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Cancer Immunology Research May 2023Cyclic GMP-AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I IFNs and...
Cyclic GMP-AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I IFNs and other cytokines. Pharmacologic activation of STING is considered a potent therapeutic strategy in cancer. In this study, we used a cell-based phenotypic screen and identified podophyllotoxin (podofilox), a microtubule destabilizer, as a robust enhancer of the cGAMP-STING signaling pathway. We found that podofilox enhanced the cGAMP-mediated immune response by increasing STING-containing membrane puncta and the extent of STING oligomerization. Furthermore, podofilox changed the trafficking pattern of STING and delayed trafficking-mediated STING degradation. Importantly, the combination of cGAMP and podofilox had profound antitumor effects on mice by activating the immune response through host STING signaling. Together, these data provide insights into the regulation of cGAMP-STING pathway activation and demonstrate what we believe to be a novel approach for modulating this pathway and thereby promoting antitumor immunity.
Topics: Animals; Mice; Podophyllotoxin; Membrane Proteins; Signal Transduction; Neoplasms; Immunity, Innate
PubMed: 36921097
DOI: 10.1158/2326-6066.CIR-22-0483 -
Cytokine Aug 2023For more than 40 years, the epipodophyllotoxin drug etoposide is prescribed to treat cancer. This semi-synthetic compound remains extensively used to treat advanced... (Review)
Review
For more than 40 years, the epipodophyllotoxin drug etoposide is prescribed to treat cancer. This semi-synthetic compound remains extensively used to treat advanced small-cell lung cancer and in various chemotherapy regimen for autologous stem cell transplantation, and other anticancer protocols. Etoposide is a potent topoisomerase II poison, causing double-stranded DNA breaks which lead to cell death if they are not repaired. It is also a genotoxic compound, responsible for severe side effects and secondary leukemia occasionally. Beyond its well-recognized function as an inducer of cancer cell death (a "killer on the road"), etoposide is also useful to treat immune-mediated inflammatory diseases associated with a cytokine storm syndrome. The drug is essential to the treatment of hemophagocytic lymphohistiocytosis (HLH) and the macrophage activation syndrome (MAS), in combination with a corticosteroid and other drugs. The use of etoposide to treat HLH, either familial or secondary to a viral or parasitic infection, or treatment-induced HLH and MAS is reviewed here. Etoposide dampens inflammation in HLH patients via an inhibition of the production of pro-inflammatory mediators, such as IL-6, IL-10, IL-18, IFN-γ and TNF-α, and reduction of the secretion of the alarmin HMGB1. The modulation of cytokines production by etoposide contributes to deactivate T cells and to dampen the immune stimulation associated to the cytokine storm. This review discussed the clinical benefits and mechanism of action of etoposide (a "rider on the storm") in the context of immune-mediated inflammatory diseases, notably life-threatening HLH and MAS. The question arises as to whether the two faces of etoposide action can apply to other topoisomerase II inhibitors.
Topics: Humans; Etoposide; Cytokine Release Syndrome; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome
PubMed: 37269699
DOI: 10.1016/j.cyto.2023.156234 -
International Journal of Radiation... Jul 2022
Topics: Carmustine; Cytarabine; Etoposide; Humans
PubMed: 35777390
DOI: 10.1016/j.ijrobp.2021.07.1704 -
Journal Der Deutschen Dermatologischen... Jun 2023Various interventions have been applied to treat molluscum contagiosum, but benefits and efficacy remain unclear. To assess the comparative efficacy and safety of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVES
Various interventions have been applied to treat molluscum contagiosum, but benefits and efficacy remain unclear. To assess the comparative efficacy and safety of interventions for molluscum contagiosum, a network meta-analysis was performed.
PATIENTS AND METHODS
Embase, PubMed, and the Cochrane Library were searched for articles published between January 1, 1990, and November 31, 2020. Eligible studies were randomized clinical trials (RCTs) of interventions in immunocompetent children and adults with genital/non-genital molluscum contagiosum lesions.
RESULTS
Twelve interventions from 25 RCTs including 2,123 participants were assessed. Compared with the placebo, ingenol mebutate had the most significant effect on complete clearance (odds ratio [OR] 117.42, 95% confidence interval [CI] 6.37-2164.88), followed by cryotherapy (OR 16.81, 95% CI 4.13-68.54), podophyllotoxin (OR 10.24, 95% CI 3.36-31.21), and potassium hydroxide (KOH) (OR 10.02, 95% CI 4.64-21.64). Data on adverse effects were too scarce for quantitative synthesis.
