Tormentic acid induces anticancer effects in cisplatin-resistant human cervical cancer cells mediated via cell cycle arrest, ROS production, and targeting mTOR/PI3K/AKT signalling pathway.

PURPOSE: Tormentic acid has been shown to exert remarkable anti-cancer potential against different cancer cell types. In this study, the anti-cancer potential of tormentic acid was examined in cisplatin-resistant cervical cancer cells (HeLa cells). Further, the effects of tormentic acid on cell cycle, reactive oxygen species (ROS) production, and mTOR/PI3K/AKT signalling pathway were evaluated as well. METHODS: Cell viability was evaluated by MTT assay and its impact on mTOR/PI3K/AKT signalling pathway was estimated via western blot assay. Colony formation was analysed through clonogenic assay and phase-contrast microscopy was used for the determination of apoptotic cell morphology along with DAPI staining. Fluorescence-activated cell sorting was performed for cell cycle analysis and ROS production was monitored by fluorescence microscopy. RESULTS: The results indicated that tormentic acid significantly supresses the proliferation of HeLa cells. These antiproliferative effects of tormentic acid were dose-dependent. Clonogenic assay revealed anti-colony formation potential of tormentic acid. Tormentic acid also induced remarkable morphological changes in HeLa cells, indicative of apoptosis. Further, DAPI staining assay showed formation of apoptotic bodies along with dead cells bearing apoptotic nuclei. Western blotting showed impressive increase in the expressions of pro-apoptotic proteins and decreased expression of anti-apoptotic proteins. Fluorescence-activated cell sorting (FACS) analysis revealed that tormentic acid induced G2/M phase cell cycle arrest and its effectiveness increased with increased doses. Fluorescence intensity indicated amplified ROS production after tormentic acid exposure. The expression of tormentic acid on mTOR/PI3K/AKT pathway revealed blocking of this pathway with a concentration-dependent manner. CONCLUSIONS: The outcomes of the present investigation suggest that tormentic acid-induced apoptotic effects in cisplatin-resistant HeLa cells were mediated via cell cycle arrest, ROS production and targeting of mTOR/PI3K/AKT signalling pathway. Thus, tormentic acid may be considered as a lead molecule in cancer therapeutics.

Efficacy of ω-3 supplementation on nutritional status, skeletal muscle, and chemoradiotherapy toxicity in cervical cancer patients: A randomized, triple-blind, clinical trial conducted in a middle-income country.

OBJECTIVES: Supplementation with ω-3 has been shown to favor the preservation of body weight and skeletal muscle. The aim of this study was to evaluate the efficacy of ω-3 supplementation on nutritional status, skeletal muscle quantity and quality, and toxicity for treatment of women with cervical cancer. METHODS: This was a randomized, triple-blinded, placebo-controlled clinical trial in women diagnosed with cervical cancer who underwent chemoradiotherapy between March 2016 and August 2017. The intervention group received four capsules with ω-3 (2.5 g/d) and the control group (CG) received the same number of identical-looking capsules with olive oil, for 45 d. Nutritional status was measured by anthropometry and Patient-Generated Subjective Global Assessment. Body composition was assessed by computed tomography. The skeletal muscle index was calculated using the range -29 to +150 HU. For skeletal muscle quality, the area comprised between -29 and +29 HU was denominated low-radiodensity skeletal muscle index and the range between +30 and +150 HU high-radiodensity skeletal muscle index, representing the skeletal muscle area with high or low intramuscular fat infiltration, respectively. RESULTS: The study population comprised 40 patients, with an average age 44.53 ± 8.73. The intervention group maintained body weight and showed an improvement in Patient-Generated Subjective Global Assessment score. A significant reduction in skeletal muscle index was observed in both groups. However, in regard to skeletal muscle quality, patients in the intervention group preserved low- and high-radiodensity skeletal muscle index, whereas those in the control group had increased low-radiodensity skeletal muscle index and significantly reduced high-radiodensity skeletal muscle index, reflecting high intramuscular fat infiltration only in the control group. The incidence of chemotherapy toxicity was significantly lower in the intervention group. CONCLUSIONS: The results suggest that ω-3 supplementation is effective in maintaining nutritional status, skeletal muscle quality, and reduced symptoms of chemoradiotherapy among women with cervical cancer.

