Curcumin, calebin A and chemosensitization: How are they linked to colorectal cancer?

Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds. Calebin A and curcumin, two polyphenolic turmeric ingredients derived from the Asian Curcuma longa plant, demonstrate versatile anti-inflammatory and cancer-reducing abilities, including CRC-combating capacity. After an insight into their epigenetics-modifying holistic health-promoting effects, this review compares functional anti-CRC mechanisms of multi-targeting turmeric-derived compounds with mono-target classical chemotherapeutic agents. Furthermore, the reversal of resistance to chemotherapeutic drugs was presented by focusing on calebin A's and curcumin's capabilities to chemosensitize or re-sensitize CRC cells to 5-FU, oxaliplatin, cisplatin, and irinotecan. Both polyphenols enhance the receptiveness of CRC cells to standard cytostatic drugs converting them from chemoresistant into non-chemoresistant CRC cells by modulating inflammation, proliferation, cell cycle, cancer stem cells, and apoptotic signaling. Therefore, calebin A and curcumin can be tested for their ability to overcome cancer chemoresistance in preclinical and clinical trials. The future perspective of involving turmeric-ingredients curcumin or calebin A as an additive treatment to chemotherapy for patients with advanced metastasized CRC is explained.

Combination Therapy Using Polyphenols: An Efficient Way to Improve Antitumoral Activity and Reduce Resistance.

Polyphenols represent a structural class of mainly natural organic chemicals that contain multiple phenol structural units. The beneficial properties of polyphenols have been extensively studied for their antitumor, anti-inflammatory, and antibacterial effects, but nowadays, their medical applications are starting to be extended to many other applications due to their prebiotic role and their impact on the microbiota. This review focused on the use of polyphenols in cancer treatment. Their antineoplastic effects have been demonstrated in various studies when they were tested on numerous cancer lines and some in in vivo models. A431 and SCC13 human skin cancer cell lines treated with EGCG presented a reduced cell viability and enhanced cell death due to the inactivation of ß-catenin signaling. Additionally, resveratrol showed a great potential against breast cancer mainly due to its ability to exert both anti-estrogenic and estrogenic effects (based on the concentration) and because it has a high affinity for estrogen receptors ERα and Erß. Polyphenols can be combined with different classical cytostatic agents to enhance their therapeutic effects on cancer cells and to also protect healthy cells from the aggressiveness of antitumor drugs due to their anti-inflammatory properties. For instance, curcumin has been reported to reduce the gastrointestinal toxicity associated with chemotherapy. In the case of 5-FU-induced, it reduced the gastrointestinal toxicity by increasing the intestinal permeability and inhibiting mucosal damage. Co-administration of EGCG and doxorubicin induced the death of liver cancer cells. EGCG has the ability to inhibit autophagic activity and stop hepatoma Hep3B cell proliferation This symbiotic approach is well-known in medical practice including in multiple chemotherapy.

Acute renal disease in patients with ovarian peritoneal carcinomatosis treated with cytoreduction and HIPEC: the influence of surgery and the cytostatic agent used.

BACKGROUND: The main objective of this study was to evaluate the differences between cisplatin and paclitaxel in the development of postoperative renal toxicity, using as a reference the RIFLE (Risk, Injury, Insufficiency, Loss, and End-stage renal function) and AKIN (Acute Kidney Injury Network) criteria in patients with primary or recurrent ovarian cancer with peritoneal dissemination treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: One hundred fifty-two patients who were treated between December 2007 and June 2017 were analyzed. RESULTS: Patients who received previous platinum-based chemotherapy had higher baseline creatinine levels than those who had not (p = 0.05). A total of 11 (7.2%) and 4 (2.6%) patients developed an acute renal dysfunction (ARD) during the postoperative period of cytoreduction and HIPEC according to the RIFLE and AKI criteria respectively. RIFLE detects a higher rate of ARD due to different parameters such as GFR (7.2% versus 2.6%, p = 0.016). Performing ostomy (p = 0.007; OR: 39.320; 95% CI = 2.74-56.13) and using of cisplatin during HIPEC treatment (p = 0.017; OR = 13.619; 95% IC = 1.600-25.95) were factors independently related to a higher rate of ARD. CONCLUSION: ARD has a multifactorial origin. Cisplatin was associated with the development of a higher rate of ARD than paclitaxel. Diagnosis of ARD did not correlate with worse survival figures.

Antitoxic Activity of Extract from Salix Viminalis Leaves under Conditions of 5-Fluorouracil Treatment.

