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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 -
Viruses Oct 2016Human cytomegalovirus is a ubiquitous β-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion...
Human cytomegalovirus is a ubiquitous β-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of-addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface. Podofilox was also able to drastically reduce infection by herpes simplex 1, an α-herpesvirus with a very similar entry process to CMV. Podofilox caused a reduced maximal plateau inhibition of infection by viruses with single step binding processes prior to fusion-like Newcastle disease virus, Sendai virus, and influenza A virus or viruses that enter via endocytosis like vesicular stomatitis virus and a clinical-like strain of CMV. These results indicate that microtubules appear to be participating in the post-binding step of virus entry including the pre- and post-penetration events. Modulation of the plasma membrane is required to promote virus entry for herpesviruses, and that podofilox, unlike colchicine or nocodazole, is able to preferentially target microtubule networks at the plasma membrane.
Topics: Antiviral Agents; Cell Line; Cytomegalovirus; Herpesvirus 1, Human; Humans; Podophyllotoxin; RNA Viruses; Tubulin Modulators; Virus Internalization
PubMed: 27783035
DOI: 10.3390/v8100295 -
Phytochemistry May 2000Podophyllin, an ethanolic extract of Podophyllum peltatum L. or P. emodi Wall (syn. P. hexandnum Royle), is a good source of the aryltetralin-type lignan,... (Review)
Review
Podophyllin, an ethanolic extract of Podophyllum peltatum L. or P. emodi Wall (syn. P. hexandnum Royle), is a good source of the aryltetralin-type lignan, podophyllotoxin. The latter compound, as well as its congeners and derivatives exhibit pronounced biological activity mainly as strong antiviral agents and as antineoplastic drugs. The podophyllotoxin derivatives etoposide, etopophos (etoposide phosphate), and teniposide are thus successfully utilized in the treatment of a variety of malignant conditions. Continued research on the Podophyllum lignans is currently focused on structure optimization to generate derivatives with superior pharmacological profiles and broader therapeutic scope, and the development of alternative and renewable sources of podophyllotoxin.
Topics: Podophyllotoxin
PubMed: 10872202
DOI: 10.1016/s0031-9422(00)00094-7 -
Lancet (London, England) Apr 1989In a double-blind trial, 0.5% podofilox (podophyllotoxin) or placebo was applied by patients to their own genital warts in up to four treatment cycles. At some time... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
In a double-blind trial, 0.5% podofilox (podophyllotoxin) or placebo was applied by patients to their own genital warts in up to four treatment cycles. At some time during the study, 25 of the 56 podofilox treated patients and none of the 53 placebo group were completely wart-free. At the end of the treatment, 73.6% of the original warts in podofilox treated patients were gone compared with only 8.3% of those in the placebo group (mean percentage of total original wart area was reduced by 82.3% compared with 4.2%). 82% of the treated warts in the podofilox group and 13% in the placebo group had resolved at 6 weeks. Recurrence was observed in 34% of the previously resolved warts. Consistent with this rate of recurrence, new warts developed in a third of the subjects in each group at sites remote from the treatment site. There were no systemic adverse reactions, although transient inflammation, erosion, pain, and burning were common.
Topics: Administration, Topical; Adult; Condylomata Acuminata; Double-Blind Method; Drug Administration Schedule; Follow-Up Studies; Humans; Male; Multicenter Studies as Topic; Penile Diseases; Podophyllotoxin; Random Allocation; Recurrence; Self Administration
PubMed: 2564912
DOI: 10.1016/s0140-6736(89)92282-4 -
Efficacy and safety of 0.5% podofilox solution in the treatment and suppression of anogenital warts.The American Journal of Medicine May 1994For the patient-administered treatment of anogenital warts, 0.5% podofilox (podophyllotoxin), one of the active compounds of podophyllin, has been shown to be more... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
For the patient-administered treatment of anogenital warts, 0.5% podofilox (podophyllotoxin), one of the active compounds of podophyllin, has been shown to be more effective than the vehicle alone. This study was designed to evaluate the safety and efficacy of 0.5% podofilox treatment followed by prophylaxis.
PATIENTS AND METHODS
A total of 103 patients were entered in stage 1 of the study. Stage 1 was an open label study, and patients self-administered 0.5% podofilox twice daily for 3 consecutive days per week for 4 weeks. A total of 100 patients remained available for efficacy and safety analyses. At the end of stage 1, patients who had a complete response proceeded to stage 2 of the study. Patients who had a 50% to 99% reduction in measured total wart area were offered cryotherapy every 10 days, up to 5 times. If cleared of warts, they were also entered into stage 2. A total of 57 patients were enrolled into stage 2, a double-blind, randomized, placebo-controlled prophylactic study of 0.5% podofilox self-administered once daily for 3 days per week for 8 weeks, on the sites of healed warts. A total of 45 patients in stage 2 were available for efficacy analysis.
RESULTS
By the end of stage 1, 68% of the warts had disappeared, and 29 of 100 patients (29%) had a complete response. A total of 49 patients had a 50% or greater improvement in wart area and underwent cryotherapy. Rates of local side effects after 1 week of treatment were 57% for inflammation, 39% for erosion, 47% for pain, 48% for burning, and 44% for itching. However, these symptoms and signs were mostly mild to moderate in intensity and diminished over time. Therefore, overall treatment was well tolerated. In stage 2, only 4 of 21 patients (19%) in the podofilox group experienced a recurrence as opposed to 12 of 24 (50%) in the placebo group (P = 0.031). As in stage 1, the side effects were modest, and the drug was well tolerated.