A Phenolic Extract Obtained from Methyl Jasmonate-Treated Strawberries Enhances Apoptosis in a Human Cervical Cancer Cell Line.

In the present study, we evaluated the effect of methyl jasmonate (MeJA) treatment on strawberry phenolic composition. Strawberry extracts contain a mixture of phenolic compounds possessing several biological properties. We demonstrated that these extracts were more effective in inducing apoptosis in HeLa cells compared to phenolic preparations derived from untreated strawberries. Treatment of strawberries with 0.5% MeJA resulted in increased polyphenols content (from 7.4 to 8.6 mM quercetin equivalents) and antioxidant properties (from 3.9 to 4.6 mM quercetin equivalents). The identification and quantification of phenolic compounds by liquid chromatography-mass spectrometry in the strawberry extracts showed that cyanidin glucoside, pelargonidin glucoside, and ellagic glucoside acid were significantly higher in strawberries treated with MeJA. Phenolic extracts from MeJA-treated strawberries significantly decreased the cell viability in HeLa cells, compared to extracts derived from untreated fruits. We hypothesized that the enhanced apoptotic activity of MeJA-treated strawberries was due to a synergistic or additive effect of different phenolic compounds present in the extract, rather than the activity of a single molecule.

Deficiencia de micronutrientes en la dieta del paciente con lesiones precancerosas del cérvix de una clínica de colposcopía en Ciudad Juárez, México / Micronutrient deficiency in the diet of the patient with precancerous cervix lesions on a colposcopy clinic at Ciudad Juárez, Mexico

Introducción: las lesiones intraepiteliales escamosas (LIE) son un estado de transición hacia el cáncer cervicouterino (CaCu) y un déficit de cronutrientes puede acelerar este proceso. Por ello, determinar la existencia de este déficit y conocer qué factores se asocian permitiría una posible prevención en esta población de riesgo. Objetivo: determinar la presencia de alguna deficiencia de micronutrientes involucrados en el proceso anticancerígeno y asociar este déficit con hábitos y factores demográficos en pacientes con LIE de Ciudad Juárez, Chihuahua, México. Métodos: en un estudio transversal analítico fueron seleccionadas 102 pacientes con LIE. Se realizó una encuesta dietaría (recordatorio de 24 horas) para estimar la ingesta de micronutrientes. La deficiencia fue determinada con un consumo < 75% de la ingesta diaria recomendada o sugerida (IDR o IDS) en México. Algunos hábitos y factores demográficos fueron obtenidos mediante la entrevista con la paciente. Se realizó un modelo de regresión logística para asociar la presencia de deficiencia con factores que afectan a la ingesta o incrementan el requerimiento de micronutrientes. Resultados: el retinol, ácido fólico, zinc, vitaminas C y E, considerados como micronutrientes en el proceso anticancerígeno del CaCu, se encontraron por debajo del 75% de la IDR. Aquellas mujeres con sobrepeso, obesidad y amas de casa se asociaron significativamente con la deficiencia de micronutrientes. Conclusión: el sobrepeso, la obesidad y la ocupación han sido asociados para presentar deficiencias de micronutrientes en este estudio. Estas variables convergen en una posible inseguridad alimentaria, la cual podría asociarse al incremento de incidencia de CaCu en México (AU)

