Xeroderma Pigmentosum: Novel Prophylactic and Therapeutic Approaches. Part One: Topical Zinc Sulfate 25% and Heat Dermabrasion plus Topical Trichloroacetic Acid.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease; relatively mild XP patients are sometimes designated as having pigmented xerodermoid or xerodermoid pigmentosum (XP-V), a variant of XP. It is commonly associated with many long-standing skin conditions and tumors, including malignancies, management of which is necessary to prevent the progress of the disease. The objective of the study was to report the use of a number of innovative therapeutic and prophylactic treatments, beyond surgery, such as topical 5-fluorouracil, topical imiquimod, other topical immunomodulators, or photodynamic therapy, in treating skin eruptions and their complications in XP patients. This was a prospective therapeutic interventional study in which 50 patients with XP-V were evaluated. Age of subjects ranged from 2 to 50 years with a mean age of 18 years. This study was divided into two parts. In part one, patients were treated by applying topical zinc sulfate 25% twice daily on entire face for 2 months, then once daily for several months or years. In another instance, two women were treated with heat dermabrasion with needle diathermy on the entire face under local anesthesia, followed by application of trichloroacetic acid 35% peeling in a single session. In part two, topical podophyllin 25% was used as therapy for 18 patients, all of whom had XP complications, such as keratoacanthoma, basal cell carcinomas and squamous cell cancers.1 Podophyllin was applied to the lesions until complete resolution was documented. All patients treated with topical zinc sulfate 25% responded well as determined by clearance of actinic keratoses (ActK) and small malignant lesions, minimization of pigmented freckles, prevention of new lesions, and ceased progress of eruptions. Heat dermabrasion administered in a single session resulted in the clearance of pigmented freckles, ActK, and small tumors, and cessation of new eruptions during follow-up that continued for up to 6 years.

Xeroderma Pigmentosum: Part Two: Treatment of Skin Tumors with Topical Podophyllin 25% in Benzoin.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease; relatively mild XP patients are sometimes designated as having pigmented xerodermoid or xerodermoid pigmentosum (XP-V), a variant of XP. It is commonly associated with many long-standing skin conditions and tumors, including malignancies, management of which is necessary to prevent the progress of the disease. The objective of the study was to evaluate an innovative therapeutic treatment, beyond surgery, surgical excision, cryotherapy, electrocautery and curettage, or Mohs surgery, for the management of skin tumors in XP.This was a prospective therapeutic interventional study comprising 50 patients with XP-V. Age of subjects ranged from 2 to 50 years, with a mean age of 18 years. Several measures were evaluated in part one of this study, and a number of others (as reviewed in part one) were successful in prophylaxis of skin tumors in XP as well as in treating earlier stigmata of XP; however, these measures were notably less successful in treating well-developed skin tumors in XP patients, and 18 of the 50 patients evaluated in part one had well-developed tumors (total 22 lesions) refractory to treatments. Podophyllin 25% in 100-mL tincture of benzoin was applied topically to lesions until complete resolution was documented in 18 patients with XP complications, such as keratoacanthoma (KA), basal cell carcinoma, or squamous cell carcinoma. Topical podophyllin 25% in benzoin was a less destructive alternative treatment for skin cancer and KA in XP patients.

Effectiveness and safety of topical application of diphenylcyclopropenone versus podophyllin in treatment of genital warts.

BACKGROUND: Many therapeutic modalities are available for treating genital warts; however, the effectiveness of both diphenylcyclopropenone and podophyllin is still controversial. AIM: To evaluate the effectiveness and safety of diphenylcyclopropenone and podophyllin in treating genital warts. METHODS: This study included 57 patients, divided randomly into two groups. Group (A): diphenylcyclopropenone (n = 29). Group (B): podophyllin 25% (n = 28). In group (A), sensitization was done with 2% diphenylcyclopropenone. Then, after 1 or 2 weeks, treatment started with a weekly application of diphenylcyclopropenone solutions ranging between 0.001 and 1% until clearance, or for a maximum of 10 sessions. In group (B), podophyllin 25% was applied weekly until clearance or for a maximum of 6 weeks. RESULTS: Higher clearance was achieved in group A, with 19 of 29 (65.5%) patients, than in group B, with 9 of 28 (32.1%) (p-value = 0.004). Also, effectiveness increases with young age in group A. Shorter wart duration was associated with better response in both groups (p-value = 0.005). No serious adverse effects occurred in either group. No recurrence was detected in group A, while seven patients (77.8%) had recurrence in group B after 1 year of follow up. CONCLUSION: Diphenylcyclopropenone shows a higher success rate than podophyllin in treating genital warts and a lower recurrence rate.