CONCLUSIONS
Ingenol mebutate, cryotherapy, podophyllotoxin, and KOH were more effective than the other interventions in achieving complete clearance, but safety concerns regarding ingenol mebutate have recently been reported. Due to the possibility of spontaneous resolution, observation is also justified for asymptomatic infection. Factors including adverse effects, cost, patient preference, and medical accessibility should be considered.
Topics: Child; Adult; Humans; Molluscum Contagiosum; Podophyllotoxin; Network Meta-Analysis; Cryotherapy; Randomized Controlled Trials as Topic
PubMed: 37199262
DOI: 10.1111/ddg.15063 -
Drug Discovery Today Aug 2023Numerous tubulin-targeted podophyllotoxin congeners have been designed and synthesized to overcome the poor water solubility of podophyllotoxin and improve its... (Review)
Review
Numerous tubulin-targeted podophyllotoxin congeners have been designed and synthesized to overcome the poor water solubility of podophyllotoxin and improve its pharmaceutical characteristics. Understanding the interaction of tubulin with its downstream signal transduction pathways is important for insights into the role of tubulin in the anticancer action of podophyllotoxin-based conjugates. In this review, we provide a detailed account of recent advances in tubulin targeting-podophyllotoxin derivatives with a focus on their antitumor action and potential molecular signaling pathways directly involved in tubulin depolymerization. Such information will be of benefit to researchers designing and developing anticancer drugs derived from podophyllotoxin. Moreover, we also discuss the associated challenges and future opportunities in this field.
Topics: Podophyllotoxin; Tubulin; Antineoplastic Agents; Structure-Activity Relationship
PubMed: 37236524
DOI: 10.1016/j.drudis.2023.103640 -
Biochemical Pharmacology Jun 2022Podophyllotoxin (PPT) has attracted researchers' attention because of its ability to treat various ailments. A series of podophyllotoxin derivatives (PPTs) have been... (Review)
Review
Podophyllotoxin (PPT) has attracted researchers' attention because of its ability to treat various ailments. A series of podophyllotoxin derivatives (PPTs) have been synthesized as candidate drugs to improve the pharmacological characteristics of PPT. Nowadays, an increasing number of reviews have summarized structure-optimization, anticancer application, and single nano delivery of PPT and PPTs. In this review, we focus on the multidirectional pharmacological properties of PPT and PPTs, with an emphasis on the crosstalk with anticancer, anti-inflammatory, immunosuppression, and antivirals. Besides, the newly uncovered mechanisms governing PPT and PPTs in anticancer property including non-apoptotic regulated cell death are discussed. Moreover, their co-delivery nanocarriers with other antitumor drugs or biological agents that have the potential to achieve increased targeting efficacy are included. We hope that a better comprehension of this subject will help to provide a reference for improving the druggability and expanding the clinical application of podophyllotoxin and its derivatives.
Topics: Antineoplastic Agents; Podophyllotoxin
PubMed: 35436465
DOI: 10.1016/j.bcp.2022.115039 -
Biomolecules Apr 2021Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is... (Review)
Review
Podophyllotoxin, along with its various derivatives and congeners are widely recognized as broad-spectrum pharmacologically active compounds. Etoposide, for instance, is the frontline chemotherapeutic drug used against various cancers due to its superior anticancer activity. It has recently been redeveloped for the purpose of treating cytokine storm in COVID-19 patients. Podophyllotoxin and its naturally occurring congeners have low bioavailability and almost all these initially discovered compounds cause systemic toxicity and development of drug resistance. Moreover, the production of synthetic derivatives that could suffice for the clinical limitations of these naturally occurring compounds is not economically feasible. These challenges demanded continuous devotions towards improving the druggability of these drugs and continue to seek structure-optimization strategies. The discovery of renewable sources including microbial origin for podophyllotoxin is another possible approach. This review focuses on the exigency of innovation and research required in the global R&D and pharmaceutical industry for podophyllotoxin and related compounds based on recent scientific findings and market predictions.
Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Cytokine Release Syndrome; Drug Discovery; Drug Repositioning; Humans; Neoplasms; Podophyllotoxin; Podophyllum; COVID-19 Drug Treatment
PubMed: 33921719
DOI: 10.3390/biom11040603 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2024Podophyllotoxin is an aryltetralin lignan lactone derived from different plants of Podophyllum. It consists of five rings with four chiral centers, one trans-lactone and... (Review)
Review
Podophyllotoxin is an aryltetralin lignan lactone derived from different plants of Podophyllum. It consists of five rings with four chiral centers, one trans-lactone and one aryl tetrahydronaphthalene skeleton with multiple modification sites. Moreover, podophyllotoxin and its derivatives showed lots of bioactivities, including anticancer, anti-inflammatory, antiviral, and insecticidal properties. The demand for podophyllotoxin and its derivatives is rising as a result of their high efficacy. As a continuation of our previous review (Chem. Eur. J., 2017, 23, 4467-4526), herein, total synthesis, biotransformation, structural modifications, bioactivities, and structure-activity relationships of podophyllotoxin and its derivatives from 2017 to 2022 are summarized. Meanwhile, a piece of update information on the origin of new podophyllotoxin analogues from plants from 2014 to 2022 was compiled. We hope that this review will provide a reference for future high value-added applications of podophyllotoxin and its analogues in the pharmaceutical and agricultural fields.
Topics: Podophyllotoxin; Structure-Activity Relationship; Lignans; Lactones; Biology
PubMed: 37814110
DOI: 10.1002/chem.202302595 -
Minerva Chirurgica Feb 2018Condylomata acuminata are the most common sexually transmitted disease worldwide. They are not usually a serious problem, but it causes emotional distress to patient and... (Review)
Review
INTRODUCTION
Condylomata acuminata are the most common sexually transmitted disease worldwide. They are not usually a serious problem, but it causes emotional distress to patient and physician alike because of its marked tendency to recurrence. The presence of anogenital warts mandates treatment, also for potential degeneration of the lesions.
EVIDENCE ACQUISITION
A review of the literature has been performed to analyze proposed treatments for anogenital warts.
EVIDENCE SYNTHESIS
Many treatments have been employed. They include cytotoxic agents, immunomodulation and physical ablation. The choice of the appropriate treatment varies depending on the number, size, and location of warts. Complications of various treatments are rare but include permanent depigmentation, itching, pain, scarring, bleeding, anal stenosis or incontinence and sepsis. The therapy of these lesions can sometimes be very painful and expensive, and therapy should not be worse than the disease.
CONCLUSIONS
No specific antiviral treatment is currently available, and no consensus has been reached on the appropriate treatment for anogenital warts. No data are available to indicate whether treatment eliminates infectivity, the primary aim of treatment being to remove the lesions. There is a paucity of published randomized trials. Despite the introduction of antiviral treatments such as interferon, immunomodulating agents or imiquimod, surgical destruction or removal remains the treatment of choice.
Topics: Aminoquinolines; Antiviral Agents; Anus Diseases; Condylomata Acuminata; Cryotherapy; Cytotoxins; Electrosurgery; Female; Humans; Imiquimod; Immunologic Factors; Interferons; Laser Therapy; Male; Papillomaviridae; Papillomavirus Infections; Photochemotherapy; Podophyllotoxin
PubMed: 29154519
DOI: 10.23736/S0026-4733.17.07554-X -
Chemistry (Weinheim An Der Bergstrasse,... Apr 2017Podophyllotoxin and its related aryltetralin cyclolignans belong to a family of important products that exhibit various biological properties (e.g., cytotoxic,... (Review)
Review
Podophyllotoxin and its related aryltetralin cyclolignans belong to a family of important products that exhibit various biological properties (e.g., cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, antispasmogenic, and hypolipidemic activities). This Review provides a survey of podophyllotoxin and its analogues isolated from plants. In particular, recent developments in the elegant total chemical synthesis, structural modifications, biosynthesis, and biotransformation of podophyllotoxin and its analogues are summarized. Moreover, a deoxypodophyllotoxin-based chemosensor for selective detection of mercury ion is described. In addition to the most active podophyllotoxin derivatives in each series against human cancer cell lines and insect pests listed in the tables, the structure-activity relationships of podophyllotoxin derivatives as cytotoxic and insecticidal agents are also outlined. Future prospects and further developments in this area are covered at the end of the Review. We believe that this Review will provide necessary information for synthetic, medicinal, and pesticidal chemistry researchers who are interested in the chemistry and biology of podophyllotoxins.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Cell Proliferation; Humans; Insecta; Insecticides; Larva; Podophyllotoxin; Podophyllum; Structure-Activity Relationship
PubMed: 27726183
DOI: 10.1002/chem.201602472