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Toxicology and Applied Pharmacology Oct 2018We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more...
We previously reported that podophyllotoxin acetate (PA) inhibits the growth and proliferation of non-small cell lung cancer (NSCLC) cells and also makes them more sensitive to radiation and chemotherapeutic agents. In an attempt to enhance PA activity, we synthesized 34 derivatives based on podophyllotoxin (PPT). Screening of the derivative compounds for anti-cancer activity against NSCLC led to the identification of β-apopicropodophyllin (APP) as a strong anti-cancer agent. In addition to its role as an immunosuppressive regulator of the T-cell mediated immune response, the compound additionally showed anti-cancer activity against A549, NCI-H1299 and NCI-460 cell lines with IC values of 16.9, 13.1 and 17.1 nM, respectively. The intracellular mechanisms underlying the effects of APP were additionally examined. APP treatment caused disruption of microtubule polymerization and DNA damage, which led to cell cycle arrest, as evident from accumulation of phospho-CHK2, p21, and phospho-Cdc2. Moreover, APP stimulated the pro-apoptotic ER stress signaling pathway, indicated by elevated levels of BiP, phospho-PERK, phospho-eIF2α, CHOP and ATF4. We further observed activation of caspase-3, -8 and -9, providing evidence that both intrinsic and extrinsic apoptotic pathways were triggered. In vivo, APP inhibited tumor growth of NSCLC xenografts in nude mice by promoting apoptosis. Our results collectively support a novel role of APP as an anticancer agent that evokes apoptosis by inducing microtubule disruption, DNA damage, cell cycle arrest and ER stress.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Death; Cell Line, Tumor; DNA Damage; Endoplasmic Reticulum Stress; Humans; Molecular Structure; Podophyllin
PubMed: 30170025
DOI: 10.1016/j.taap.2018.08.022 -
Pediatric Dermatology Sep 2019Anogenital verrucae (AV) are benign, human papillomavirus (HPV)-induced tumors of the anogenital skin and mucosa. Medical therapy for AV in preadolescents has not been...
BACKGROUND/OBJECTIVES
Anogenital verrucae (AV) are benign, human papillomavirus (HPV)-induced tumors of the anogenital skin and mucosa. Medical therapy for AV in preadolescents has not been well studied. We explore the efficacy and safety profile of sinecatechins 15% ointment and imiquimod 5% cream in the treatment of AV, alone and in combination therapy with other commonly used medications.
METHODS
A single-institution, retrospective review of children under 12 years of age with AV treated with imiquimod 5% cream and sinecatechins 15% ointment was performed. Demographic data, side effects, and outcomes of therapy were recorded for each patient, and overall efficacy was determined.
RESULTS
A total of 37 patients met inclusion criteria. Responses were seen in 8 out of 9 patients treated with sinecatechins 15% ointment (5 full, 3 partial, and 1 no response) and 9 out of 17 patients treated with imiquimod 5% cream (4 full, 5 partial, and 8 no response). Combination therapy with one or more of the following treatments (podophyllin, cimetidine, candida antigen injection, and HPV vaccine) were evaluated, but no combination was objectively superior to the others. No significant difference was found in overall efficacy between sinecatechins and imiquimod. Side effects were mild and limited to irritation and erythema.
CONCLUSIONS
Both imiquimod 5% cream and sinecatechins 15% ointment are moderately effective in the treatment of AV in preadolescent children, with a trend toward greater effectiveness of sinecatechins. Combination therapy with other treatments did not significantly increase the effectiveness of topical therapies. Each modality has a tolerable side effect profile with a low risk of serious complications.
Topics: Administration, Topical; Antineoplastic Agents; Antioxidants; Catechin; Child; Child, Preschool; Combined Modality Therapy; Condylomata Acuminata; Dermatologic Agents; Female; Humans; Imiquimod; Infant; Male; Retrospective Studies; Treatment Outcome
PubMed: 31197875
DOI: 10.1111/pde.13881 -
International Journal For Parasitology.... Dec 2017Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages....
Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian - mouse non-infected splenocytes and liver HepG2 cells - in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C-7α was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites.
Topics: Animals; Hep G2 Cells; Humans; Leishmania infantum; Liver; Mice; Microtubules; Podophyllin; Podophyllotoxin; Spleen; Structure-Activity Relationship; Tubulin; Tubulin Modulators
PubMed: 28719882
DOI: 10.1016/j.ijpddr.2017.06.003 -
Health Technology Assessment... Mar 2016Typically occurring on the external genitalia, anogenital warts (AGWs) are benign epithelial skin lesions caused by human papillomavirus infection. AGWs are usually... (Review)
Review
BACKGROUND
Typically occurring on the external genitalia, anogenital warts (AGWs) are benign epithelial skin lesions caused by human papillomavirus infection. AGWs are usually painless but can be unsightly and physically uncomfortable, and affected people might experience psychological distress. The evidence base on the clinical effectiveness and cost-effectiveness of treatments for AGWs is limited.