Trends of genital wart in Korea according to treatment method classification: Big data analysis of health care in 2010-2019.

PURPOSE: The purpose of this study is to investigate disease trend of genital wart through changes in each treatment method over the past 10 years in Korea. MATERIALS AND METHODS: From 2010 to 2019, surgical treatment including cauterization, excision, cryotherapy, and laser therapy, non-surgical treatment such as podophyllin, and surgical treatment for anorectal lesion were extracted and analyzed from 2010 to 2019. For each treatment method, characteristics such as sex, age, region, medical cost and average number of procedures were analyzed. RESULTS: The number of patients following all treatment modalities increased every year. Surgical treatment of genital wart and anorectal wart showed a significant increase in male patients. Number of non-surgical treatment decreased in males but increased in females. Surgical removal of the anorectal wart increased more than 250% in over 10 years, and males underwent surgery 4 times more than females. In both surgery and non-surgery, the mean session was higher in males. Most of them were carried out in primary medical institutions. In Seoul and Gyeonggi-do, the largest number of patients received treatment regardless of treatment method. CONCLUSIONS: Treatment for genital warts has increased rapidly over the past 10 years, and the increase in males is remarkable. The main treatment was surgery, and males mainly received surgical treatment, and females mainly received drug treatment. The primary medical institution was in charge of the most treatment. As the number of patients and related medical expenses are increasing rapidly, more attention and response to diseases are needed.

Condiloma ano-perineal en una niña de 2 años, 8 meses y tratamiento con podofilina en combinación con ácido glicirricínico y ácido tricloroacético. Reporte de caso / Ano-perineal condyloma in a girl aged 2 years, 8 months and treatment with podophyllin in combination with glycyrrhizinic acid and trichloroacetic acid. Case report

Introducción: Los condilomas o verrugas anogenitales son secundarios a una infección causada por el virus del papiloma humano en sitios específicos, como la piel de la región anogenital, en las mucosas vaginal y anal. Es una infección de transmisión sexual rara en la edad pediátrica, muy frecuente entre los adultos y adolescentes sexualmente activos; la causa en los infantes, sin descartar el abuso sexual podría ser: 1. En el momento del parto, en la etapa neonatal y durante los primeros años; 2. Autoinoculación o hetero-inoculación de los genitales de otros niños, de adultos, familiares como la madre o cuidadores. Podría manifestarse como pequeños papilomas o crecimientos verrugosos en la piel anogenital, en la mucosa de la vagina o el ano. Este caso tiene importancia clínica ya que los tratamientos convencionales presentan recidivas a corto plazo y muchos de ellos no son bien tolerados por los pequeños pacientes. Hay tratamientos agresivos como la criocirugía; el uso de medicamentos costosos como el Imiquimod; sin embargo, las reci-divas son muy frecuentes con estos tratamientos convencionales.Objetivo: Describir el uso de un esquema de terapia de tratamiento con podofilina en combina-ción con ácido glicirricínico y ácido tricloroacético, en una paciente pediátrica con diagnóstico de condiloma ano-perineal, para ayudar a disminuir las recidivas, los costos y sobre todo los efectos psicológicos que provocan los métodos dolorosos en los pequeños pacientes. Presentación del caso: Paciente que presentó lesiones verrucosas, puntiagudos en la región ano-perineal; y, luego de haber sido intervenida en un centro de salud por varios días mediante la topicación sobre las lesiones una solución de ácido tricloro acético a 5% combinada con podofi-lina al 50%; sin embargo, el cuadro se exacerbó extendiéndose las lesiones hasta cerca del área genital. Luego de lo cual acudió a nuestra consulta, donde además de la combinación anterior, más la adición de ácido glicirricinico tópico y logrando a los 30 días la remisión de las lesiones.Conclusiones y recomendaciones: La combinación de una sustancia corrosiva, el ácido tricloro acético, con una sustancia que detiene la multiplicación celular como la podofilina; y el ácido glicirricinico el cual disminuye la replicación de los virus en un estadio temprano, impide la salida del virión de su cápside y con esto su penetración a las células. La aplicación de esta triple terapia mejoró los resultados para condilomatosis en pacientes pediátricos.