CONCLUSION
This study confirms the efficacy and good tolerance of 0.5% podofilox in the treatment of anogenital warts. It also establishes the safety and superior efficacy of patient-administered podofilox over the vehicle alone as prophylaxis against recurrence of lesions. Although long-term efficacy and tolerance remain to be established, podofilox appears to be a useful agent in the control of this disease.
Topics: Adult; Anus Diseases; Combined Modality Therapy; Condylomata Acuminata; Cryosurgery; Dermatitis, Contact; Double-Blind Method; Female; Follow-Up Studies; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Pain; Placebos; Podophyllotoxin; Pruritus; Recurrence; Remission Induction; Safety
PubMed: 8192173
DOI: 10.1016/0002-9343(94)90168-6 -
Archives of Dermatology Jan 1998To determine the safety and efficacy of a new gel formulation of podofilox in the treatment of anogenital warts. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
OBJECTIVE
To determine the safety and efficacy of a new gel formulation of podofilox in the treatment of anogenital warts.
DESIGN
Double-blind, randomized, multicenter, vehicle-controlled investigation.
SETTING
Private dermatology practices, university clinics (dermatology, gynecology, and infectious diseases), and contract research organizations.
PATIENTS
Three hundred twenty-six patients with anogenital warts.
MAIN OUTCOME MEASURE
Number of patients with clearing of all treated warts (treatment success).
RESULTS
The 0.5% podofilox gel was significantly better than vehicle gel for successfully eliminating and reducing the number and size of anogenital warts. In the intent-to-treat population, 62 (37.1%) of 167 patients treated with 0.5% podofilox gel had complete clearing of the treated areas (treatment successes) compared with 2 (2.3%) of 86 patients who had clearing of warts with the vehicle gel (P < .001) after 4 weeks. Nineteen additional patients treated with 0.5% podofilox gel and 2 patients treated with vehicle gel had clearing of warts with continued treatment up to 8 weeks. After 8 weeks, 35.9% of the baseline anogenital warts treated with 0.5% podofilox gel remained; this was significantly fewer than in the vehicle-treated group (88.4% of the baseline number) (P = .001). The 0.5% podofilox gel was generally well tolerated, with predominantly mild or moderate local adverse reactions occurring in the majority of patients. Only 7 patients (3.2%), all receiving 0.5% podofilox gel, discontinued study treatment because of drug-related local reactions.
CONCLUSIONS
The results demonstrated that 0.5% podofilox gel is safe and significantly more effective than vehicle gel in the treatment of anogenital warts.
Topics: Administration, Cutaneous; Adult; Anus Diseases; Condylomata Acuminata; Double-Blind Method; Drug Eruptions; Female; Gels; Genital Diseases, Female; Genital Diseases, Male; Headache; Humans; Keratolytic Agents; Male; Pharmaceutical Vehicles; Podophyllotoxin; Pruritus; Safety; Sensation Disorders; Treatment Outcome
PubMed: 9449907
DOI: 10.1001/archderm.134.1.33 -
American Family Physician Dec 2004Genital warts caused by human papillomavirus infection are encountered commonly in primary care. Evidence guiding treatment selection is limited, but treatment... (Review)
Review
Genital warts caused by human papillomavirus infection are encountered commonly in primary care. Evidence guiding treatment selection is limited, but treatment guidelines recently have changed. Biopsy, viral typing, acetowhite staining, and other diagnostic measures are not routinely required. The goal of treatment is clearance of visible warts; some evidence exists that treatment reduces infectivity, but there is no evidence that treatment reduces the incidence of cervical and genital cancer. The choice of therapy is based on the number, size, site, and morphology of lesions, as well as patient preferences, cost, convenience, adverse effects, and clinician experience. Patient-applied therapy such as imiquimod cream or podofilox is increasingly recommended. Podofilox, imiquimod, surgical excision, and cryotherapy are the most convenient and effective options. Fluorouracil and interferon are no longer recommended for routine use. The cost per successful treatment course is approximately dollars 200 to dollars 300 for podofilox, cryotherapy, electrodesiccation, surgical excision, laser treatment, and the loop electrosurgical excision procedure.
Topics: Algorithms; Aminoquinolines; Condylomata Acuminata; Cryotherapy; Decision Trees; Diagnosis, Differential; Electrosurgery; Evidence-Based Medicine; Family Practice; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Imiquimod; Keratolytic Agents; Laser Therapy; Male; Patient Selection; Podophyllotoxin; Practice Guidelines as Topic; Primary Health Care; Treatment Outcome
PubMed: 15617297
DOI: No ID Found -
Current Medicinal Chemistry 2015
Topics: Antineoplastic Agents, Phytogenic; Biological Products; Camptothecin; Humans; Paclitaxel; Podophyllotoxin; Vinca Alkaloids
PubMed: 26502948
DOI: 10.2174/092986732230151019101908 -
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 -
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