RESUMO
BACKGROUND: Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies. METHODS: The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay. RESULTS: E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10-8 M (45.36 µg/ml) to 6.71 × 10-8 M (26.66 µg/ml) and Ifosfamide from 12.52 × 10-5 M (32.7 µg/ml) to 8.206 × 10-5 M (21.43 µg/ml). Flow cytometry analysis demonstrated a significant increase in apoptosis for combination treatments, with apoptosis rates rising from 11.02 % (Oxaliplatin alone) and 16.98 % (Ifosfamide alone) to 24.8 % (Oxaliplatin + E5-siRNA) and 34.9 % (Ifosfamide + E5-siRNA). The sub-G1 cell population increased from 15.7 % (Oxaliplatin alone) and 18 % (Ifosfamide alone) to 21.9 % (Oxaliplatin + E5-siRNA) and 27.1 % (Ifosfamide + E5-siRNA), indicating cell cycle arrest. The colony formation assay revealed a substantial decrease in the number of colonies following combination treatment. qRT-PCR analysis showed decreased expression of stemness-related genes CD44 and Nanog, and migration-related genes MMP2 and CXCL8 in the combination groups. Apoptosis-related genes Casp-3, Casp-9, and pP53 showed increased expression following combination therapy, while BAX expression increased and BCL2 expression decreased relative to the control. CONCLUSION: The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.
Assuntos
Apoptose , Papillomavirus Humano 16 , Ifosfamida , Oxaliplatina , RNA Interferente Pequeno , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Oxaliplatina/farmacologia , Feminino , RNA Interferente Pequeno/genética , Linhagem Celular Tumoral , Ifosfamida/farmacologia , Apoptose/efeitos dos fármacos , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Sobrevivência Celular/efeitos dos fármacos , Proteínas Oncogênicas Virais/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
The WHO (World Health Organization) conducted an elimination of cervical cancer program using triple pillar intervention strategy to target 90%-70%-90% of women before the year 2030, including (1) a full vaccination of HPV (human papillomavirus) vaccine to 90% of girls <15 years of age; (2) a high-performance screening procedure to 70% of women during the reproductive age (at the age of 35 and 45 years of age); and (3) an appropriate and adequate treatment to 90% of women with confirmed diagnosis of cervical lesions. Among the aforementioned three pillars, a full HPV vaccination has been introduced in our previous review, of which we have discussed the policy and strategy of HPV vaccination in the world and also reviewed the efficacy of HPV vaccination, with a successful reduction of over 90% of HPV-associated neoplasms. The aims of the current review will target another pillar-an appropriate and adequate treatment to 90% of women with confirmed diagnosis of cervical lesions. Since the early-stage cervical cancer has a favorable outcome and the treatment recommendation has been established, therefore, the current review focuses on women with persistent, recurrent and metastatic cervical cancers (advanced cervical cancers), which are still a biggest challenge based on its extremely worse outcomes before the introduction of immune checkpoint inhibitors (ICIs). Integration of ICIs into conventional chemotherapy (paclitaxel-cisplatin) has become the new standard therapy for those patients with advanced cervical cancers. The recent clinical trials, such as KENOTE 826 and KENOTE A18 showing a dramatical improvement of both progression free survival and overall survival have approved the therapeutic efficacy of this combination as ICI plus paclitaxel-platinum (cisplatin or carboplatin) with/without bevacizumab to women with persistent, recurrent and metastatic cervical cancers.
Assuntos
Recidiva Local de Neoplasia , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/tratamento farmacológico , Recidiva Local de Neoplasia/terapia , Vacinas contra Papillomavirus/administração & dosagem , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêuticoRESUMO
Lactoferrin is a multifunctional glycoprotein naturally found in mammalian secretions, predominantly in colostrum and milk. As a key component of dairy foods, lactoferrin enhances viral protection and boosts human health, owing to its fundamental properties including antiviral, anti-inflammatory, and immune-modulatory effects. Importantly, the antiviral effect of lactoferrin has been shown against a range of viruses causing serious infections and threatening human health. One of the viruses that lactoferrin exerts significant antiviral effects on is the human papillomavirus (HPV), which is the most prevalent transmitted infection affecting a myriad of people around the world. Lactoferrin has a high potential to inhibit HPV via different mechanisms, including direct binding to viral envelope proteins or their cell receptors, thereby hindering viral entry and immune stimulation by triggering the release of some immune-related molecules through the body, such as lymphocytes. Along with HPV, lactoferrin also can inhibit a range of viruses including coronaviruses and hepatitis viruses in the same manner. Here, we overview the current knowledge of lactoferrin and its effects on HPV and other viral infections.
