diagnosed GBM as the adjuvant monotherapy after completion of combined radiation and TMZ and failed to demonstrate survival benefit in a large phase III trial (RTOG 0525). Thus its role in TMZ-pretreated, recurrent GBM should be carefully pursuit in randomized trials, e.g., planned JCOG 1308 trial comparing a 7-days on/7-days off ddTMZ regimen used upfront at the first relapse followed by bevacizumab on progression versus bevacizumab alone, investigating whether insertion of ddTMZ prior to bevacizumab could bestow better outcome in the recurrent setting. In this article, mode of action, past trials, and future directions of ddTMZ therapy are discussed.
Topics: Antineoplastic Agents, Alkylating; Clinical Trials as Topic; Dacarbazine; Disease Progression; Dose-Response Relationship, Drug; Glioblastoma; Humans; Recurrence; Temozolomide
PubMed: 25744349
DOI: 10.2176/nmc.ra.2014-0277 -
Toxicology Letters Feb 2020Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to... (Review)
Review
Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to asthma, bronchitis, bronchiectasis, airway stenosis, and pulmonary fibrosis. As there are no specific therapeutics available for victims of mustard gas poisoning, current clinical treatments mostly provide only symptomatic relief. In this article, the long-term effects of mustards on the respiratory tract are described in humans and experimental animal models in an effort to define cellular and molecular mechanisms contributing to lung injury and disease pathogenesis. A better understanding of mechanisms underlying pulmonary toxicity induced by mustards may help in identifying potential targets for the development of effective clinical therapeutics aimed at mitigating their adverse effects.
Topics: Alkylating Agents; Animals; Chemical Warfare Agents; Humans; Lung; Lung Injury; Mustard Compounds; Pulmonary Fibrosis; Respiratory Tract Diseases
PubMed: 31698045
DOI: 10.1016/j.toxlet.2019.10.026 -
Marine Drugs Feb 2015Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological... (Review)
Review
Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression-free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas.
Topics: Animals; Antineoplastic Agents, Alkylating; Clinical Trials, Phase II as Topic; Dioxoles; Humans; Sarcoma; Tetrahydroisoquinolines; Trabectedin
PubMed: 25686274
DOI: 10.3390/md13020974 -
Current Opinion in Chemical Biology Oct 2023Per- and polysulfides are sulfane sulfur species produced inside living cells, in organisms as diverse as bacteria, plants and humans, but their biological roles remain... (Review)
Review
Per- and polysulfides are sulfane sulfur species produced inside living cells, in organisms as diverse as bacteria, plants and humans, but their biological roles remain to be fully understood. Unfortunately, due to their reactivity, per- and polysulfides are easily altered, interconverted or lost during the processing and analysis of biological material. Thus, all current analytical methods make use of alkylating agents, to quench reactivity of hydropersulfides and hydropolysulfides and also to prevent free thiols from attacking sulfur chains in hydropolysulfides and dialkyl polysulfides. However, recent findings reveal that alkylating agents can also destroy per- and polysulfides, to varying degrees, depending on the choice of alkylating agent. Here, we discuss the challenges associated with the alkylation of per- and polysulfides, the single most important step for their preservation and detection in biological samples.
Topics: Humans; Alkylating Agents; Sulfides; Sulfur; Sulfhydryl Compounds
PubMed: 37473483
DOI: 10.1016/j.cbpa.2023.102368