Introduction: Anogenital condylomas or warts are secondary to an infection caused by the human papillomavirus in specific sites, such as the skin of the anogenital region, in the vaginal and anal mucosa. It is a rare sexually transmitted infection in pediatric age, very common among sexually active adults and adolescents; The cause in infants, without ruling out sexual abuse, could be: 1. At the time of birth, in the neonatal stage and during the first years; 2. Autoinoculation or he-tero-inoculation of the genitals of other children, adults, family members such as the mother or caregivers. It could manifest as small papillomas or warty growths on the anogenital skin, on the mucosa of the vagina or anus. This case has clinical importance since conventional treatments present short-term recurrences and many of them are not well tolerated by young patients. There are aggressive treatments such as cryosurgery; the use of expensive medications such as Imiqui-mod; However, recurrences are very common with these conventional treatments.Objective: To describe the use of a treatment regimen with podophyllin in combination with glycyrr-hizinic acid and trichloroacetic acid, in a pediatric patient diagnosed with anoperineal condyloma, to help reduce recurrences, costs and, above all, psychological effects. that painful methods cause in young patients.Case presentation: The patient presents sharp, verrucous lesions in the ano-perineal region; and, after having been operated on in a health center for several days by topicalizing a 5% trichloroace-tic acid solution combined with 50% podophyllin on the lesions; However, the condition worsened, with the lesions extending close to the genital area. After which he came to our consultation, where in addition to the previous combination, plus the addition of topical glycyrrhizinic acid and achie-ving remission of the lesions after 30 days.Conclusions and recomendations: The combination of a corrosive substance, trichloroacetic acid, with a substance that stops cell multiplication such as podophyllin; and glycyrrhizinic acid, which decreases virus replication at an early stage, prevents the release of the virion from its cap-sid and thus its penetration into the cells. The application of this triple therapy improved the results for condylomatosis in pediatric patients.

Cantharidin-Podophyllin-Salicylic Acid Formulation as a First-Line Treatment for Plantar Warts? A Case Report with Multiple Plantar Warts of Human Papillomavirus Biotype 27 and Previous Failed Treatments.

BACKGROUND Plantar warts are benign skin tumors caused by the human papillomavirus (HPV). There are multiple treatments, but none ensure absolute success. Successful treatment depends on several factors, such as the location, number of lesions, HPV biotype, and the patient's health condition. This report presents a 53-year-old woman who had multiple recalcitrant plantar warts with HPV biotype 27 that were treated using a cantharidin-podophyllin-salicylic acid (CPS) formulation after 2 failed treatments. CASE REPORT A 53-year-old woman was seen on October 25, 2021. She had 6 plantar warts due to HPV biotype 27, which was confirmed by polymerase chain reaction using a sample of hyperkeratosis scales obtained from the wart after debridement. Five cryotherapy sessions were applied, without clinical improvement. Two sessions of nitric-acid-zinc complex were then applied, from which the patient reported severe pain, without clinical improvement. Finally, 3 sessions of CPS formulation were applied, and the HPV remitted in all warts. CONCLUSIONS Conservative treatments, such as cryotherapy, have not been effective in a case of multiple recalcitrant plantar warts. The combined action of the 3 compounds of CPS formulation was key in the resolution of this case. Plantar wart treatment should be easy to apply, effective, fast, and efficient. In cases of recalcitrant or numerous warts, treatment should be more aggressive from the beginning if the patient's lifestyle allows it. It would be interesting to conduct randomized clinical trials to find out which patients could be indicated for the CPS formulation as a first line of treatment.

Intralesional bivalent human papilloma virus vaccine as a treatment for anogenital warts versus topical podophyllin resin 25%: A pilot study.

A role of human papilloma virus (HPV) vaccines as a therapy for genital warts was suggested, nevertheless; it has not been established in clinical trials and has yet to be determined. The objective of this study is to evaluate a potential benefit of intralesional injection of bivalent HPV (Cervarix) vaccine as a treatment for anogenital warts versus topical podophyllin resin 25%. Forty-four patients with anogenital warts were included in the study, 22 patients received intralesional Cervarix every 2 weeks until clearance of lesions or for a maximum of five sessions. The other 22 patients received topical podophyllin resin 25% twice weekly until complete resolution or for a maximum of 4 weeks. Follow up was done for 6 months. Dermatology life quality index (DLQI) was measured. Complete clearance of warts was achieved in 10 patients (45.5%) in Cervarix group versus six patients (27.3%) in Podophyllin group. The difference was statistically insignificant. No recurrence of warts was reported in Cervarix group while two patients (33.3%) showed recurrence in Podophyllin group. Both treatments were well tolerated. All patients reported significant improvement of their DLQI. Intralesional Cervarix is a promising modality showing higher rates of complete response, high safety, and no recurrence.