Assuntos
Antivirais , Lactoferrina , Infecções por Papillomavirus , Lactoferrina/uso terapêutico , Lactoferrina/farmacologia , Humanos , Infecções por Papillomavirus/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêutico , Papillomaviridae/efeitos dos fármacos , Animais , Internalização do Vírus/efeitos dos fármacos , Papillomavirus HumanoRESUMO
Ellagic acid (EA) is a phenolic phytochemical found in many plants and their fruits. Vaginal epithelial cells are the first line of defense against pathogen invasion in the female reproductive tract and express antimicrobial peptides, including hBD2 and SLPI. This study investigated the in vitro effects of EA (1) on vaginal innate immunity using human vaginal epithelial cells, and (2) on HPV16 pseudovirus infection. Vaginal cells were cultured in the presence or absence of EA, and the expression of hBD2 and SLPI was determined at both transcriptional and translational levels. In addition, secretion of various cytokines and chemokines was measured. Cytotoxicity of EA was determined by CellTiter-blue and MTT assays. To investigate the ability of EA to inhibit HPV16 infection, EA was used to treat HEK-293FT cells in pre-attachment and adsorption steps. We found significant increases in both hBD2 mRNA (mean 2.9-fold at 12.5 µM EA, p < 0.001) and protein (mean 7.1-fold at 12.5 µM EA, p = 0.002) in response to EA. SLPI mRNA also increased significantly (mean 1.4-fold at 25 µM EA, p = 0.01), but SLPI protein did not. Secretion of IL-2 but not of other cytokines/chemokines was induced by EA in a dose-dependent manner. EA was not cytotoxic. At the pre-attachment step, EA at CC20 and CC50 showed a slight trend towards inhibiting HPV16 pseudovirus, but this was not significant. In summary, vaginal epithelial cells can respond to EA by producing innate immune factors, and at tested concentrations, EA is not cytotoxic. Thus, plant-derived EA could be useful as an immunomodulatory agent to improve vaginal health.
Assuntos
Ácido Elágico , Papillomavirus Humano 16 , Imunidade Inata , Infecções por Papillomavirus , Vagina , Humanos , Feminino , Ácido Elágico/farmacologia , Imunidade Inata/efeitos dos fármacos , Vagina/virologia , Vagina/imunologia , Vagina/efeitos dos fármacos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/tratamento farmacológico , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , beta-Defensinas/metabolismo , Células HEK293RESUMO
Persistent infection with high-risk human papillomavirus remains the primary factor associated with the progression of cervical squamous intraepithelial lesions and the development of cervical cancer. Nevertheless, a combination of factors, including genetic predisposition, immune response, hormonal influences, and nutritional status, contribute synergistically to the development of cervical cancer. Among the various factors involved in the pathogenesis and therapy of cervical cancer, retinoids have gained considerable attention due to their multifaceted roles in different cellular processes. This review investigates defects within the vitamin A metabolism pathway and their correlation with cervical cancer. Additionally, it integrates epidemiological and experimental findings to discuss the potential utility of retinoid-based therapies, either alone or combined with other therapies, as agents against premalignant lesions and cervical cancer.
Assuntos
Lesões Pré-Cancerosas , Retinoides , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Feminino , Retinoides/uso terapêutico , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Vitamina A/uso terapêuticoRESUMO
OBJECTIVE: High-risk human papillomavirus (HR-HPV) infection is the chief cause of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. The Erhuang suppository (EHS) is a traditional Chinese medicine (TCM) prepared from realgar (As2S2), Coptidis rhizoma, alumen, and borneolum syntheticum and has been used for antiviral and antitumor purposes. However, whether EHS can efficiently alleviate HR-HPV infection remains unclear. This study was conducted to evaluate the efficacy of EHS for the treatment of persistent HR-HPV infection in the uterine cervix. METHODS: In this study, we evaluated the therapeutic efficacy of EHS in a randomized controlled clinical trial with a 3-month follow-up. Totally, 70 patients with persistent HR-HPV infection were randomly assigned to receive intravaginal administration of EHS or placebo. HPV DNA, ThinPrep cytologic test (TCT), colposcopy, and safety evaluation were carried out after treatment. Microarray analysis was performed to compare transcriptome profiles before and after EHS treatment. A K14-HPV16 mouse model was generated to confirm the efficiency of EHS. RESULTS: After 3 months, 74.3% (26/35) of the patients in the treatment group were HPV negative, compared to 6.9% (2/29) in the placebo group. High-throughput microarrays revealed distinct transcriptome profiles after treatment. The differentially expressed genes were significantly enriched in complement activation, immune response, and apoptotic processes. The K14-HPV16 mouse model also validated the remarkable efficacy of EHS. CONCLUSION: This study demonstrated that EHS is effective against HR-HPV infection and cervical lesions. Additionally, no obvious systemic toxicity was observed in patients during the trial. The superior efficacy and safety of EHS demonstrated its considerable value as a potential cost-effective drug for the treatment of HPV infection and HPV-related cervical diseases.