Introduction: Squamous Intraepithelial Lesions (SIL) is a state of transition to cervical cancer (CC), and micronutrient deficiencies can speed up this process. Therefore, determining the existence of this deficit and know what factors are associated would allow for possible prevention in this population at risk. Objective: To determine the presence of some micronutrient deficiencies involved in the anti-carcinogenic process, also associate this deficit with habits and demographic factors in patients with SIL in Ciudad Juarez, Chihuahua, Mexico. Methods: An analytic cross-sectional study, 102 patients were selected with SIL. A dietary survey (24-hour recall) was performed to estimate the intake of micronutrients. The deficiency was determined when the consumption was less than 75% of the Recommended Dietary Allowances (RDA) or suggested in Mexico. Some habits and demographic factors were obtained by interview with the patient. A logistic regression was performed to associate the presence of deficiencies with factors that affecting the intake or increase the requirement of micronutrients. Results: Retinol, folic acid, zinc, vitamins C and E, considered micronutrients in the anti-carcinogenic process CC, were less than 75% of the RDA. Women with overweight, obesity and housewives, were significantly associated with micronutrient deficiencies. Conclusion: Overweight, obesity and occupation have been associated to present micronutrient deficiencies in this study. These variables converge on a possible food insecurity, which could be associated with increased incidence of CC in Mexico (AU)

Antioxidant supplementation during oncology treatment has no effect on cervical cancer recurrence / La suplementación con antioxidantes durante el tratamiento oncológico no tiene efecto sobre la recurrencia de cáncer cervicouterino

Introduction and aim: Antioxidant therapy with chemotherapy and radiotherapy in cervical cancer patients is controversial. While some evidence suggests that the use of antioxidants diminishes side effects from anticancer therapy, there is also data to suggest that antioxidants increase the risk of recurrence by affecting oncology treatments. Methods: We conducted a controlled clinical trial in cervical cancer patients supplemented with an antioxidant mixture or a placebo during four years after their antineoplastic treatment was completed and the effect on recurrence. We also conducted data on used hemoglobin and albumin levels. Differences between groups were analyzed using chi-square test. Survival was calculated by the Multivariate COX regression with omnibus test and the enter method. Results: 103 treated patients were in clinical stages IIB and IIIB of cervical cancer, 48% (n = 49) of the patients were treated with antioxidant supplementation and 52% (n =54) of the patients were in the placebo group. Of the original 103 patients, were able to follow up on 88 patients for an additional four years. 23.9% (n = 21) of the patients presented cancer recurrence and 76.1% (n = 67) did not, 21.6% (n = 19) patients showed metastasis. 8% (n = 7) patients were in the antioxidant group and 15.9% (n = 14) were in the placebo group (p > 0.05). Regarding implications of cancer survivors, antioxidant supplementation apparently seems not to have interference with recurrence in cervical cancer patients but there is not enough evidence to prove it. A different dosage may have the expected effect; however, further studies with another dosage and criteria are necessary. Conclusions: Supplementation with antioxidants during treatment of cervical cancer has no effect on cancer recurrence after 4 years of follow-up (AU)

Introducción y objetivos: la terapia con antioxidantes durante la quimioterapia y radioterapia en pacientes con cáncer cervicouterino es controvertida. Mientras existe evidencia que sugiere que el uso de antioxidantes disminuye los efectos secundarios propios del tratamiento contra el cáncer, hay datos que sugieren que los antioxidantes incrementan el riesgo de recurrencia de cáncer por la afectación de la terapia de los tratamientos. Métodos: se dirigió un estudio clínico controlado en pacientes con cáncer cervicouterino que fueron suplementados con una mezcla de antioxidantes o placebo, con seguimiento por 4 años posteriores al término de su tratamiento antineoplásico para evaluar el efecto de los antioxidantes en la recurrencia. Tomamos datos de niveles de hemoglobina y albúmina. Se analizaron las diferencias entre grupos con la prueba de Chi-cuadrado, la sobrevida se calculó con un análisis multivariado por medio de regresión de COX. Resultados: se dio seguimiento a 103 pacientes con cáncer cervicouterino en etapa clínica IIB y IIIB de los cuales 48% fueron tratados con suplementación de antioxidantes y el 52% con placebo, originalmente y de estos se dio seguimiento a 88 pacientes durante 4 años. El 23,9% de los pacientes tratados presentaron recurrencia por cáncer mientras que el 76,1% no la presentó. El 21,6% de los pacientes presentaron metástasis, el 8% de los pacientes perteneció al grupo de antioxidantes y el 15,9% al grupo placebo (p > 0,05). Implicaciones para los pacientes supervivientes: la suplementación con antioxidantes aparentemente no interfiere con la recurrencia por cáncer, sin embargo no hay evidencia suficiente para probarlo. Posiblemente una dosis distinta sea la clave para un mejor efecto, pero serán necesarios futuros estudios que prueben efectos sobre otro tipo de dosis. Conclusiones: la suplementación con antioxidantes durante el tratamiento de pacientes con cáncer cervicouterino no tiene efectos en la recurrencia por cáncer a 4 años de seguimiento (AU)