Radiosensitizer Effect of ß-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.

ß-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Giant perianal condyloma successfully treated with podophyllin at 25% in solid petrolatum

Purpose: Giant perianal condyloma (GPC) is a rare condition. The effective treatment is a multidisciplinary challenge; topical treatments are usually ineffective, and surgical resection has significant morbidity. Podophyllin at 25% in solid petrolatum (25%PSP) can be an effective treatment option for GPC. The aim of the present study was to assess its response and tolerability. Methods: This retrospective, single-center case series evaluated the clinical response of 14 patients with GPC treated with 25%PSP in a public hospital in Buenos Aires between December 2015 and December 2019. After obtaining a full history and performing a physical exam, the lesions were measured and photographed. Biopsies were performed to exclude malignancy, as well as exams to rule out pregnancy. Podophyllin at 25% in solid petrolatum was administered topically in cases of GPC and washed off by the patients at home after 4 hours. The patients underwent at least 4 weekly visits, which included interval history, photodocumentation of the lesions, and provider-applied 25%PSP. The response rate was assessed by comparingmeasurements and the overall decrease in volume of the GPC based on photos from the first and last sessions. Adverse outcomes were noted. Results: In total, 10 men, 3 women, and 1 transgender woman with GPC unresponsive to prior treatments and a mean age of 34.5 years were included. A total of 12 patients were immunosuppressed. All the perianal lesions were circumferential and measured between 8 cm and 20 cm. Overall, 7 patients had genital condyloma outside of the anus and perianus; the histology showed low-grade squamous intraepithelial lesions in all cases. While on treatment, 7 patients reported dermatitis, and 71% of the patients had 75% reduction in lesion size. Conclusions: Podophyllin at 25% in solid petrolatum is an effective, well-tolerated topical treatment option for GPC. (AU)

[Consensus on HPV of the Portuguese Society of Andrology, Sexual Medicine and Reproduction: Treatment]. / Consensos em HPV Masculino da Sociedade Portuguesa de Andrologia, Medicina Sexual e Reprodução: Tratamento.

The treatment of condyloma is generally a challenge in clinical practice. Although the spontaneous resolution rate is high, a significant proportion of patients seek treatment, not because of symptomatology, but mainly for aesthetic issues and concerns related to the transmission or worsening of existing lesions. The available treatments should be applied only for clinically evident macroscopic lesions. Ideally, available therapies should have rapid action onset and clearance, resolve symptoms, reduce recurrence rate and viral load, be effective in treating small lesions, and be well tolerated. However, none of the currently available treatments is clearly more effective than the others and there is no ideal treatment for all patients or for all condyloma. Therefore, the therapeutic decision should be based on the clinician's experience, available resources, lesion morphology, size, number and location, primary or recurrent lesions, disease severity, patient preference and expectations, patient's immune competence, convenience, tolerance, cost of treatment and results of previous therapies. The available treatments are divided into three groups: applied by the patient himself (imiquimod 3.75 or 5%, podophyllotoxin .5%, synecatekines 10% or 15%), applied by the health care provider (bi- and tricloacetic acids 80%-90%, intralesional interferon alpha, cryotherapy, surgical removal, electrofulguration, laser ablation) and experimental or alternative therapies (topical cidofovir, intralesional bleomycin, photodynamic therapy). Treatment methodologies can be further divided into their action - ablative or destructive treatment (cryotherapy, electrofulguration, laser ablation, surgical excision), cytotoxic or proapoptotic treatments (podophyllotoxin .5%, 5-fluoruracil, bleomycin) and immunomodulatory treatments (imiquimod 3.75% or 5%, synecatekines 10% or 15%, intralesional interferon alpha). The overall success rate of the various treatments available ranges from 23% to 94%. Only treatments that include cryotherapy or surgical excision are suitable in condyloma with any anatomical location and that have the highest success rate in monotherapy. Recurrences are common regardless of the treatment received. In contrast, immunomodulatory therapies despite having lower initial clearance rates appear to have higher probabilities of cure in the medium term, with low recurrence rates. Some treatments may be combined with each other and the effectiveness of combined therapies appears to be superior to monotherapy (proactive sequential treatment). The consensuses for the treatment of HPV also consider special situations: immunocompromised patients, meatus and intraurethral lesions and treatment of the partner.