Assuntos
Colo do Útero , Medicamentos de Ervas Chinesas , Infecções por Papillomavirus , Transcriptoma , Humanos , Feminino , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Adulto , Supositórios , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Colo do Útero/efeitos dos fármacos , Colo do Útero/virologia , Colo do Útero/patologia , Transcriptoma/efeitos dos fármacos , Animais , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Camundongos , Displasia do Colo do Útero/tratamento farmacológico , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologiaRESUMO
Tirbanibulin 1% ointment is a synthetic antiproliferative agent approved in 2021 by the European Union for treating actinic keratoses (AK). Topical tirbanibulin has clinically resolved HPV-57 ( +) squamous cell carcinoma (SCC), HPV-16 ( +) vulvar high-grade squamous intraepithelial lesion, epidermodysplasia verruciformis, and condyloma. We examined how tirbanibulin might affect HPV oncoprotein expression and affect other cellular pathways involved in cell proliferation and transformation. We treated the HeLa cell line, containing integrated HPV-18, with increasing doses of tirbanibulin to determine the effects on cell proliferation. Immunoblotting was performed with antibodies against the Src canonical pathway, HPV 18 E6 and E7 transcription regulation, apoptosis, and invasion and metastasis pathways. Cell proliferation assays with tirbanibulin determined the half-maximal inhibitory concentration (IC50) of HeLa cells to be 31.49 nmol/L. Increasing concentrations of tirbanibulin downregulates the protein expression of Src (p < 0.001), phospho-Src (p < 0.001), Ras (p < 0.01), c-Raf (p < 0.001), ERK1 (p < 0.001), phospho-ERK1 (p < 0.001), phospho-ERK2 (p < 0.01), phospho-Mnk1 (p < 0.001), eIF4E (p < 0.01), phospho-eIF4E (p < 0.001), E6 (p < 0.01), E7 (p < 0.01), Rb (p < 0.01), phospho-Rb (p < 0.001), MDM2 (p < 0.01), E2F1 (p < 0.001), phospho-FAK (p < 0.001), phospho-p130 Cas (p < 0.001), Mcl-1 (p < 0.01), and Bcl-2 (p < 0.001), but upregulates cPARP (p < 0.001), and cPARP/fPARP (p < 0.001). These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins via the Src- MEK- pathway. Tirbanibulin significantly downregulates oncogenic proteins related to cell cycle regulation and cell proliferation while upregulating apoptosis pathways.
Tirbanibulin is Promising Novel Therapy for Human Papillomavirus (HPV)-associated Diseases.Tirbanibulin 1% ointment is an approved synthetic topical ointment for treating actinic keratoses (AK), a precancer of skin cancer. Topical tirbanibulin has previously been reported to clinically resolve human papillomavirus (HPV)-( +) diseases.In this study, we examine how tirbanibulin may affect the HPV and pathways associated with cancer.We treated the HeLa cell line to determine the effects on HPV cell proliferation. Increasing the concentration of tirbanibulin statistically significantly affected numerous cellular pathways often associated with cancer.These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins and thereby kill cancer cells.