Injection of 5-fluorouracil to animals caused a pronounced toxic effect. Therapeutic and preventive treatment with Salix viminalis leaf extract significantly reduced the negative effects of the antitumor drug: promoted recovery of the bone marrow, peripheral blood, and visceral parameters and prevented ulceration. Combined use of the cytostatic and Salix viminalis extract increased the efficiency of antitumor therapy.

Treatment of echinococcosis: albendazole and mebendazole--what else?

The search for novel therapeutic options to cure alveolar echinococcosis (AE), due to the metacestode of Echinococcus multilocularis, is ongoing, and these developments could also have a profound impact on the treatment of cystic echinococcosis (CE), caused by the closely related Echinococcus granulosus s.l. Several options are being explored. A viable strategy for the identification of novel chemotherapeutically valuable compounds includes whole-organism drug screening, employing large-scale in vitro metacestode cultures and, upon identification of promising compounds, verification of drug efficacy in small laboratory animals. Clearly, the current focus is targeted towards broad-spectrum anti-parasitic or anti-cancer drugs and compound classes that are already marketed, or that are in development for other applications. The availability of comprehensive Echinococcus genome information and gene expression data, as well as significant progress on the molecular level, has now opened the door for a more targeted drug discovery approach, which allows exploitation of defined pathways and enzymes that are essential for the parasite. In addition, current in vitro and in vivo models that are used to assess drug efficacy should be optimized and complemented by methods that give more detailed information on the host-parasite interactions that occur during drug treatments. The key to success is to identify, target and exploit those parasite molecules that orchestrate activities essential to parasite survival.

Magnetite nanostructures functionalized with cytostatic drugs exhibit great anti-tumoral properties without application of high amplitude alternating magnetic fields.

Here, we report the synthesis, characterization and the impact of magnetite nanoparticles functionalized with cytostatic drugs, epirubicin (Epi) and fludarabine (Flu) (Fe3O4@Epi, Fe3O4@Flu) prepared by chemical co-precipitation method on tumoral cells in vitro. The average diameter of the resulted particles was about 4 nm for both Fe3O4@Epi and for Fe3O4@Flu. These bioactive nanostructured materials proved to significantly enhance the antitumor effect of tested cytostatic drugs in vitro. The most significant result was obtained in the case of Epi, where the tested magnetite nanostructured material enhanced the cytotoxic effect of this drug with more than 50%.

Aspectos a tener en cuenta en la atención integral de enfermería durante la quimioterapia en pediatría: issues to consider in nursing comprehensive care / Chemotherapy in children: issues to consider in nursing comprehensive care

La manipulación de fármacos citostáticos constituye una de las actividades más frecuentes de los profesionales de enfermería por la amplia administración de estos medicamentos en nuestros días. En la actualidad, en el mundo se han ido desarrollando estrategias para el manejo seguro de estos fármacos. El perfeccionamiento de la enfermería en Cuba ha permitido un gran avance en la especialidad y un real aporte al diagnóstico, tratamiento y monitoreo de las enfermedades hematológicas, por el elevado nivel profesional alcanzado por el personal de enfermería dentro de la especialidad. Se exponen las recomendaciones generales para la atención integral de enfermería que todo niño con leucemia debe recibir, esté hospitalizado o reciba atención ambulatoria. Se abordan los elementos fundamentales del manejo de los citostáticos y los elementos para garantizar la bioseguridad en el trabajo con estos medicamentos(AU)

The handling ofcytostatic drugsis one ofthe most frequent activitiesofnursesfor the extensiveadministration of these drugs nowadays.Today,strategies have been developed throughout the world forsafe handling ofantineoplasic agents. The developmentof nursing inCubahas alloweda breakthroughin the art anda real contributionto the diagnosis, treatment and monitoringofhematologicaldiseases, due to the highprofessional levelreachedby nurseswithin the specialty. General recommendations forcomprehensivenursing care every child withleukemiashould receive are described, whether hospitalizedor in outpatient care. Basic handling of cytostaticsand elementsto guarantee biosecurity when working withthese medications are included(AU)

Aspectos a tener en cuenta en la atención integral de enfermería durante la quimioterapia en pediatría: issues to consider in nursing comprehensive care / Chemotherapy in children: issues to consider in nursing comprehensive care