Ingenol Mebutate Gel 0.05% in the Treatment of Anogenital Warts: A Prospective Controlled Trial Comparing It With Topical Podophyllin Solution 25.

BACKGROUND: Anogenital warts (AGWs) are a common therapeutic challenge. All therapies are associated with burning, pain, and frustrating high rate of recurrence. The search for a new alternative continues. Recently, a diterpene ester extracted from the Euphorbia peplus plant (ingenol mebutate [IM]) has been shown to possess activity against AGWs. OBJECTIVE: This study aimed to compare and evaluate the therapeutic efficacy and safety of topical 0.05% ingenol gel with another herbal extract medication (topical 25% podophyllin solution) in treatment of AGWs. METHODS: This was a comparative single blinded nonrandomized, 2-arm trial of ingenol 0.05% gel versus podophyllin solution 25% administered up to 6 times to patients with AGWs. To evaluate the therapeutic efficacy, the complete clearance rate and recurrence rate were assessed 1 and 12 weeks after last treatment, respectively. Safety was assessed by occurrence and severity of pain and local skin reaction (LSR). RESULTS: Of 31 and 36 patients in the IM group and podophyllin group who completed the study, initial complete resolution was observed in 20 (64.5%) and 14 (38.9%) patients, respectively (P = 0.03). The initial clearance was faster in the IM group (2.00 ± 0.91 weeks) compared with the podophyllin group (4.21 ± 1.05 weeks, P = 0.00). After 3 months, recurrence was seen in 13 (65.0%) of 20 patients in the IM group and 6 (42.8%) of 14 in the podophyllin group (P = 0.20). The number of patients with complete resolution after 3 months was not different between the 2 groups (7/31 in the IM group and 8/36 in the podophyllin group, P = 0.97). The mean ± SD severity scores for LSR and pain in the IM group were 6.65 ± 1.76 and 6.13 ± 2.57, respectively, which was significantly higher than their scores (3.39 ± 1.57 and 2.58 ± 1.38) in the podophyllin group (P = 0.00). CONCLUSION: Ingenol mebutate 0.05% gel is effective as podophyllin 25% solution in treating AGWs, with further benefit of being much more rapid. However, high recurrence rate, sever pain, and LSR limit its use.

Unusual presentation of a disseminated oral HPV infection after combined antiretroviral therapy initiation.

HPV clinical manifestations have their characteristics modified by the use of combined antiretroviral therapy (cART), although its incidence is unaffected by cART. We report an unusual presentation of oral HPV infection and discuss an effective treatment for disseminated HPV lesions. A 52-year-old male of Asian-origin, HIV-seropositive, presented with extensive nodular lesions throughout the oral mucosa extending to the oropharyngeal region. Biopsy followed by histopathological examination and HPV genotyping were performed. The treatment was initiated with topical application of podophyllin and trichloroacetic acid. HPV lesions in oral mucosa are generally easy to handle. Extensive lesions can make it difficult to choose an effective treatment that meets the patient's particularities and medication availability.

Real-life treatment of cutaneous warts with cantharidin podophyllin salicylic acid solution.

Patients often request treatment of their burdensome cutaneous warts. However, a safe and effective treatment for cutaneous warts is lacking. This study evaluates treatment outcome, side effects, and patient satisfaction after topical application of cantharidin 1% podophyllin 2% salicylic acid 30% (CPS1) solution in a large series of children and adults with cutaneous warts. Fifty-two children and 83 adults with warts, treated with CPS1 solution between October 2012 and October 2014, were included. Complete clearance of warts occurred in 86.5% of children and 62.7% of adults treated with CPS1 solution (p < .01). Resolution of warts was partial in 3.9 and 24.1% and absent in 9.6 and 13.2% of children and adults respectively. Side effects were present in 41.2% of children and 46.3% of adults (p = .7). Most common side effects were blistering, pain, and burning sensation. No serious adverse events occurred. On a 10-point scale, median patient satisfaction score was 9.0 (interquartile range 7.8-10.0) and 8.0 (interquartile range 5.1-9.7) for children and adults respectively (p < .01). CPS1 solution is a safe and promising treatment modality with a high clearance and high patient satisfaction rate for the management of cutaneous warts, particularly in children.

