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The Journal of Clinical Investigation Aug 2019Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few...
Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death (ICD)-inducing drugs available that can kill cancer cells, enhance tumor immunogenicity, increase the in vivo immune infiltration, and thereby boosting a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immuno-stimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still investigational. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and T cell activation assay. We identified that teniposide, a DNA topoisomerase II inhibitor, could induce high mobility group box 1 (HMGB1) release and type I interferon signaling in tumor cells, and teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling including NF-κB activation and STING-dependent type I interferon signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 on multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity, and enabled a potential chemo-immunotherapeutic approach to potentiate the therapeutic efficacy of anti-PD1 immunotherapy.
Topics: Animals; Cell Line, Tumor; Female; HEK293 Cells; Humans; Immunity, Cellular; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Proteins; Neoplasms, Experimental; Nucleotidyltransferases; Signal Transduction; T-Lymphocytes; Teniposide; Topoisomerase II Inhibitors; Xenograft Model Antitumor Assays
PubMed: 31408442
DOI: 10.1172/JCI127471 -
Pharmacological Research Jun 2018In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop... (Review)
Review
In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2 BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.
Topics: Animals; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Drug Delivery Systems; Humans
PubMed: 29604436
DOI: 10.1016/j.phrs.2018.03.021 -
Journal For Immunotherapy of Cancer Aug 2022Emerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity....
BACKGROUND
Emerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity. Previous studies demonstrate that the conventional chemotherapy agent, teniposide, effectively promotes the therapeutic efficacy of programmed cell death protein-1 antibody (PD-1 Ab) through robust cGAS-STING activation. Unfortunately, the cGAS expression of tumor cells is reported to be severely suppressed by the hypoxic status in solid tumor. Clinically, enhancing chemotherapy-induced, DNA-activated tumor STING signaling by alleviating tumor hypoxia might be one possible direction for improving the currently poor response rates of patients with hepatocellular carcinoma (HCC) to PD-1 Ab.
METHODS
Teniposide was first screened out from several chemotherapy drugs according to their potency in inducing cGAS-STING signaling in human HCC cells. Teniposide-treated HCC cells were then cultured under hypoxia, normoxia or reoxygenation condition to detect change in cGAS-STING signaling. Next, oxaliplatin/teniposide chemotherapy alone or combined with hyperbaric oxygen (HBO) therapy was administered on liver orthotopic mouse tumor models, after which the tumor microenvironment (TME) was surveyed. Lastly, teniposide alone or combined with HBO was performed on multiple mouse tumor models and the subsequent anti-PD-1 therapeutic responses were observed.
RESULTS
Compared with the first-line oxaliplatin chemotherapy, teniposide chemotherapy induced stronger cGAS-STING signaling in human HCC cells. Teniposide-induced cGAS-STING activation was significantly inhibited by hypoxia inducible factor 1α in an oxygen-deficient environment in vitro and the inhibition was rapidly removed via effective reoxygenation. HBO remarkably enhanced the cGAS-STING-dependent tumor type Ⅰ interferon and nuclear factor kappa-B signaling induced by teniposide in vivo, both of which contributed to the activation of dendritic cells and subsequent cytotoxic T cells. Combined HBO with teniposide chemotherapy improved the therapeutic effect of PD-1 Ab in multiple tumor models.
CONCLUSIONS
By combination of two therapies approved by the Food and Drug Administration, we safely stimulated an immunogenic, T cell-inflamed HCC TME, leading to further sensitization of tumors to anti-PD-1 immunotherapy. These findings might enrich therapeutic strategies for advanced HCC andwe can attempt to improve the response rates of patients with HCC to PD-1 Ab by enhancing DNA-activated STING signaling through effective tumor reoxygenation.