OBJECTIVES
To systematically review the evidence on the clinical effectiveness of medical and surgical treatments for AGWs and to develop an economic model to estimate the cost-effectiveness of the treatments.
DATA SOURCES
Electronic databases (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Web of Science) were searched from inception (or January 2000 for Web of Science) to September 2014. Bibliographies of relevant systematic reviews were hand-searched to identify potentially relevant studies. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for ongoing and planned studies.
REVIEW METHODS
A systematic review of the clinical effectiveness literature was carried out according to standard methods and a mixed-treatment comparison (MTC) undertaken. The model implemented for each outcome was that with the lowest deviance information criterion. A de novo economic model was developed to assess cost-effectiveness from the perspective of the UK NHS. The model structure was informed through a systematic review of the economic literature and in consultation with clinical experts. Effectiveness data were obtained from the MTC. Costs were obtained from the literature and standard UK sources.
RESULTS
Of 4232 titles and abstracts screened for inclusion in the review of clinical effectiveness, 60 randomised controlled trials (RCTs) evaluating 19 interventions were included. Analysis by MTC indicated that ablative techniques were typically more effective than topical interventions at completely clearing AGWs at the end of treatment. Podophyllotoxin 0.5% solution (Condyline(®), Takeda Pharmaceutical Company Ltd; Warticon(®) solution, Stiefel Laboratories Ltd) was found to be the most effective topical treatment evaluated. Networks for other outcomes included fewer treatments, which restrict conclusions on the comparative effectiveness of interventions. In total, 84 treatment strategies were assessed using the economic model. Podophyllotoxin 0.5% solution first line followed by carbon dioxide (CO2) laser therapy second line if AGWs did not clear was most likely to be considered a cost-effective use of resources at a willingness to pay of £20,000-30,000 per additional quality-adjusted life-year gained. The result was robust to most sensitivity analyses conducted.
LIMITATIONS
Limited reporting in identified studies of baseline characteristics for the enrolled population generates uncertainty around the comparability of the study populations and therefore the generalisability of the results to clinical practice. Subgroup analyses were planned based on type, number and size of AGWs, all of which are factors thought to influence treatment effect. Lack of data on clinical effectiveness based on these characteristics precluded analysis of the differential effects of treatments in the subgroups of interest. Despite identification of 60 studies, most comparisons in the MTC are informed by only one RCT. Additionally, lack of head-to-head RCTs comparing key treatments, together with minimal reporting of results in some studies, precluded comprehensive analysis of all treatments for AGWs.
CONCLUSIONS
The results generated by the MTC are in agreement with consensus opinion that ablative techniques are clinically more effective at completely clearing AGWs after treatment. However, the evidence base informing the MTC is limited. A head-to-head RCT that evaluates the comparative effectiveness of interventions used in clinical practice would help to discern the potential advantages and disadvantages of the individual treatments. The results of the economic analysis suggest that podophyllotoxin 0.5% solution is likely to represent a cost-effective first-line treatment option. More expensive effective treatments, such as CO2 laser therapy or surgery, may represent cost-effective second-line treatment options. No treatment and podophyllin are unlikely to be considered cost-effective treatment options. There is uncertainty around the cost-effectiveness of treatment with imiquimod, trichloroacetic acid and cryotherapy.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42013005457.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Condylomata Acuminata; Cost-Benefit Analysis; Humans; Laser Therapy; Papillomaviridae; Podophyllotoxin; Quality-Adjusted Life Years; Technology Assessment, Biomedical; Treatment Outcome
PubMed: 27034016
DOI: 10.3310/hta20240 -
Jos Journal of Medicine 2022Condyloma acuminata is an extremely common cutaneous sexually transmitted disease often diagnosed clinically, on the basis of its warty, cauliflower, and verrucous...
BACKGROUND
Condyloma acuminata is an extremely common cutaneous sexually transmitted disease often diagnosed clinically, on the basis of its warty, cauliflower, and verrucous appearance. It is caused by the "low risk" Human papillomavirus types 6 and 11 in 90 percent of cases. The immune system plays a critical role in determining the course of viral infection, with immune-suppression and advanced age increasing the risk for long term wart persistence. Treatment options include the use of a wide variety of topical medications as well as surgical excision by cauterisation.
PATIENT
A rare case of florid vulvar warts in a 21-year old nulliparous immuno-competent woman is presented and the literature reviewed. She had a 7-month history of progressive vulva swelling with associated itching, contact bleeding, and malodorous discharge. It measured about 14 × 10 cm in dimensions, occupying the posterior two-thirds of the labia majora and minora and obliterating the posterior commissure.