A detailed comparative study between chemical and bioactive properties of Ganoderma lucidum from different origins.

A detailed comparative study on chemical and bioactive properties of wild and cultivated Ganoderma lucidum from Serbia (GS) and China (GCN) was performed. This species was chosen because of its worldwide use as medicinal mushroom. Higher amounts of sugars were found in GS, while higher amounts of organic acids were recorded in GCN. Unsaturated fatty acids predominated over saturated fatty acids. GCN revealed higher antioxidant activity, while GS exhibited inhibitory potential against human breast and cervical carcinoma cell lines. No cytotoxicity in non-tumour liver primary cell culture was observed for the different samples. Both samples possessed antibacterial and antifungal activities, in some cases even better than the standard antimicrobial drugs. This is the first study reporting a comparison of chemical compounds and bioactivity of G. lucidum samples from different origins.

Suplementos dietéticos como tratamiento en el cáncer cervicouterino; revisión sistemática / Dietary supplements as a treatment for cervical cancer; a systemic review

Introducción: En el cáncer cervicouterino (CaCu) y neoplasias intraepiteliales cervicales (NIC) se requiere de una cuidadosa selección de terapias convencionales y complementarias, la inclusión de suplementos dietéticos dentro de ellas marcaría la pauta dentro de los tratamientos. Sin embargo, no se tiene algún reporte de qué tipo de suplementos pudieran ser utilizados para brindar una mejor respuesta ante la enfermedad por estas pacientes. Objetivo: En la presente revisión se analizan los ensayos clínicos de los últimos 20 años que evaluaron suplementos dietéticos en esta población, con el objetivo de dar a conocer cuáles de ellos son viables para ser administrados. Metodología: Se realizó una búsqueda de ensayos clínicos que utilizaron algún suplemento dietario en mujeres con CaCu y algún grado de NIC analizando en ellos el modo de utilización del suplemento; el tratamiento convencional; si existe una deficiencia del nutriente ó compuesto a evaluar; las características de la población, del ensayo clínico y del suplemento; así como la dosis y los efectos esperados. Resultados: Veinte fueron en total el número de estudios analizados. Los artículos fueron clasificados según la naturaleza del suplemento: Retinoides, vitamina E, probióticos, indoles, multivitamínico, ácido fólico y selenio. Conclusión: Para el tratamiento de CaCu y NIC resultaron efectivos algunos de los suplementos encontrados en esta revisión, sin embargo su efecto dependerá de diferentes factores propios de la enfermedad. Debido a esto, es necesario el manejo correcto de los suplementos dietéticos para poder ser utilizados eficientemente como tratamiento complementario en esta población (AU)