Topics: Animals; Antibodies; Carcinoma, Hepatocellular; Humans; Hyperbaric Oxygenation; Hypoxia; Liver Neoplasms; Membrane Proteins; Mice; Nucleotidyltransferases; Oxaliplatin; Oxygen; Teniposide; Tumor Microenvironment; United States
PubMed: 36002188
DOI: 10.1136/jitc-2021-004006 -
Pharmaceuticals (Basel, Switzerland) Oct 2023Topoisomerases are very important enzymes that regulate DNA topology and are vital for biological actions like DNA replication, transcription, and repair. The emergence... (Review)
Review
Topoisomerases are very important enzymes that regulate DNA topology and are vital for biological actions like DNA replication, transcription, and repair. The emergence and spread of cancer has been intimately associated with topoisomerase dysregulation. Topoisomerase inhibitors have consequently become potential anti-cancer medications because of their ability to obstruct the normal function of these enzymes, which leads to DNA damage and subsequently causes cell death. This review emphasizes the importance of topoisomerase inhibitors as marketed, clinical and preclinical anti-cancer medications. In the present review, various types of topoisomerase inhibitors and their mechanisms of action have been discussed. Topoisomerase I inhibitors, which include irinotecan and topotecan, are agents that interact with the DNA-topoisomerase I complex and avert resealing of the DNA. The accretion of DNA breaks leads to the inhibition of DNA replication and cell death. On the other hand, topoisomerase II inhibitors like etoposide and teniposide, function by cleaving the DNA-topoisomerase II complex thereby effectively impeding the release of double-strand DNA breaks. Moreover, the recent advances in exploring the therapeutic efficacy, toxicity, and MDR (multidrug resistance) issues of new topoisomerase inhibitors have been reviewed in the present review.
PubMed: 37895927
DOI: 10.3390/ph16101456 -
Avicenna Journal of Phytomedicine 2017The aim of the present review is to give an overview about the role, biosynthesis, and characteristics of Podophyllotoxin (PTOX) as a potential antitumor agent with... (Review)
Review
OBJECTIVE
The aim of the present review is to give an overview about the role, biosynthesis, and characteristics of Podophyllotoxin (PTOX) as a potential antitumor agent with particular emphasis on key biosynthesis processes, function of related enzymes and characterization of genes encoding the enzymes.
MATERIALS AND METHODS
Google scholar, PubMed and Scopus were searched for literatures which have studied identification, characterization, fermentation and therapeutic effects of PTOX and published in English language until end of 2016.
RESULTS
PTOX is an important plant-derived natural product, has derivatives such as etoposide and teniposide, which have been used as therapies for cancers and venereal wart. PTOX structure is closely related to the aryltetralin lactone lignans that have antineoplastic and antiviral activities. Wall. (syn. ) and L. (Berberidaceae) are the major sources of PTOX. It has been shown that ferulic acid and methylenedioxy substituted cinnamic acid are the enzymes involved in PTOX synthesis. PTOX prevents cell growth via polymerization of tubulin, leading to cell cycle arrest and suppression of the formation of the mitotic-spindles microtubules.
CONCLUSION
Several investigations have been performed in biosynthesis of PTOX such as cultivation of these plants, though they were unsuccessful. Thus, it is important to find alternative sources to satisfy the pharmaceutical demand for PTOX. Moreover, further preclinical studies are warranted to explore the molecular mechanisms of these agents in treatment of cancer and their possible potential to overcome chemoresistance of tumor cells.
PubMed: 28884079
DOI: No ID Found -
Plants (Basel, Switzerland) Sep 2022Lignans are a group of natural polyphenols present in medicinal plants and in plants which are a part of the human diet for which more and more pharmacological... (Review)
Review
Lignans are a group of natural polyphenols present in medicinal plants and in plants which are a part of the human diet for which more and more pharmacological activities, such as antimicrobial, anti-inflammatory, hypoglycemic, and cytoprotective, are being reported. However, it is their cytotoxic activities that are best understood and which have shed light on this group. Two anticancer drugs, etoposide, and teniposide, were derived from a potent cytotoxic agent-podophyllotoxin from the roots of . The evidence from clinical and observational studies suggests that human microbiota metabolites (enterolactone, enterodiol) of dietary lignans (secoisolariciresinol, pinoresinol, lariciresinol, matairesinol, syringaresinol, medioresinol, and sesamin) are associated with a reduced risk of some hormone-dependent cancers. The biological in vitro, pharmacological in vivo investigations, and clinical studies demand significant amounts of pure compounds, as well as the use of well-defined and standardized extracts. That is why proper extract preparation, optimization of lignan extraction, and identification are crucial steps in the development of lignan use in medicine. This review focuses on lignan extraction, purification, fractionation, separation, and isolation methods, as well as on chromatographic, spectrometric, and spectroscopic techniques for their qualitative and quantitative analysis.