Podophyllin Toxicity with Systemic Manifestations in a Young Male.

Podophyllin poisoning is a rare but a fatal poisoning with a long term systemic and neurological sequela. There has been no case report reported in an adult in India. We present a 28-year-old young male with podophyllin poisoning. This report confirms the transient central neurotoxicity of podophyllin and persistent peripheral neurotoxicity of podophyllin.

Multiple approaches to sexually transmitted infections: from diagnosis to treatment

ABSTRACT Sexually transmitted infections are mainly caused by viruses and bacteria. They are transmitted trough sexual intercourse, without a condom, with an infected individual. The anus, vagina, and mouth may become involved. This study aimed to present six clinical cases with the diagnosis of sexually transmitted infections, but in which different treatment approaches were required. This demonstrates the dynamic and unique character of the disease in each individual. That is, the behavior of sexually transmitted infections will vary not only according to its causative microorganism (virus or bacteria), but also according to the characteristics of the combination of etiologic agent and host.

RESUMO As infecções sexualmente transmissíveis são causadas, principalmente, por vírus e bactérias. Por meio do contato sexual, sem preservativo, com um indivíduo que esteja infectado. O ânus, a vagina e a boca podem se tornar órgãos acometidos. O objetivo deste trabalho é apresentar 06 casos clínicos com o diagnóstico de infecções sexualmente transmissíveis, mas que para serem tratados foram necessárias diferentes abordagens. Isso demonstra o caráter dinâmico e singular da doença em cada indivíduo. Ou seja, o comportamento das infecções sexualmente transmissíveis vai variar não somente conforme o seu microrganismo causador (vírus × bactéria), mas também de acordo com o conjunto (agente etiológico + hospedeiro).

ß-Apopicropodophyllin functions as a radiosensitizer targeting ER stress in non-small cell lung cancer.

AIMS: In this study, we examined whether ß-apopicropodophyllin (APP) could act as a radiosensitizer in non-small cell lung cancer (NSCLC) cells. MAIN METHODS: The in vitro radiosensitizing activity of APP was demonstrated with clonogenic assay, immunoblotting, Annexin V-Propidium iodide (PI) assay, BrdU incorporation, detection of mitochondrial ROS/intracellular of H2O2, mitochondrial membrane potential detection, and performing of isolation of mitochondrial and cytosolic fractions. The in vivo radiosensitizing activity of APP was determined in xenografted mice with co-treatment of APP and IR based on measurement of tumor volumes and apoptotic cell death. KEY FINDINGS: The results of a clonogenic assay indicated that a combination of APP and γ-ionizing radiation (IR) inhibits cell growth and increases cell death in NSCLC cells. Several signal transduction pathways were examined for their potential involvement in the apparent radiosensitization effect of APP, as assessed by immunoblotting analyses and mitochondrial potential determination in vitro. Treatment of NCI-H460 cells with 15 nM APP and NCI-H1299 cells with 10 nM APP yielded dose-enhancement ratios of 1.44 and 1.24, respectively. Enhanced ER stress, disrupted mitochondrial membrane potential, and increased reactive oxygen species (ROS) were observed in cells co-treated with APP and IR, and this was followed by the cytosolic release of cytochrome c and consequent activation of caspase-3 and -9. Notably, inhibition of JNK, which prevents caspase activation, blocked the APP/IR-induced activations of ER stress and apoptotic cell death. In NCI-H460 or NCI-H1299 cell-xenografted mice, APP/IR treatment delayed the time it took tumors to reach a threshold size by 22.38 and 16.83 days, respectively, compared with controls, to yield enhancement factors of 1.53 and 1.38, respectively. SIGNIFICANCE: APP has a radiosensitizing function derived from its ability to induce apoptotic cell death via activation of ER stress, disruption of mitochondrial membrane potential, and induction of the caspase pathway.

Concise Synthesis of (+)-ß- and γ-Apopicropodophyllins, and Dehydrodesoxypodophyllotoxin.

Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans (+)-ß- and γ-apopicropodophyllins, and arylnaphthalene lignan dehydrodesoxypodophyllotoxin. The key reaction is regiocontrolled oxidations of stereodivergent aryltetralin lactones, which were easily accessed from a nickel-catalyzed reductive cascade approach developed in our group.

A novel anti-cancer role of ß-apopicropodophyllin against non-small cell lung cancer cells.

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 ß-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 IC50 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.