Introduction: Cervical cancer and cervical intraepithelial neoplasia (CIN) require a careful selection of conventional and complementary therapies. The inclusion of dietary supplements within the aforementioned treatments set the tone within treatments. However, there are no reports of what kind of supplements could be used to provide a better response to the disease in these patients. Objective: In this review, we analyze clinical trials of the past 20 years that evaluated dietary supplements on this population, with the objective to raise awareness on which of them are viable to be administered. Methods: We performed a search for clinical trials that used a dietary supplement in women with cervical cancer and some degree of NIC analyzing them how to use the supplement, the conventional treatment, deficiency of the nutrient or compound to be evaluated, the characteristics of the population, the clinical trial and the supplement, as well as dosage and their effects. Results: Twenty were in total the number of studies reviewed. The articles were classified according to the nature of the supplement: Retinoids, vitamin E, probiotics, indoles, multivitamin, folic acid and selenium. Conclusion: Some supplements were found to be effective in the treatment of cervical cancer and CIN. However, their effect depends on specific factors of the disease. The correct management of dietary supplements is an effective aid to help the patient with cancer and therefore, it is important to define what complementary therapies can be used for this population (AU)

Probiotics enhance the clearance of human papillomavirus-related cervical lesions: a prospective controlled pilot study.

Probiotics have been proposed for a number of urogenital infectious conditions. In this study, we examine a possible effect on human papillomavirus (HPV)-related precancerous lesions in cervical cytology. We conducted a prospective controlled pilot study, in which 54 women with an HPV+low-grade squamous intraepithelial lesion diagnosis in their PAP smear were followed for 6 months. The intervention group consumed a daily probiotic drink during the study period; the control group received no treatment, according to common care policy. Outcome measures were the control PAP smear and HPV status after 6 months. Probiotic users had a twice as high chance of clearance of cytological abnormalities (60 vs. 31%, P=0.05). HPV was cleared in 19% of control patients versus 29% of probiotic users (P=0.41). This exploratory pilot study suggests that the probiotic studied promotes the clearance of HPV-related cytological abnormalities. If confirmed, this would represent an entirely new option to manage cervical cancer precursors.

A dietary pattern associated with LINE-1 methylation alters the risk of developing cervical intraepithelial neoplasia.

There is a paucity of research examining the relationships between dietary patterns and risk of developing precancerous lesions as well as biomarkers associated with such dietary patterns. The purpose of the current study was to identify dietary patterns that are associated with higher grades of cervical intraepithelial neoplasia (CIN 2+) and to determine whether these dietary patterns are associated with the degree of DNA methylation in the long interspersed nucleotide elements (L1s) of peripheral blood mononuclear cells (PBMCs), a biomarker associated with risk of developing CIN 2+. Study population consisted of 319 child-bearing age women. Dietary patterns were derived by factor analysis. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models were used to evaluate the associations between dietary patterns and CIN 2+. Similar models were used to evaluate the associations between dietary patterns and degree of PBMC L1 methylation in women free of CIN 2+. Women with the unhealthiest dietary pattern were 3.5 times more likely to be diagnosed with CIN 2+ than women with the healthiest dietary pattern [OR = 3.5; 95% confidence interval (CI), 1.2-10.1; P = 0.02]. Women at risk for developing CIN 2+ with the healthiest dietary pattern were 3.3 times more likely to have higher PBMC L1 methylation than women with the unhealthiest dietary pattern (OR = 3.3; 95% CI, 1.0-10.6; P = 0.04). Our findings suggest that human papilloma virus associated risk of developing CIN 2+ may be reduced by improving dietary patterns. The degree of PBMC L1 methylation may serve as a biomarker for monitoring the effectiveness of dietary modifications needed for reducing the risk of CIN 2+.

[Coriolus versicolor--innovation in prevention of oncogynecological diseases, especially HPV].

Coriolus-MRL is a nutrient adjuvant, which contains biomass of the fungus Coriolus versicolor and is studied to reverse early stages of cervical cancer and to reduce risk factors of reoccurring HPV virus.

Iron withdrawal strategies fail to prevent the growth of SiHa-induced tumors in mice.