PubMed: 36079704
DOI: 10.3390/plants11172323 -
Avicenna Journal of Phytomedicine 2021Many pharmaceutical factories have dramatically improved the quality of herbal remedies in cancer treatment. The results of somestudies have shown anticancer effect of... (Review)
Review
OBJECTIVE
Many pharmaceutical factories have dramatically improved the quality of herbal remedies in cancer treatment. The results of somestudies have shown anticancer effect of genus Therefore, the aim of this article was to review the chemical ingredients and biological effects of genus especially from the family Apiaceae (Umbelliferae).
MATERIALS AND METHODS
Online databases ScienceDirect, PubMed, Scopus, and Google Scholar were searched using the keywords , Apiaceae, Biologic, Phytochemistry, and Benzodioxole to retrieve studies published between 1970 and 2020.
RESULTS
The genus has two species, (Boiss.) Drude and (L.) Drude. In this genus, 5 new biologically active phytochemicals with benzodioxole structure were introduced and their biological effects were assessed.
CONCLUSION
Since many of the most commonly used anticancer drugs such as etoposide, teniposide, podophyllotoxin and sanguinarine have benzodioxole structureand according to the results of biological tests, it seems that more researchwith these perspectives should be done on this genus.
PubMed: 33628716
DOI: No ID Found -
Journal of Ethnopharmacology Jan 2021The subtribe Hyptidinae contains approximately 400 accepted species distributed in 19 genera (Hyptis, Eriope, Condea, Cantinoa, Mesosphaerum, Cyanocephalus, Hypenia,... (Review)
Review
ETHNOPHARMACOLOGICAL RELEVANCE
The subtribe Hyptidinae contains approximately 400 accepted species distributed in 19 genera (Hyptis, Eriope, Condea, Cantinoa, Mesosphaerum, Cyanocephalus, Hypenia, Hyptidendron, Oocephalus, Medusantha, Gymneia, Marsypianthes, Leptohyptis, Martianthus, Asterohyptis, Eplingiella, Physominthe, Eriopidion and Rhaphiodon). This is the Lamiaceae clade with the largest number of species in Brazil and high rates of endemism. Some species have been used in different parts of the world mainly as insecticides/pest repellents, wound healing and pain-relief agents, as well as for the treatment of respiratory and gastrointestinal disorders.
AIM OF THE REVIEW
This review aims to discuss the current status concerning the taxonomy, ethnobotanical uses, phytochemistry and biological properties of species which compose the subtribe Hyptidinae.
MATERIALS AND METHODS
The available information was collected from scientific databases (ScienceDirect, Pubmed, Web of Science, Scopus, Google Scholar, ChemSpider, SciFinder ACS Publications, Wiley Online Library), as well as other literature sources (e.g. books, theses).
RESULTS
The phytochemical investigations of plants of this subtribe have led to the identification of almost 300 chemical constituents of different classes such as diterpenes, triterpenes, lignans, α-pyrones, flavonoids, phenolic acids and monoterpenes and sesquiterpenes, as components of essential oils. Extracts, essential oils and isolated compounds showed a series of biological activities such as insecticide/repellent, antimicrobial and antinociceptive, justifying some of the popular uses of the plants. In addition, a very relevant fact is that several species produce podophyllotoxin and related lignans.
CONCLUSION
Several species of Hyptidinae are used in folk medicine for treating many diseases but only a small fraction of the species has been explored and most of the traditional uses have not been validated by current investigations. In addition, the species of the subtribe appear to be very promising as alternative sources of podophyllotoxin-like lignans which are the lead compounds for the semi-synthesis of teniposide and etoposide, important antineoplastic agents. Thus, there is a wide-open door for future studies, both to support the popular uses of the plants and to find new biologically active compounds in this large number of species not yet explored.
Topics: Animals; Anti-Ulcer Agents; Ethnobotany; Ethnopharmacology; Humans; Hypoglycemic Agents; Lamiaceae; Medicine, Traditional; Phytochemicals; Plant Extracts
PubMed: 32763419
DOI: 10.1016/j.jep.2020.113225