INTERVENTION
There was no positive response to Podophyllin application, however, it was eventually excised and histologic analysis excluded malignancy.
CONCLUSION
Florid vulvar warts though rare in immune-competent patients, could occur. Patients with persistent and recurrent infection often require surgical procedures as was performed in our patient with the possibility of speedy recovery and restoration of normal anatomy and cosmesis.
PubMed: 38155766
DOI: No ID Found -
Journal of Cutaneous Medicine and... 2024No single treatment is ideal for genital warts with high rate of resistance using conventional modalities as topical podophyllin; however, several intralesional... (Comparative Study)
Comparative Study
BACKGROUND
No single treatment is ideal for genital warts with high rate of resistance using conventional modalities as topical podophyllin; however, several intralesional immunotherapies are being tested nowadays, with variable results. In this study, we compared the safety and efficacy of treating resistant and recurrent genital warts by 2 intralesional immunotherapies [ antigen and measles, mumps, and rubella (MMR) vaccine] and compared them with topical podophyllin.
PATIENTS/METHODS
A total of 45 patients with resistant or recurrent genital warts were enrolled in this study. Size and number of warts were detected in each patient, patients were divided into 3 groups. Group A injected with intralesional antigen. Group B with intralesional MMR vaccine. Group C were treated with topical 25% podophyllin. Patients received a session every 2 weeks for 3 treatment sessions.
RESULTS
With regard to the reduction in size and number of all warts, the best response was obtained in antigen group where 46.7% showed complete clearance and 40% showed partial response followed by MMR group and the last was the podophyllin group, with no significant difference between them. Complete clearance of mother warts was noticed in 86.7% of group, 53.3% in MMR group, and last 40% in podophyllin group, with a significantly better response in the group ( = .027).
CONCLUSION
Both intralesional antigen and MMR vaccine are simple, safe, and effective treatment options with comparable results and better response than topical podophyllin.
Topics: Humans; Measles-Mumps-Rubella Vaccine; Male; Adult; Female; Injections, Intralesional; Antigens, Fungal; Condylomata Acuminata; Podophyllin; Young Adult; Candida; Adolescent; Middle Aged; Immunotherapy; Administration, Topical; Treatment Outcome
PubMed: 38497287
DOI: 10.1177/12034754241238012 -
Experimental and Therapeutic Medicine Jun 2022Giant condyloma acuminatum (GCA), or Buschke-Löwenstein tumor (BLT), represents an infrequent sexually transmitted disease (STD), caused by human papillomavirus (HPV),...
Giant condyloma acuminatum (GCA), or Buschke-Löwenstein tumor (BLT), represents an infrequent sexually transmitted disease (STD), caused by human papillomavirus (HPV), especially genotype 6 or 11. There are numerous risk factors for HPV, such as multiple sexual partners, homosexuality, prostitution, chronic genital infections, as well as the lack of proper hygiene. HPV infection is a field infection, where large areas of cells at a tissue surface are affected by the HPV virus; therefore, once the GCA is excised, treatment of the whole affected genital area needs to be undertaken. The treatment is classified into topical therapy (podophyllin, 5-FU, radiotherapy, topical photodynamic therapy), excisional therapy (CO laser, cryotherapy, electrotherapy, surgery) and immunotherapy (imiquimod). However, the 'gold standard' therapy is represented by wide surgical excision without grafting, since it is considered that healing is an improved approach, because there is no risk of recurrences on fibrotic tissue. A total of 7 cases of the BLT with comorbidities and particularities are presented and it is recommended that it be taken into consideration that the incidence of the disease is increasing, emphasizing the importance of an early diagnosis, as well as an adequate treatment.
PubMed: 35495587
DOI: 10.3892/etm.2022.11320 -
Biochimica Et Biophysica Acta. General... Mar 2018Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been reported to exhibit antitumor effects. However, the detailed molecular mechanism...
BACKGROUND
Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been reported to exhibit antitumor effects. However, the detailed molecular mechanism underlying this has not been elucidated.
METHODS
Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and Flow cytometry assays, respectively. Cell invasion and migration were examined by Transwell invasion and wound healing assays. Western blot analysis was performed to examine the protein expressions of zeste homolog 2 (EZH2), DNA methyltransferase 1 (DNMT1). QRT-PCR was used to examine the levels of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR). Small interfering RNAs (siRNAs) method was used to knockdown HOTAIR. Exogenously expressions of HOTAIR, DNMT1 and EZH2 were carried out by Transient transfection assays. EZH2 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. A nude mice xenograft model was used to confirm the findings in vitro.
