curcumin and Papillomavirus-Infections

Curcumin is a polyphenolic substance extracted from plants such as Curcuma longa, Curcuma zedoaria, and radix curcumae, and it has attracted much attention because of the anti-inflammatory, antioxidant, anti-tumor, antibacterial and other multiple pharmacological effects. Cervical cancer is one of the most common malignant tumors in women. With the application of HPV (human papillomavirus) vaccine, the incidence of cervical cancer is expected to be reduced, but it remains difficult to promote the vaccine among low-income population. As a commonly used food additive, curcumin has recently been found to have a significant therapeutic effect in the treatment of cervical cancer. In recent years, numerous in vitro and in vivo studies have found that curcumin can have significant efficacy in anti-cervical cancer treatment by promoting apoptosis, inhibiting tumour cell proliferation, metastasis and invasion, inhibiting HPV and inducing autophagy in tumour cells. However, due to poor water solubility, rapid catabolism, and low bioavailability of curcumin, studies on curcumin derivatives and novel formulations are increasing. Curcumin has a wide range of mechanisms of action against cervical cancer and may become a novel antitumor drug in the future, opening up new ideas for the research of curcumin in the field of antitumor. There is a lack of systematic reviews on the mechanism of action of curcumin against cervical cancer. Therefore, this study is a review of the literature based on the mechanism of action of curcumin against cervical cancer, with a view to providing reference information for scientific and clinical practitioners.

Topics: Antineoplastic Agents; Curcumin; Female; Humans; Papillomavirus Infections; Systematic Reviews as Topic; Uterine Cervical Neoplasms

Curcumin, the bioactive polyphenolic ingredient of turmeric, has been extensively studied for its effects on human papilloma virus (HPV) infection as well as primary and malignant squamous cervical cancers. HPV infections, especially those related to HPV 16 and 18 types, have been established as the leading cause of cervical cancer; however, there are also additional contributory factors involved in the etiopathogenesis of cervical cancers. Curcumin has emerged as having promising chemopreventive and anticancer effects against both HPV-related and nonrelated cervical cancers. In this review, we first discuss the biological relevance of curcumin and both its pharmacological effects and pharmaceutical considerations from a chemical point of view. Next, the signaling pathways that are modulated by curcumin and are relevant to the elimination of HPV infection and treatment of cervical cancer are discussed. We also present counter arguments regarding the effects of curcumin on signaling pathways and molecular markers dysregulated by benzo(a)pyrene (Bap), a carcinogen found in pathological cervical lesions of women who smoke frequently, and estradiol, as two important risk factors involved in persistent HPV-infection and cervical cancer. Finally, various strategies to enhance the pharmacological activity and pharmacokinetic characteristics of curcumin are discussed with examples of studies in experimental models of cervical cancer. © 2016 BioFactors, 43(3):331-346, 2017.

Topics: Animals; Antineoplastic Agents, Phytogenic; bcl-2-Associated X Protein; Curcumin; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Papillomaviridae; Papillomavirus Infections; Reactive Oxygen Species; Retinoblastoma Protein; Risk Factors; Signal Transduction; Smoking; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

Curcumin and curcumin containing polyherbal preparations have demonstrated anti-microbial and anti- viral properties in pre-clinical studies. Till date no therapeutic intervention has been proved to be effective and safe in clearing established cervical human papillomavirus (HPV) infection. The present study evaluated the efficacy of Basant polyherbal vaginal cream (containing extracts of curcumin, reetha, amla and aloe vera) and of curcumin vaginal capsules to eliminate HPV infection from cervix. Women were screened by Pap smear and HPV DNA test by PCR. HPV positive women without high grade cervical neoplasias (N=287) were randomized to four intervention arms to be treated with vaginal Basant cream, vaginal placebo cream, curcumin vaginal capsules and placebo vaginal capsules respectively. All subjects were instructed to use one application of the assigned formulation daily for 30 consecutive days except during menstruation and recalled within seven days of the last application for repeat HPV test, cytology and colposcopy. HPV clearance rate in Basant arm (87.7%) was significantly higher than the combined placebo arms (73.3%). Curcumin caused higher rate of clearance (81.3%) than placebo though the difference was not statistically significant. Vaginal irritation and itching, mostly mild to moderate, was significantly higher after Basant application. No serious adverse events were noted.