Assuntos
Proliferação de Células , Regulação para Baixo , Papillomavirus Humano 18 , Proteínas Oncogênicas Virais , Humanos , Células HeLa , Proliferação de Células/efeitos dos fármacos , Proteínas Oncogênicas Virais/metabolismo , Regulação para Baixo/efeitos dos fármacos , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/tratamento farmacológico , Proteínas E7 de Papillomavirus/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Quinases da Família src/metabolismo , Quinases da Família src/antagonistas & inibidores , Feminino , Papillomavirus Humano , Proteínas de Ligação a DNARESUMO
OBJECTIVES: Exophytic Sinonasal Papilloma (ESP) is a benign tumor of the sinonasal tract. Complete surgical excision by endoscopic surgery is the treatment of choice. However, a high recurrence rate (36% at 5-year follow-up) is associated with this method, which may indicate the presence of microorganisms such as Human Papillomavirus (HPV). It is important to note that the standard treatment for ESP does not include antiviral drugs. In our study, we are testing the effectiveness of an interferon-containing drug in reducing recurrence and postoperative reactions in patients with ESP. METHODS: We included 78 patients aged 23-83 years with a confirmed diagnosis of ESP by rhinoscopy and nasal endoscopy and a positive PCR test for HPV in nasal scrapings. To compare the results, we divided the patients into main and control groups. The main group received recombinant human interferon after surgery, while the control group did not receive the drug. We performed a statistical analysis to compare the proportion of patients without reactive manifestations at different stages of the postoperative period, as well as to compare the proportion of patients with recurrent ESP at certain stages of observation. RESULTS: The introduction of recombinant human interferon accelerated the resolution of postoperative reactions and promoted the healing of the nasal mucosa after surgical removal of the ESP. We also found a statistically significant association between treatment with recombinant interferon and a reduction in the recurrence rate of ESP. CONCLUSION: According to the results of the study, it was found that in the main group of patients who received rhIFN-α2b (recombinant human Interferon alpha 2b) in the postoperative period, the frequency of relapses of ESP and the time of postoperative recovery were significantly lower than in patients in the control group who did not take the drug. LEVEL OF EVIDENCE: Cohort Study.
Assuntos
Interferon alfa-2 , Interferon-alfa , Papiloma , Infecções por Papillomavirus , Humanos , Pessoa de Meia-Idade , Adulto , Idoso , Masculino , Feminino , Interferon alfa-2/uso terapêutico , Infecções por Papillomavirus/tratamento farmacológico , Idoso de 80 Anos ou mais , Adulto Jovem , Interferon-alfa/uso terapêutico , Resultado do Tratamento , Papiloma/tratamento farmacológico , Papiloma/cirurgia , Papiloma/virologia , Neoplasias Nasais/cirurgia , Neoplasias Nasais/tratamento farmacológico , Neoplasias Nasais/virologia , Proteínas Recombinantes/uso terapêutico , Recidiva Local de Neoplasia , Antivirais/uso terapêuticoRESUMO
Despite therapeutic advancements, cervical cancer caused by high-risk subtypes of the human papillomavirus (HPV) remains a leading cause of cancer-related deaths among women worldwide. This study aimed to discover potential drug candidates from the Asian medicinal plant Andrographis paniculata, demonstrating efficacy against the E6 protein of high-risk HPV-16 subtype through an in-silico computational approach. The 3D structures of 32 compounds (selected from 42) derived from A. paniculata, exhibiting higher binding affinity, were obtained from the PubChem database. These structures underwent subsequent analysis and screening based on criteria including binding energy, molecular docking, drug likeness and toxicity prediction using computational techniques. Considering the spectrometry, pharmacokinetic properties, docking results, drug likeliness, and toxicological effects, five compounds-stigmasterol, 1H-Indole-3-carboxylic acid, 5-methoxy-, methyl ester (AP7), andrographolide, apigenin and wogonin-were selected as the potential inhibitors against the E6 protein of HPV-16. We also performed 200 ns molecular dynamics simulations of the compounds to analyze their stability and interactions as protein-ligand complexes using imiquimod (CID-57469) as a control. Screened compounds showed favorable characteristics, including stable root mean square deviation values, minimal root mean square fluctuations and consistent radius of gyration values. Intermolecular interactions, such as hydrogen bonds and hydrophobic contacts, were sustained throughout the simulations. The compounds displayed potential affinity, as indicated by negative binding free energy values. Overall, findings of this study suggest that the selected compounds have the potential to act as inhibitors against the E6 protein of HPV-16, offering promising prospects for the treatment and management of CC.