OBJECTIVE: Cervical carcinoma is a human papillomavirus (HPV)-associated cancer for which treatment options still mainly rely on surgical procedures, with or without adjuvant radiotherapy and chemotherapy. We have previously shown that the chemically unrelated iron chelators desferrioxamine and deferiprone inhibit the growth and induce the apoptosis of HPV-positive cervical carcinoma cell lines, suggesting that iron chelators may represent a potential therapeutic approach for the treatment of cervical carcinoma. The present study was designed to investigate the effect of iron deprivation on the growth of human cervical carcinoma xenografts in athymic nude mice. METHODS: Nude mice (nu/nu) of BALB/c background were treated with iron chelators [desferrioxamine (DFO), deferiprone (L1), or starch-DFO conjugate] or were fed with an iron-poor diet 6 weeks prior to subcutaneous injection of Si-Ha cells. These treatments were continued for 5 weeks after injection of the tumor cells. Treatment with the maximum tolerated doses of DFO, L1, or starch-DFO conjugate induced no significant iron deprivation in non-iron-overloaded mice, while an iron-poor diet led to a dramatic decrease in serum iron, transferrin iron saturation, and ferritin levels. However, neither iron chelators nor an iron-poor diet could significantly inhibit tumor growth. CONCLUSION: Despite a potent antitumor effect in vitro, iron chelators fail to prevent the growth of cervical carcinoma xenografts in mice. On the basis of these results, clinical trials with iron chelators in patients with cervical carcinoma appear inappropriate.

High vegetable and fruit diet intervention in premenopausal women with cervical intraepithelial neoplasia.

OBJECTIVE: To examine whether diet intervention can promote increased vegetable and fruit intake, as reflected in increased plasma carotenoid and decreased plasma total homocysteine concentrations, in premenopausal women with cervical intraepithelial neoplasia, a precancerous condition. DESIGN: Randomized controlled diet intervention study. SUBJECTS: Fifty-three free-living premenopausal women who had been diagnosed with cervical intraepithelial neoplasia, were randomly assigned to an intervention (n = 27) or a control (n = 26) group. INTERVENTION: Individualized dietary counseling to increase vegetable and fruit intake. MAIN OUTCOME MEASURES: Diet was assessed by food frequency questionnaire. Plasma carotenoids and total homocysteine were measured at enrollment and at 6 months follow up. ANALYSIS: Associations between baseline plasma concentrations of carotenoids and homocysteine and influencing factors were examined with multiple regression analysis. Repeated measures analysis of variance was used to test for group by time effects in these plasma concentrations. Plasma carotenoids at baseline and 6 months in the study groups, and differences in homocysteine concentrations from baseline to 6 months, were compared with independent sample t tests. RESULTS: Repeated measures analysis of variance showed significant group by time effects (P<.01) in plasma carotenoid and homocysteine concentrations. In the intervention group, total plasma carotenoids increased by an average of 91%, from 2.04+/-0.13 (mean+/-standard error of the mean) to 3.90+/-0.56 micromol/L and plasma total homocysteine was reduced by 11%, from 9.01+/-0.40 to 8.10+/-0.44 micromol/L (P<.003). Neither changed significantly in the control group. APPLICATIONS: Individualized dietary counseling can effectively promote increased vegetable and fruit intake in premenopausal women. This dietary pattern may reduce risk for cancer and other chronic diseases and also promote an improvement in folate status.

Can cervical dysplasia and cancer be prevented with nutrients?

Invasive cervical cancer accounts for 11.6% of all cancers worldwide and is the second most common cancer among women. It is the most common cancer among women living in less developed countries. Although infection with oncogenic-type human papillomaviruses (HPV) is associated with most cases of cervical cancer, HPV infection alone is an insufficient cause of cervical cancer. Research from the last two decades suggests a role for nutrients in the prevention of cervical cancer. However, results from phase III folic acid and beta-carotene chemoprevention trials have been negative. Potential reasons for the lack of treatment effect are discussed within the context of cervical carcinogenesis.