Topics: Adult; Cervix Uteri; Curcumin; Female; Humans; Papanicolaou Test; Papillomaviridae; Papillomavirus Infections; Plant Extracts; Plants, Medicinal; Vaginal Creams, Foams, and Jellies; Vaginal Smears

The phytochemical mixture TriCurin (curcumin, epigallocatechin gallate (EGCG) and resveratrol) eliminates human papillomavirus (HPV) (+) cancer cells in vitro and in vivo. In this study, we further evaluate TriCurin.. The activity of TriCurin and its individual compounds was assayed on W12 cells, derived from a cervical precancer containing episomal and integrated HPV16 DNA, using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, microscopy and reverse transcription-polymerase chain reaction (RT-PCR), and on HeLa cells by gene expression analysis. The stability and toxicity of TriCurin microemulsion were tested in an organotypic cervical tissue model.. TriCurin and its individual compounds inhibit the growth of W12 cells, episomal, type 1 and 2 integrants; the relative order of activity is TriCurin, EGCG, curcumin, or resveratrol. RT-PCR shows that TriCurin activates p53 and suppresses HPV16 mRNAs E1, E2, E4, E6 and E7 at 24 h in W12 cells. Gene expression analysis shows that TriCurin activates pro-apoptotic genes and represses anti-apoptotic genes in HeLa cells. TriCurin in a microemulsion is stable and non-toxic to cervical tissue. The combination of TriCurin and tanshinone IIA exhibits additional synergy against HeLa cells.. TriCurin, and the combination of TriCurin with tanshinone IIA, are effective against HPV (+) cells. The phytochemical mixture, in the microemulsion-based cream, is a promising therapeutic for the prevention and treatment of cervical cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Catechin; Cell Proliferation; Curcumin; DNA, Viral; Female; Human papillomavirus 16; Humans; Papillomavirus Infections; Resveratrol; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Vulvar intraepithelial neoplasia (VIN) is associated with human papillomavirus (HPV) infection. Curcumin is a natural bioactive compound with antineoplastic properties. The use of nanoparticles containing curcumin could allow a better performance of this compound in therapies. So, VIN biopsies were collected and HPV DNA detection was performed by PCR, positive samples were genotyped by Restriction Fragment Length Polymorphism (RFLP) and HPV-16 variants were determined by sequencing. HPV-16 positive vulva carcinoma cells (A431) were transduced with E-P and E-350G HPV-16 E6 variants. The viability of the transduced cells treated with nanoemulsions was determined by MTT assay. Besides, apoptosis was evaluated by enzymatic activity of Caspase-3/7. The cell viability assay showed that both the empty nanoemulsion (NE-V) and the nanoemulsion of curcumin (NE-CUR) had little effect on cell viability as compared to control cells. Additionally, we observed that cells irradiated in the presence of NE-CUR presented 90% of cell death. The apoptosis assay further revealed a significant increase in the activity of caspases 3 and 7 in A431 cells expressing both HPV-16 E6 variants after treatment with NE-CUR. Finally, we submitted the HPV transduced A431 cells to organotypic cultures and observed that the combination of treatments affected tissue architecture with evident signals of tissue damage. We concluded that nanoemulsions attain good biocompatibility, since no cytotoxicity was observed and NE-CUR associated with photoactivation showed promising results, leading to death only in cells subjected to irradiation. This drug delivery system associated with photodynamic therapy may become promising in the treatment of vulva lesions.

Topics: Adult; Antiviral Agents; Carcinoma in Situ; Cell Line, Tumor; Cell Survival; Curcumin; Emulsions; Female; Genotype; Human papillomavirus 16; Humans; Light; Nanoparticles; Oncogene Proteins, Viral; Papillomavirus Infections; Photosensitizing Agents; Repressor Proteins; Vulvar Neoplasms