La manipulación de fármacos citostáticos constituye una de las actividades más frecuentes de los profesionales de enfermería por la amplia administración de estos medicamentos en nuestros días. En la actualidad, en el mundo se han ido desarrollando estrategias para el manejo seguro de estos fármacos. El perfeccionamiento de la enfermería en Cuba ha permitido un gran avance en la especialidad y un real aporte al diagnóstico, tratamiento y monitoreo de las enfermedades hematológicas, por el elevado nivel profesional alcanzado por el personal de enfermería dentro de la especialidad. Se exponen las recomendaciones generales para la atención integral de enfermería que todo niño con leucemia debe recibir, esté hospitalizado o reciba atención ambulatoria. Se abordan los elementos fundamentales del manejo de los citostáticos y los elementos para garantizar la bioseguridad en el trabajo con estos medicamentos

The handling ofcytostatic drugsis one ofthe most frequent activitiesofnursesfor the extensiveadministration of these drugs nowadays.Today,strategies have been developed throughout the world forsafe handling ofantineoplasic agents. The developmentof nursing inCubahas alloweda breakthroughin the art anda real contributionto the diagnosis, treatment and monitoringofhematologicaldiseases, due to the highprofessional levelreachedby nurseswithin the specialty. General recommendations forcomprehensivenursing care every child withleukemiashould receive are described, whether hospitalizedor in outpatient care. Basic handling of cytostaticsand elementsto guarantee biosecurity when working withthese medications are included

Individualización de dosis en el paciente oncológico con insuficiencia hepática / Customization of doses in oncological patients with impaired hepatic function

Objetivo: determinar qué citostáticos requieren ajuste de dosis en pacientes con insuficiencia hepática. Métodos: se realizó una búsqueda en PubMed de toda la bibliografía publicada hasta julio de 2011 sobre dosificación de citostáticos en pacientes con función hepática alterada. Se procedió a su valoración según la clasificación de la Scottish Intercollegiate Guidelines Network. Se sintetizó un índice de fuerza de la recomendación farmacoterapéutica, para lo que se asoció el grado de recomendación de la evidencia encontrada y el número de pacientes incluidos en los estudios encontrados. Se clasificó la recomendación para cada fármaco como de fuerza alta, media o baja. Resultados: se encontraron un total de 46 publicaciones con información sobre dosificación en pacientes con insuficiencia hepática para un total de 17 citostáticos. El 67 por ciento (n= 31) de las publicaciones fueron estudios de cohortes con un nivel de evidencia 2+. No pudieron establecerse recomendaciones de fuerza alta, pero sí de fuerza moderada (76 por ciento; 13 fármacos) y baja (24 por ciento; 4 fármacos). Conclusiones: aunque el nivel de la evidencia disponible fue bajo, podrían establecerse recomendaciones sobre la dosificación de citostáticos en pacientes con insuficiencia hepática para mejorar la seguridad en el uso de estos fármacos en el referido grupo de enfermos(AU)

Objective: to determine the cytostatic drugs requiring dose adjustment in patients with impaired hepatic function. Methods: aliterature review of all the papers about dosage of cytostatic drug in patients with impaired hepatic function published till July 2011 in Pubmed search was made. They were assessed as rated by the Scottish Intercollegiate Guidelines Network. An index of pharmacotherapy recommendation strength was developed, for which the grade of recommendation of the evidence found and the number of patients included in the studies were then correlated, ranking the strength of recommendation for each drug as high, medium or low. Results: atotal of 46 publications with information about dosing in liver failure were found for 17 cytostatic drugs. Sixty seven percent (n= 31) of the publications were cohort studies with a level of evidence 2+. High strength recommendations could not been established, but moderate strength (76 percent; 13 drugs) and low strength (24 percent; 4 drugs) recommendations were finally established. Conclusions: although level of evidence was low, dosage recommendations of cytostatic drugs to be used in liver failure patients were established to improve safety in the use of these drugs in the stated group of patients(AU)

La gestión del proceso de fibrilación auricular: un abordaje integral / Managing the atrial fibrillation process: An integral approach