Assuntos
Andrographis , Papillomavirus Humano 16 , Simulação de Acoplamento Molecular , Proteínas Oncogênicas Virais , Neoplasias do Colo do Útero , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , Humanos , Feminino , Proteínas Oncogênicas Virais/metabolismo , Proteínas Oncogênicas Virais/química , Andrographis/química , Papillomavirus Humano 16/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Simulação por Computador , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Simulação de Dinâmica Molecular , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/virologia , Diterpenos/farmacologia , Diterpenos/química , Ligação ProteicaRESUMO
The study utilized 5-ALA-PDT to treat patients with CIN or VaIN and assessed their clinical response, HPV clearance, and influencing factors after photodynamic therapy (PDT). This study involved 56 patients who received 5-ALA-PDT in a single center from May 2020 to March 2022, including 12 patients with CIN, 30 patients with VaIN, and 14 patients with both CIN and VaIN. Follow-up were conducted within 6 and 12 months after treatment to evaluate the clinical effectiveness of PDT. The assessment criteria included histological response (ER, elimination rate, RR, regression rate) and HPV clearance. Additionally, factors that could potentially influence the outcomes were analyzed. After PDT, the histological response showed an ER of 48.2% (27/56) and a RR of 80.4% (45/56) within 6 months of follow-up. The elimination rate increased to 69.6% (39/56) within 12 months, along with a regression rate of 82.1% (46/56). The rates of HPV clearance were observed to be 37.5% (21/56) and 44.6% (25/56) within 6 and 12 months, respectively. The study also revealed that HPV clearance significantly influenced histologic elimination within 6 months (p < 0.001) and histologic regression within 12 months (p < 0.01). Furthermore, premenopausal women exhibited a higher HPV clearance rate compared to postmenopausal women (61.5% vs. 30.0%, p = 0.036). 5-ALA PDT can be considered as an available option for the treatment of lower genital squamous intraepithelial lesions. The efficacy of its histologic response depends on HPV clearance. Additionally, it has been found that premenopausal women may benefit more from this treatment.
Assuntos
Ácido Aminolevulínico , Fotoquimioterapia , Fármacos Fotossensibilizantes , Humanos , Feminino , Fotoquimioterapia/métodos , Ácido Aminolevulínico/uso terapêutico , Ácido Aminolevulínico/administração & dosagem , Adulto , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/administração & dosagem , Pessoa de Meia-Idade , Resultado do Tratamento , Displasia do Colo do Útero/tratamento farmacológico , Displasia do Colo do Útero/virologia , Displasia do Colo do Útero/patologia , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , Adulto Jovem , IdosoRESUMO
To date, more than 400 types of human papillomavirus (HPV) have been identified. Despite the creation of effective prophylactic vaccines against the most common genital HPVs, the viruses remain among the most prevalent pathogens found in humans. According to WHO data, they are the cause of 5% of all cancers. Even more frequent are persistent and recurrent benign lesions such as genital and common warts. HPVs are resistant to many disinfectants and relatively unsusceptible to external conditions. There is still no drug available to inhibit viral replication, and treatment is based on removing lesions or stimulating the host immune system. This paper presents the systematics of HPV and the differences in HPV structure between different genetic types, lineages, and sublineages, based on the literature and GenBank data. We also present the pathogenesis of diseases caused by HPV, with a special focus on the role played by E6, E7, and other viral proteins in the development of benign and cancerous lesions. We discuss further prospects for the treatment of HPV infections, including, among others, substances that block the entry of HPV into cells, inhibitors of viral early proteins, and some substances of plant origin that inhibit viral replication, as well as new possibilities for therapeutic vaccines.
Assuntos
Papillomaviridae , Infecções por Papillomavirus , Humanos , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/tratamento farmacológico , Papillomaviridae/fisiologia , Papillomaviridae/patogenicidade , Papillomaviridae/classificação , Papillomaviridae/genética , Replicação Viral/efeitos dos fármacos , Vacinas contra Papillomavirus/uso terapêutico , Vacinas contra Papillomavirus/imunologia , Antivirais/uso terapêutico , Antivirais/farmacologiaRESUMO
OBJECTIVE: This systematic review and meta-analysis aimed to investigate the effects of herbal treatments on cervicovaginal human papillomavirus infection. METHODS: A comprehensive literature search was conducted in PubMed, Scopus, Science Direct, and the Cochrane Library until December 2023, following Cochrane guidelines. Data were analyzed using the Review Manager computer program (Version 5.4.1). RESULTS: Five randomized controlled trials involving a total sample size of 662 women were included in the study. The pooled odds ratio for individuals testing negative for human papillomavirus after herbal intervention among human papillomavirus-positive patients was 1.86 (95% confidence interval (CI) 0.64-5.43), according to the fixed-effects model. Three out of the five studies indicated a significant relationship. The relationship between positive human papillomavirus infection and herbal treatments, measured by the fixed-effects model, resulted in a pooled odds ratio of 0.41 (95%CI 0.17-1.01), reporting a significant association (p=0.05). Subgroup analysis revealed a significant reduction in the relationship between herbal treatment and atypical squamous cells of undetermined significance (OR 0.16, 95%CI 0.03-0.88, p=0.04) but no significant impact on the relationship between herbal treatment and low-grade squamous intraepithelial lesion (OR 0.33, 95%CI 0.01-8.77, p=0.51). CONCLUSION: The meta-analysis suggests that herbal treatments reduce human papillomavirus infections. While herbal treatments show a significant reduction in atypical squamous cells of undetermined significance, they do not significantly impact the regression of low-grade squamous intraepithelial lesions.