Human papillomavirus (HPV) has been directly related to acuminate warts and cervical cancer, the second most common neoplasia among women. Given the lack of treatment against the virus itself, many medications have been utilised, mainly aiming in modifying the host's immunological response. We present the case of a 54 years old postmenopausal patient with a history of vaginal cuff wart and HPV persistence that we managed in our clinic for 6 months with a mix of curcumin, aloe vera, amla and other natural ingredients. As the patient was found to be intolerant to imiquimod (one of the most common conservative methods of treatment) we attempted the use of curcumin, which was applied to the area of the wart three times per week for 6 months. Both clinical and colposcopical improvement was noted in regular clinic visits with regression of the lesion. The outcome of this case encourages our view that curcumin should be considered as a significant treatment modality against HPV infection and acuminate warts.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; beta-Glucans; Colposcopy; Condylomata Acuminata; Curcumin; Drug Combinations; Fatty Alcohols; Female; Humans; Imiquimod; Lactic Acid; Middle Aged; Papanicolaou Test; Papillomavirus Infections; Phyllanthus emblica; Phytotherapy; Plant Preparations; Squamous Intraepithelial Lesions of the Cervix; Vaginal Creams, Foams, and Jellies; Vaginal Diseases; Vaginal Smears

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased in recent decades due to human papillomavirus (HPV)-mediated oncogenesis. Unfortunately, a growing number of HPV-positive (+) OPSCC survivors are living with the irreversible side effects of treatment. The novel, well-tolerated chemotherapeutics with improved side effect profiles are, therefore, in high demand. Metformin is one such drug, widely used as a first-line oral agent in the treatment of type 2 diabetes mellitus. Curcumin is another well-tolerated agent quickly gaining attention for its medicinal properties. Both metformin and curcumin have been shown to display anticancer properties. This study aimed to determine the antitumor effects of these agents, individually and combined, in HPV+​​​​ ​​​and HPV-negative (-) head and neck squamous cell carcinoma (HNSCC) cell lines. This was achieved by assessing the efficacy of varying drug concentrations on the overall cell viability, proliferation, and expression of common HNSCC biomarkers. The results from protein and RNA expression data are highly variable, as expected, with multiple pathways being affected in cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and immunofluorescence microscopy suggest that both agents are capable of slowing proliferation and inducing apoptosis. We conclude that curcumin and metformin display effective antitumor effects in both HPV+ and HPV- HNSCC cell lines. The curcumin effects appear more pronounced in the HPV- cell lines. Metformin appears to be more effective at reducing the overall cell numbers in HPV+ cell lines. Metformin and curcumin combined did not appear to have synergistic effects on the proliferation or apoptosis of the treated cell lines.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Ki-67 Antigen; Metformin; Papillomaviridae; Papillomavirus Infections; Squamous Cell Carcinoma of Head and Neck

Our earlier studies reported a unique potentiated combination (TriCurin) of curcumin (C) with two other polyphenols. The TriCurin-associated C displays an IC50 in the low micromolar range for cultured HPV+ TC-1 cells. In contrast, because of rapid degradation in vivo, the TriCurin-associated C reaches only low nano-molar concentrations in the plasma, which are sub-lethal to tumor cells. Yet, injected TriCurin causes a dramatic suppression of tumors in TC-1 cell-implanted mice (TC-1 mice) and xenografts of Head and Neck Squamous Cell Carcinoma (HNSCC) cells in nude/nude mice. Here, we use the TC-1 mice to test our hypothesis that a major part of the anti-tumor activity of TriCurin is evoked by innate and adaptive immune responses. TriCurin injection repolarized arginase1

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Catechin; Curcumin; Female; Head and Neck Neoplasms; Humans; Killer Cells, Natural; Lung Neoplasms; Macrophages; Mice; Mice, Inbred C57BL; Mice, Nude; Papillomaviridae; Papillomavirus Infections; Resveratrol; T-Lymphocytes, Cytotoxic; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Cyclo-oxygenase-2 (COX2) plays a prominent role in carcinogenesis. This study addresses the effects of two nutraceutical compounds on the expression of COX2 and tumor-associated inflammation in human papillomavirus type 16 (HPV16)-transgenic mice.. Six-week-old FVB/n mice were supplemented with rutin or curcumin for 24 weeks: HPV16. Rutin reduced COX2 expression in the dermis (immunostaining score 7.83 versus 11.25 in untreated HPV16-transgenic mice) and epidermis (4.5 versus 10.0). Curcumin led to dermal and epidermal scores of 10.5 and 4.5. Both compounds reduced leukocytic infiltration, but neither prevented epidermal dysplasia.. COX2 expression in HPV16-induced lesions may be modulated by nutraceuticals, reducing tumor-associated inflammation. However, this was not sufficient to block carcinogenesis, calling for additional studies focused on combination therapies.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Cyclooxygenase 2; Disease Progression; Down-Regulation; Female; Human papillomavirus 16; Humans; Inflammation; Leukocytes; Mice, Transgenic; Papillomavirus Infections; Rutin; Skin; Skin Neoplasms