Objetivos. El estudio se ha desarrollado en 3 fases cuyos respectivos objetivos han sido: definir el proceso de gestión más adecuado para la fibrilación auricular (FA) desde el punto de vista de profesionales y pacientes. Conocer cómo se gestiona en la práctica diaria. Identificar los cambios necesarios para que esta práctica diaria se aproxime a una gestión adecuada del proceso. Material y métodos. Diseño: 1.a fase: se han utilizado técnicas de consenso, un análisis de modos de fallo y sus efectos (AMFE) y un grupo focal con pacientes. 2.a fase: se ha desarrollado mediante encuesta. 3.a fase: se han realizado 3 grupos nominales y 3 grupos focales. Emplazamiento: Atención Primaria y Cardiología. Participantes: en la primera fase médicos de familia, cardiólogos y pacientes. En la segunda y tercera, médicos de familia. Mediciones principales: 1.a fase: se ha definido el diagrama de flujo, con sus notas explicativas, del proceso correcto de atención para la FA. 2.a fase: se ha investigado como se atiende en la práctica en la actualidad. 3.a fase: se han identificado las barreras para una correcta atención del proceso y se han definido propuestas para su mejora. Resultados. Casi el 40% de los médicos de familia se implicó en el diagnóstico y tratamiento de sus pacientes con FA. Se identificó la formación, la colaboración entre especialidades, motivación, trabajo en equipo con enfermería y cambios organizacionales como factores imprescindibles para una correcta gestión del proceso. Conclusiones. La FA puede ser gestionada desde Atención Primaria. Para ello son necesarios cambios relevantes en la organización de la asistencia. Se ven como imprescindibles tanto la formación como el apoyo y comunicación entre niveles(AU)

Objectives. The study was developed in 3 phases, with the following aims: To define the most appropriate management process for atrial fibrillation (AF) from the point of view of the health professionals and the patients. To determine how it is managed in daily practice. To identify the changes required in order that this daily practice may come closer to that of an appropriate management process. Material and methods. Design: 1st phase: consensus techniques were used, as well as a failure modes and effects analysis (FMEA), and a focus group with patients. 2nd phase: included a questionnaire. 3rd phase: 3 nominal groups and 3 focus groups were formed. Setting: Primary Care and Cardiology. Participants: Family doctors, cardiologists, and patients, in the first phase, and family doctors in the second and third phases. Main measurements: 1st phase: a flow diagram was designed with its explanatory notes on the correct care process for AF. 2nd phase: how AF was managed in current practice. 3rd phase: barriers for using the correct care process were identified, and proposals for their improvement were defined. Results. Almost 40% of the family doctors were involved in the diagnosis and treatment of their patients with FA. Training, cooperation between specialties, motivation, working in a team with nursing, and organisational changes were identified as essential factors for a proper management process. Conclusions. AF can be managed from Primary Care. To do this, important changes are required in the care organisation. Training, along with support and communication between care levels are also seen as necessary(AU)

Effect of sorafenib combined with cytostatic agents on hepatoblastoma cell lines and xenografts.

BACKGROUND: Sorafenib has recently been shown to reduce tumour growth in hepatoblastoma (HB) xenografts. The effect of a combined administration with cytostatic agents was now investigated. METHODS: Cell viability after treatment with sorafenib and different cytostatic agents was evaluated in two HB cell lines (HUH6 and HepT1) using MTT assay. ERK signalling was investigated by western blot, NOXA expression by rt-PCR, and formation of DNA adducts using immunocytology. NMRI mice bearing subcutaneous HUH6-derived tumours were treated with sorafenib alone or in combination with cisplatin. Tumour progression, viability, apoptosis, and vascularisation were monitored by tumour volume, AFP levels, TUNEL assay, and CD31 immunostaining, respectively. RESULTS: The combination of sorafenib and cisplatin led to a remarkable decrease in cell viability. The cisplatin-induced enhanced ERK1/2 activation, but not NOXA expression and the formation of DNA adducts was partly abrogated by sorafenib. In HB xenografts, both, sorafenib and alternated application of sorafenib and cisplatin significantly reduced tumour growth (P<0.05). Levels of AFP were lower in both treated groups (P=0.08). Relative apoptotic areas were increased (P=0.003). Mean vascular density was the lowest in the sorafenib/CDDP group (P=0.02). CONCLUSION: The combination of sorafenib with cisplatin might be a promising treatment option for high risk or recurrent HB.

Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery:hypoxia-inducible factor-1 (HIF-1)-active cells as a target for cancer therapy.

The microenvironment of solid tumors is characterized by low pO(2) that is well below physiological levels. Intratumoral hypoxia is a major factor contributing to cancer progression and is exacerbated as a result of oxygen consumption by rapidly proliferating tumor cells near blood vessels, poor lymphatic drainage resulting in high interstitial pressure, and irregular blood supply through immature tumor vasculature. Hypoxia-inducible factor-1 (HIF-1) is the main transcription factor that regulates cellular responses to hypoxia. Cellular changes induced by HIF-1 are extremely important targets for cancer therapy. Therefore, targeting strategies to counteract HIF-1-active cells are essential for cancer therapy. In this study, we introduce a novel strategy for targeting HIF-1-active cells.

Tea tree oil might combat melanoma.