RESULTS
We showed that PPI significantly inhibited growth, induced cell cycle arrest of castration-resistant prostate cancer (CRPC) cells. In addition, PPI also reduced the migration and invasion in CRPC cells. In mechanism, we found that PPI decreased the protein expressions of EZH2, DNMT1 and levels of HOTAIR. Interestingly, silenced HOTAIR reduced EZH2 and DNMT1 protein expressions. On the contrary, exogenously expressed HOTAIR resisted PPI-inhibited EZH2 and DNMT1 protein expressions, EZH2 promoter activity and cell growth. Moreover, excessive EZH2 antagonized PPI-suppressed DNMT1 protein expression or vice versa. Consistent with this, PPI inhibited tumor growth, HOTAIR, the protein expressions of DNMT1 and EZH2 in vivo.
CONCLUSION
Our results show that PPI inhibits growth of CRPC cells through inhibition of HOTAIR expression, subsequently; this results in the repression of DNMT1 and EZH2 expressions. The interactions among HOTAIR, DNMT1 and EZH2, and reciprocal regulation of DNMT1 and EZH2 contribute to the overall responses of PPI. This study reveals a novel mechanism for HOTAIR-mediated regulating DNMT1 and EZH2 in response to PPI in inhibition of the growth of CRPC cells.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Line, Tumor; Cell Movement; DNA (Cytosine-5-)-Methyltransferase 1; Enhancer of Zeste Homolog 2 Protein; Epigenetic Repression; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Nude; Neoplasm Invasiveness; Neoplasm Proteins; Podophyllin; Prostatic Neoplasms; RNA, Long Noncoding; RNA, Neoplasm; Random Allocation; Transcription, Genetic; Transfection; Xenograft Model Antitumor Assays
PubMed: 29221985
DOI: 10.1016/j.bbagen.2017.12.001 -
Journal of Cutaneous and Aesthetic... 2016Epidermal naevi are benign hamartomatous growths of the skin which are generally asymptomatic with a benign course but are cosmetically disagreeable. Topical treatments...
BACKGROUND
Epidermal naevi are benign hamartomatous growths of the skin which are generally asymptomatic with a benign course but are cosmetically disagreeable. Topical treatments such as steroids, calcipotriol, 5 fluorouracil, podophyllin, retinoids and cryotherapy are ineffective and surgical excision results in scar formation. Therapy is often challenging.
AIM OF THE STUDY
To study the response of carbon dioxide (CO) laser in the management of epidermal naevi.
SUBJECTS AND METHODS
We conducted a study of CO laser treatment on 15 patients of epidermal naevi, eight with verrucous epidermal naevi and seven with sebaceous naevi. A thorough history and examination was done to rule out any epidermal naevus syndrome. The diagnosis was confirmed by histopathology. The number of treatment sessions varied from 1 to 8.
RESULTS
Response was excellent (>90% reduction in lesion size) in three patients, very good (>75% reduction) in five, good (>50% reduction in lesion size) in five and poor (<50% reduction in lesion size) in two patients. The side effects were hyperpigmentation and scarring. Long-term follow-up over a period of 10 months showed a recurrence rate of 20%.
CONCLUSION
We conclude that CO laser treatment might be an effective option with long-term safety, minimal discomfort and rapid recovery.
PubMed: 27761089
DOI: 10.4103/0974-2077.191646 -
International Journal of STD & AIDS Apr 2024This study evaluated the presence of Epstein-Barr virus type 1 (EBV-1) DNA in patients living with HIV, before and after three different topical therapy protocols for...
BACKGROUND
This study evaluated the presence of Epstein-Barr virus type 1 (EBV-1) DNA in patients living with HIV, before and after three different topical therapy protocols for oral hairy leukoplakia (OHL).
METHODS
The sample consisted of five patients treated with topical solution of 25% podophyllin resin; six with 25% podophyllin resin plus 5% acyclovir cream; and four with 25% podophyllin resin plus 1% penciclovir cream. DNA was extracted from OHL scrapings and amplified by the PCR using specific primers for EBV-1 (EBNA-1).
RESULTS
Clinical healing of OHL lesions was observed across all treatment groups over time. At baseline, EBNA-1 was detected in all OHL lesions. After treatment, OHL samples from three patients treated with 25% podophyllin resin plus 5% acyclovir cream and from one patient treated with 25% podophyllin resin plus 1% penciclovir cream exhibited negative EBNA-1 viral gene encoding. Despite the clinical resolution of OHL, 11 patients (73.3%) showed EBNA-1 positivity immediately after the lesion disappeared. Three patients (20%) treated with podophyllin resin displayed both EBNA-1 positivity and a recurrence of OHL, in contrast to no recurrence in the other two groups.
CONCLUSIONS
These findings suggest potential associations between treatment formulations, EBNA-1 persistence, and the recurrence of OHL lesions.
PubMed: 38606785
DOI: 10.1177/09564624241246298