Transcription factor AP-1 plays a central role in HPV-mediated cervical carcinogenesis. AP-1 has also been implicated in chemo-radio-resistance but the mechanism(s) remained unexplored. In the present study, cervical cancer stem-like cells (CaCxSLCs) isolated and enriched from cervical cancer cell lines SiHa and C33a demonstrated an elevated AP-1 DNA-binding activity in comparison to non-stem cervical cancer cells. Upon UV-irradiation, CaCxSLCs showed a UV exposure duration-dependent higher proliferation and highly increased AP-1 activity whereas it was completely abolished in non-stem cancer cells. CaCxSLCs also showed differential overexpression of c-Fos and c-Jun at transcript as well as in protein level. The loss of AP-1 activity and expression was accompanied by decrease in cell viability and proliferation in UV-irradiated non-stem cancer cells. Interestingly, CaCxSLCs treated with curcumin prior to UV-irradiation abolished AP-1 activity and a concomitant reduction in SP cells leading to abrogation of sphere forming ability, loss of proliferation, induction of apoptosis and the cells were poorly tumorigenic. The curcumin pre-treatment abolished the expression of c-Fos and c-Jun but upregulated Fra-1 expression in UV-irradiated CaCxSLCs. Thus, the study suggests a critical role of AP-1 protein in the manifestation of radioresistance but targeting with curcumin helps in radiosensitizing CaCxSLCs through upregulation of Fra-1.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; DNA; Female; Human papillomavirus 16; Humans; Neoplastic Stem Cells; Papillomavirus Infections; Transcription Factor AP-1; Ultraviolet Rays; Uterine Cervical Neoplasms

Topics: Alphapapillomavirus; Antineoplastic Agents; Antiviral Agents; Curcumin; Humans; Neoplasms; Papillomavirus Infections

Curcumin (diferuloyl methane), the major yellow pigment from the rhizomes of turmeric (Curcuma longa Linn), has anticancer properties. Infection with high-risk human papillomaviruses (HPV) leads to development of cervical carcinoma, predominantly through the action of viral oncoproteins E6 and E7. The present study aims at analyzing the antitumor and antiviral properties of curcumin, on HPV associated cervical cancer cells. Our findings indicate curcumin to be cytotoxic to cervical cancer cells in a concentration-dependent and time-dependent manner. The cytotoxic activity was selectively more in HPV16 and HPV18 infected cells compared to non-HPV infected cells. Balance between tumor cell proliferation and spontaneous cell death via apoptosis had an important role in regulation of tumor cell growth. Curcumin-induced apoptosis in cervical cancer cells. Morphological hallmarks of apoptosis such as nuclear fragmentation and internucleosomal fragmentation of DNA were observed. Curcumin also selectively inhibited expression of viral oncogenes E6 and E7, evident from RT-PCR and Western blotting data. Electrophoretic mobility shift assay revealed that activation of NFkappaB-induced by TNFalpha is down regulated by curcumin. Curcumin blocked IkBalpha phosphorylation and degradation, leading to abrogation of NFkappaB activation. Curcumin also down regulated the expression of COX-2, a gene regulated by NFkappaB. Binding of AP-1, an indispensable component for efficient epithelial tissue-specific gene expression of HPV was also selectively down regulated by curcumin. These results provide attractive data for the possible use of curcumin in the management of HPV associated tumors.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Proliferation; Curcumin; Cyclooxygenase 2; DNA-Binding Proteins; Down-Regulation; Electrophoretic Mobility Shift Assay; Epidermal Growth Factor; Female; Humans; NF-kappa B; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus Infections; Protein Transport; Protein-Tyrosine Kinases; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Uterine Cervical Neoplasms