Assuntos
Infecções por Papillomavirus , Humanos , Feminino , Infecções por Papillomavirus/tratamento farmacológico , Fitoterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
BACKGROUND: Prevention of high-risk HPV (HR-HPV) infection and effective medical intervention of persistent HPV infection and precancerous lesions are critical for the prevention of cervical cancer. AIMS: The aim of this retrospective comparative study was to evaluate the outcomes of ALA PDT and observation only in the management of low-grade squamous intraepithelial lesions (LSIL). METHODS: In PDT Group (n = 138), ALA PDT was applied to patients with colposcopic biopsy confirmed cervical LSIL accompanied with HR-HPV infection longer than 1 year or HPV 16/18 subtype infection. Cervical LSIL only patients received 3 times of ALA PDT and those with concurrent cervical canal or vaginal lesions received 6 times ALA PDT. Control Group (n = 69) received observation only. Colposcopy, TCT and HPV typing were performed before and after treatment. Patients were followed up for up to two years. RESULT: The observation group showed 26.1%, 34.8% and 53.6% HR-HPV negative conversion at 3-6, 12 and 24 months, respectively. LSIL regression rate of the observation group was 33.33%, 36.23% and 65.22% at 3-6, 12 and 24 months, respectively. There was 62.32%, 80.56% and 89.22% patients achieved HPV clearance at 3-6, 12 and 24 months after PDT treatment, respectively. The LSIL remission rate was 89.86%, 94.40% and 96.08% at 3-6, 12 and 24 months after ALA PDT, respectively. The abnormal TCT (⧠ASCUS) was reduced from 92% to 10.1%, 4.6% and 3.9% at 3-6, 12 and 24 months after ALA PDT, respectively. The patient age was not a factor affecting the clearance of HPV infection and the LSIL regression rate of PDT treatment. CONCLUSIONS: This study demonstrates that the application of multiple ALA PDT treatments has added value in achieving both short-term and long-term HPV and lesion clearance.
Assuntos
Ácido Aminolevulínico , Infecções por Papillomavirus , Fotoquimioterapia , Fármacos Fotossensibilizantes , Humanos , Feminino , Fotoquimioterapia/métodos , Ácido Aminolevulínico/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Infecções por Papillomavirus/tratamento farmacológico , Lesões Intraepiteliais Escamosas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Penile cancer is a rare malignancy with a poor prognosis. Studies with single-agent immune checkpoint inhibitors (ICIs) have demonstrated efficacy, but response rates are low. Studies combining ICIs with both chemotherapy and targeted therapy are ongoing. Up to 50% of penile cancer cases are associated with human papillomavirus (HPV). HPV-targeting therapies, such as HPV-targeting vaccines and T-cell receptor therapies, are an area of active investigation. Penile cancer cells also express cell surface antigens that may be targeted by the emerging class of antibody-drug conjugates.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias Penianas , Humanos , Neoplasias Penianas/terapia , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/patologia , Masculino , Inibidores de Checkpoint Imunológico/uso terapêutico , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Imunoterapia/métodos , Metástase Neoplásica , Terapia de Alvo MolecularRESUMO
Epidemiological studies have shown that HPV-related diseases are the most prevalent sexually transmitted infections. In this context, this report will present various clinical cases demonstrating the effectiveness of Acyclovir (ACV) or its prodrug Valaciclovir (VCV), both acyclic guanosine analogs commonly used for the treatment of HHV-1 and HHV-2, for the treatment of HPV-related diseases. The report shows the remission of five cases of penile condyloma and a case of remission in a woman affected by cervical and vaginal condylomas and a vulvar giant condyloma acuminate of Buschke and Lowenstein. The literature review shows that ACV is effective in treating skin warts when administered orally, topically, and intralesionally, suggesting its therapeutic potential in other diseases associated with HPV. ACV was also used successfully as an adjuvant therapy for juvenile and adult forms of laryngeal papillomatosis, also known as recurrent respiratory papillomatosis, prolonging the patient's symptom-free periods. Although the prevention of HPV infections is certainly achieved with the HPV vaccine, ACV and VCV have shown to be effective even against genotypes not included in the current vaccine and can be helpful for those problematic clinical cases involving unvaccinated individuals, immunocompromised patients, people who live with HIV, or non-responders to the vaccine. We and others concluded that randomized clinical trials are necessary to determine the efficacy of ACV and VCV for HPV-related diseases.