In this study we present new data from experiments focused on the antitumor activity of tea tree oil (TTO), an essential oil distilled from Melaleuca alternifolia. TTO proved to be capable of inhibiting the growth of melanoma cells and of overcoming multidrug resistance (MDR), as we reported in our previous study. Moreover, the survival role of the MDR-marker P-glycoprotein appears to be involved in the mechanism of invasion of melanoma cells. The results reported herein indicate that TTO and its main active component, terpinen-4-ol, can also interfere with the migration and invasion processes of drug-sensitive and drug-resistant melanoma cells.

Paullinia cupana Mart. var. sorbilis, guarana, increases survival of Ehrlich ascites carcinoma (EAC) bearing mice by decreasing cyclin-D1 expression and inducing a G0/G1 cell cycle arrest in EAC cells.

The objective of this work is to report the antiproliferative effect of P. cupana treatment in Ehrlich Ascites Carcinoma (EAC)-bearing animals. Female mice were treated with three doses of powdered P. cupana (100, 1000 and 2000 mg/kg) for 7 days, injected with 10(5) EAC cells and treated up to day 21. In addition, a survival experiment was carried out with the same protocol. P. cupana decreased the ascites volume (p = 0.0120), cell number (p = 0.0004) and hemorrhage (p = 0.0054). This occurred through a G1-phase arrest (p < 0.01) induced by a decreased gene expression of Cyclin D1 in EAC cells. Furthermore, P. cupana significantly increased the survival of EAC-bearing animals (p = 0.0012). In conclusion, the P. cupana growth control effect in this model was correlated with a decreased expression of cyclin D1 and a G1 phase arrest. These results reinforce the cancer therapeutic potential of this Brazilian plant.

MAPKs are not involved in triptolide-induced cell growth inhibition and apoptosis in prostate cancer cell lines with different p53 status.

Triptolide showed excellent antitumor activity against several solid tumors. However, its mechanism has not been fully understood. To further elucidate it, the effects of mitogen activated protein kinases (MAPKs) on the activity of triptolide towards prostate cancer cell lines were investigated in the present study using both LNCaP (p53 positive and androgen-dependent) and PC-3 (p53 deficient and androgen-independent) cells. Our results showed that triptolide exerted potent growth inhibitory and apoptotic effects on both cell lines, and the effects were independent of the expression of p53. Although upregulation of ERK and JNK phosphorylation was observed after the triptolide treatment, the results with inhibitors showed that these MAPKs were not involved in the mechanism of triptolide activity in human prostate cancer cell lines with different p53 status.

More than antioxidant: N-acetyl-L-cysteine in a murine model of endometriosis.

N-acetyl-L-cysteine exerts a complex action on endometrial cells, involving regulation of gene expression and protein activity and location, all converging into a decreased proliferation and a switch toward a differentiating, less invasive, and less inflammatory phenotype. Also considering the lack of undesired side effects, including unaffected fertility potential, this suggests a beneficial use of NAC in endometriosis clinical treatment.

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect.

In metastatic colorectal and other locally advanced gastrointestinal cancers, the mechanisms of tumor growth and/or immune escape by residual cancer cells after curative resection often provoke tumor recurrence. Current adjuvant therapy is based on pharmacological administration up to 6-8 months after surgery. We hypothesized that the long-term, cytostatic action from repeated post-adjuvant administration of 5-fluorouracil (FU)-leucovorin (LV) cycles, as a result of the downregulation of the above-mentioned cellular mechanisms, could halt tumor progression. An active prospective cohort, including 19 patients (study group) at high risk of relapse, was considered. All patients received repeated post-adjuvant administration of 5-FU-LV cycles for up to 52-60 months following curative surgery (total cumulative dose of about 90 g and mean follow-up of 70.6 ± 49.7 months). The 5-year disease-free interval (DFS) and overall survival (OS) were 80.4 ± 10.2% and 87.1 ± 8.6%, respectively, which is very different from the recent literature that has reported 5-year DFS and OS values of 31.8% and 40.1%, respectively. These findings suggest that this new pharmacological approach based on the long-term maintenance of a cytostatic effect with 5-FU-LV can produce a relevant improvement in the outcome of this population.

Antiproliferative activity of Greek propolis.

The butanolic extract and the isolated chemical constituents, mainly diterpenes and flavonoids, from Greek propolis have been tested for their cytostatic activities against human malignant and normal cell strains. The extract and the diterpenes were found to be the most active against HT-29 human colon adenocarcinoma cells, without affecting normal human cells. Manool, a diterpene isolated for the first time from Greek propolis, was the most active compound, arresting the cancer cells at the G(2)/M phase of the cell cycle.