-
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 -
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 -
AJNR. American Journal of Neuroradiology Sep 2010Temozolomide, an oral alkylating agent, is a commonly used medicine in the treatment of anaplastic astrocytoma and glioblastoma multiforme. This paper will present the...
Temozolomide, an oral alkylating agent, is a commonly used medicine in the treatment of anaplastic astrocytoma and glioblastoma multiforme. This paper will present the mechanism of action as well as the clinical role for this chemotherapeutic drug.
Topics: Administration, Oral; Antineoplastic Agents, Alkylating; Astrocytoma; Brain Neoplasms; Dacarbazine; Drug Costs; Glioblastoma; Humans; Temozolomide
PubMed: 20538821
DOI: 10.3174/ajnr.A2170 -
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 -
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 -
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 -
Future Oncology (London, England) Jun 2014Trabectedin (Yondelis®; PharmaMar, Madrid, Spain), a synthetic anticancer agent originally isolated from the Caribbean tunicate, Ecteinascidia turbinata, is currently... (Review)
Review
Trabectedin (Yondelis®; PharmaMar, Madrid, Spain), a synthetic anticancer agent originally isolated from the Caribbean tunicate, Ecteinascidia turbinata, is currently approved in more than 70 countries worldwide for the treatment of soft tissue sarcoma (STS). Trabectedin is an isoquinoline alkylating agent that, unlike other alkylating agents, binds in the DNA minor groove to initiate cytotoxic activity. Other multitarget mechanisms of action of trabectedin include important effects within the tumor microenvironment; in particular, trabectedin possesses indirect anti-inflammatory and anti-angiogenic activity via tumor-associated macrophages and high-specificity modulation of various transcription factors. The clinical efficacy of trabectedin, administered intravenously over 24 h every 3 weeks, has been demonstrated in several studies in patients with STS. In the Phase II STS-201 trial, 270 patients with liposarcoma or leiomyosarcoma were randomized to receive trabectedin 1.5 mg/m(2) given as a 24-h intravenous (iv.) infusion every 3 weeks or as a weekly regimen (0.58 mg/m(2); 3-h iv. infusion for three consecutive weeks in a 4-week cycle). There was a statistically significant and clinically relevant 27% reduction in the risk of disease progression (primary end point) with trabectedin given as a 24-h infusion q3w (p = 0.0302) with an overall survival rate at 12 months of 60%. Trabectedin was generally well tolerated; the most frequently reported severe adverse events were neutropenia (47% of patients) and elevated transaminases (47%). Overall, the majority of adverse events were mild to moderate and, despite a long duration of exposure to trabectedin in some patients, no cumulative toxicities were experienced.
Topics: Animals; Antineoplastic Agents, Alkylating; Clinical Trials, Phase II as Topic; Dioxoles; Humans; Sarcoma; Tetrahydroisoquinolines; Trabectedin; Treatment Outcome
PubMed: 25048043
DOI: 10.2217/fon.14.117 -
Frontiers in Endocrinology 2022Alkylating agents (AAs) that are commonly used for cancer therapy cause great damage to the ovary. Pyrroloquinoline-quinine (PQQ), which was initially identified as a...
Alkylating agents (AAs) that are commonly used for cancer therapy cause great damage to the ovary. Pyrroloquinoline-quinine (PQQ), which was initially identified as a redox cofactor for bacterial dehydrogenases, has been demonstrated to benefit the fertility of females. The aim of this study was to investigate whether PQQ dietary supplementation plays a protective role against alkylating agent-induced ovarian dysfunction. A single dose of busulphan (20 mg/kg) and cyclophosphamide (CTX, 120 mg/kg) were used to establish a mouse model of ovarian dysfunction. Feed containing PQQNa (5 mg/kg) was provided starting 1 week before the establishment of the mouse model until the date of sacrifice. One month later, estrous cycle period of mice were examined and recorded for consecutive 30 days. Three months later, some mice were mated with fertile male mice for fertility test. The remaining mice were sacrificed to collect serum samples and ovaries. One day before sacrifice, some mice received a single injection of BrdU to label proliferating cells. Serum samples were used for test hormonal levels. Ovaries were weighted and used to detect follicle counts, cell proliferation, cell apoptosis and cell senescence. In addition, the levels of inflammation, oxidative damage and Pgc1α expression were detected in ovaries. Results showed that PQQ treatment increased the ovarian weight and size, partially normalized the disrupted estrous cycle period and prevented the loss of follicles of mice treated with AAs. More importantly, we found that PQQ treatment significantly increased the pregnancy rate and litter size per delivery of mice treated with AAs. The protective effects of PQQ appeared to be directly mediated by promoting cell proliferation of granulosa, and inhibiting cell apoptosis of granulosa and cell senescence of ovarian stromal cells. The underlying mechanisms may attribute to the anti-oxidative stress, anti-inflammation and pro-mitochondria biogenesis effects of PQQ.Our study highlights the therapeutic potential of PQQ against ovarian dysfunction caused by alkylating agents.
Topics: Alkylating Agents; Animals; Dietary Supplements; Female; Male; Mice; Ovarian Follicle; Pregnancy; Pyrroles; Quinine; Quinolines
PubMed: 35340329
DOI: 10.3389/fendo.2022.781404 -
Molecules (Basel, Switzerland) Aug 2014PM00104 (Zalypsis®) is a synthethic tetrahydroisoquinolone alkaloid, which is structurally similar to many marine organisms. The compound has been proposed as a... (Review)
Review
PM00104 (Zalypsis®) is a synthethic tetrahydroisoquinolone alkaloid, which is structurally similar to many marine organisms. The compound has been proposed as a potential chemotherapeutic agent in the treatment of solid human tumors and hematological malignancies. PM00104 is a DNA binding agent, causing inhibition of the cell cycle and transcription, which can lead to double stranded DNA breaks. After rigorous pre-clinical testing, the drug has been evaluated in a number of phase II clinical trials. This manuscript provides a review of current trials and appraises the efficacy of PM00104 as a future cancer treatment.
Topics: Antineoplastic Agents, Alkylating; Aquatic Organisms; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Humans; Neoplasms; Tetrahydroisoquinolines
PubMed: 25153860
DOI: 10.3390/molecules190812328