Assuntos
Antivirais , Infecções por Papillomavirus , Adulto , Feminino , Humanos , Masculino , Aciclovir/uso terapêutico , Aciclovir/farmacologia , Antivirais/uso terapêutico , Antivirais/farmacologia , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/virologia , Resultado do Tratamento , Valaciclovir/uso terapêuticoRESUMO
BACKGROUND/AIM: Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising in incidence. Compared to HPV-negative (HPV-) OPSCC, HPV+ cases have a better 5-year survival. With its severe side-effects, today's chemoradiotherapy has not improved outcome compared to radiotherapy alone, so new therapies are needed. Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 3 (FGFR3) and cell division cycle 27 (CDC27) are found in HPV+ OPSCC, and in vitro targeted therapy combining PI3K and FGFR inhibitors showed synergistic effects. Here the effects of targeting CDC27 with curcumin with/without various inhibitors or cisplatin on OPSCC cell lines were examined. MATERIALS AND METHODS: Curcumin was administered to HPV+ OPSCC cell lines CU-OP-2, CU-OP-3 and CU-OP-20, and HPV- CU-OP-17 with/without PI3K, cyclin-dependent kinase 4/6, FGFR, poly (ADP-ribose) polymerase or WEE1 inhibitors (BYL719, PD-0332991, JNJ-42756493, BMN-673 and MK-1775, respectively), or cisplatin. The cell lines were then assessed for 72 h after treatment for viability, proliferation and cytotoxicity. RESULTS: Curcumin led to dose-dependent responses with reduced viability and proliferation; upon combining it with BYL719, additional positive effects were found for most OPSCC lines grown as monolayers, and these effects were validated in CU-OP-2 cells grown as spheroids. Curcumin with MK-1775 or PD-0332991 also elicited some positive effects on CU-OP-2 and CU-OP-17 cells. CONCLUSION: Curcumin alone led to dose-dependent responses and when combined with BYL719, positive effects were revealed, as they were when it was combined with MK-1775 or PD-0332991, suggesting a potential use of some of these combinations for HPV+ OPSCC.
Assuntos
Curcumina , Neoplasias Orofaríngeas , Humanos , Curcumina/farmacologia , Linhagem Celular Tumoral , Neoplasias Orofaríngeas/virologia , Neoplasias Orofaríngeas/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proliferação de Células/efeitos dos fármacos , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Papillomaviridae/efeitos dos fármacos , Cisplatino/farmacologiaRESUMO
Persistent infection with high-risk human papillomavirus (HR-HPV) is a well-established risk factor to the development of cervical intraepithelial neoplasia (CIN), a condition that can progress to cervical cancer (CC) a major health problem worldwide. Recently, there has been growing interest in exploring alternative therapies utilizing natural products, among which is the algae species Laurencia johnstonii Setchell & Gardner, 1924 (L. johnstonii), proposed for the management of precancerous lesions. The aim of this work was to determine the effect of an organic extract from L. johnstonii (ELj) in early cervical lesions (CIN 1). These CIN 1 lesions were generated in a murine model expressing the HR-HPV16 E7 oncoprotein (K14E7HPV transgenic mice) with a single exogenous hormonal stimulus using 17ß-estradiol. The histopathological studies, the determination of cell proliferation and of the apoptotic levels in cervical tissue, showed that, seven doses of ELj (30 mg/kg weight per day diluted in a DMSO-saline solution [1:7]) lead to recovery the architecture of cervical epithelium. Accordingly, in the transgenic mice it was observed a statistically significant decrease of the PCNA expression levels, a marker of cell proliferation, and a statistically significant increase in the apoptosis levels using Caspase 3 as a marker. In addition, we determined the expression levels of the tumor suppressor miR-218 and the oncomiRNA miR-21. Interestingly, our results may suggest that ELj treatment tended to restore the normal expression of both miRNAs as compared with controls being more evident in the non-transgenic induced mice. Differences of p < 0.05 were considered statistically significant through the whole study. Based on these results, we propose that the use of ELj could be an alternative for the treatment of cervical early lesions.
Assuntos
Laurencia , MicroRNAs , Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Humanos , Camundongos , Animais , Laurencia/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/patologia , MicroRNAs/genética , Camundongos Transgênicos , Carcinogênese , Papillomaviridae/genéticaRESUMO
The use of conventional chemotherapy in conjunction with targeted and immunotherapy drugs has emerged as an option to limit the severity of side effects in patients diagnosed with head and neck cancer (HNC), particularly oropharyngeal cancer (OPC). OPC prevalence has increased exponentially in the past 30 years due to the prevalence of human papillomavirus (HPV) infection. This study reports a comprehensive review of clinical trials registered in public databases and reported in the literature (PubMed/Medline, Scopus, and ISI web of science databases). Of the 55 clinical trials identified, the majority (83.3%) were conducted after 2015, of which 77.7% were performed in the United States alone. Eight drugs have been approved by the FDA for HNC, including both generic and commercial forms: bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo). The most common drugs to treat HPV-associated OPC under these clinical trials and implemented as well for HPV-negative HNC include cisplatin, nivolumab, cetuximab, paclitaxel, pembrolizumab, 5-fluorouracil, and docetaxel. Few studies have highlighted the necessity for new drugs specifically tailored to patients with HPV-associated OPC, where molecular mechanisms and clinical prognosis are distinct from HPV-negative tumors. In this context, we identified most mutated genes found in HPV-associated OPC that can represent potential targets for drug development. These include TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A.
Assuntos
Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Cetuximab/uso terapêutico , Docetaxel , Nivolumabe , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Neoplasias Orofaríngeas/etiologia , Neoplasias Orofaríngeas/terapiaRESUMO
BACKGROUND: Cervical cancer has been linked to human papillomavirus (HPV) types 16 and 18. Essential oils (EOs) are vital natural products of plants with various therapeutic and biological properties. OBJECTIVES: The purpose of this study is to investigate and assess Tanacetum sinaicum essential oil's possible antiviral and anticancer properties, with a focus on its in vitro effects on human cervical cancer and human breast adenocarcinoma cell lines. MATERIALS AND METHODS: Tanacetum sinaicum EO was extracted via hydrodistillation (HD) and characterized using gas chromatography-mass spectrometry (GC-MS). MTT assay was used to determine the cell viability of Hela (a human epithelial cervical cancer) and MCF-7 (human breast adenocarcinoma) cell lines. Quantitative real-time polymerase chain reaction (PCR) was utilized to assess the antiviral efficacy of EO against HPV-16 and 18, and anti-metastatic characteristics. The biological activity of EO was assessed using Autophage and Cell genotoxicity via the comet assay. RESULTS: EO is mostly composed of chrysanthenyl acetate, thujone, and verbenol. The cell viability was reduced after 24 hours of incubation at doses from 100 to 400 µg/ml. Concentrations of 800 to 3,200 µg/ml significantly inhibit cell growth. After a 24-hour incubation period, doses ranging from 100 to 400 µg/ml reduced cell viability from 62 to 72%. Concentrations of 800 to 3,200 µg/ml significantly suppress cell growth by over 95%. In MCF7 and HeLa cell lines, EO lowered virus copy numbers in a dose-dependent manner, with higher concentrations of the oil inhibiting virus replication more effectively. EO treatment increased the number of autophagosomes/autolysosomes and acidic vesicular organelles in both cell lines. On the HeLa and MCF7 cell lines, EO demonstrated antiproliferative and antimetastatic effects. The results demonstrated that EO had dose-dependent genotoxic effects on both cancer cell lines, as evidenced by DNA damage. CONCLUSION: Tanacetum sinaicum EO is a prospective source of natural bioactive compounds that can be employed in pharmaceutical and medicinal applications due to its antiviral, antiproliferative, anti-metastatic and genotoxic properties.