Protective Autophagy in 5-Fluorouracil-Resistant Colorectal Cancer Cells and ERK-RSK-ABCG2 Linkage / Autofagia Protectora en Células de Cáncer Colorrectal Resistentes al 5-Fluorouracilo y Enlace ERK-RSK-ABCG2

SUMMARY: To evaluate the anti-cancer effects of yeast extract on resistant cells, autophagy and necroptosis were investigated in 5-fluorouracil (5-FU)-resistant colorectal cancer cells. Further underlying characteristics on drug resistance were evaluated, focused on ERK-RSK-ABCG2 linkage. SNU-C5 and 5-FU resistant SNU-C5 (SNU-C5/5-FUR) colorectal cancer cells were adopted for cell viability assay and Western blotting to examine the anti-cancer effects of yeast extract. Yeast extract induced autophagy in SNU-C5 cells with increased Atg7, Atg12-5 complex, Atg16L1, and LC3 activation (LC3-II/LC3-I), but little effects in SNU-C5/5-FUR cells with increased Atg12-5 complex and Atg16L1. Both colorectal cancer cells did not show necroptosis after yeast extract treatment. Based on increased ABCG2 and RSK expression after yeast extract treatment, drug resistance mechanisms were further evaluated. As compared to wild type, SNU-C5/5-FUR cells showed more ABCG2 expression, less RSK expression, and less phosphorylation of ERK. ABCG2 inhibitor, Ko143, treatment induces following changes: 1) more sensitivity at 500 mM 5-FU, 2) augmented proliferation, and 3) less phosphorylation of ERK. These results suggest that protective autophagy in SNU-C5/5-FUR cells with increased ABCG2 expression might be candidate mechanisms for drug resistance. As the ERK responses were different from each stimulus, the feasible mechanisms among ERK-RSK-ABCG2 should be further investigated in 5-FU-resistant CRC cells.

Para evaluar los efectos anticancerígenos del extracto de levadura en células resistentes, se investigaron la autofagia y la necroptosis en células de cáncer colorrectal resistentes al 5-fluorouracilo (5-FU). Además se evaluaron otras características subyacentes de la resistencia a los medicamentos centrándose en el enlace ERK-RSK-ABCG2. Se usaron células de cáncer colorrectal SNU-C5 (SNU-C5/5-FUR) resistentes a SNU-C5 y 5- FU para el ensayo de viabilidad celular y la transferencia Western para examinar los efectos anticancerígenos del extracto de levadura. El extracto de levadura indujo autofagia en células SNU-C5 con mayor activación de Atg7, complejo Atg12-5, Atg16L1 y LC3 (LC3-II/LC3-I), pero pocos efectos en células SNU-C5/5-FUR con aumento de Atg12-5 complejo y Atg16L1. Ambas células de cáncer colorrectal no mostraron necroptosis después del tratamiento con extracto de levadura. Se evaluaron los mecanismos de resistencia a los medicamentos. en base al aumento de la expresión de ABCG2 y RSK después del tratamiento con extracto de levadura.En comparación con las de tipo salvaje, las células SNU-C5/5-FUR mostraron más expresión de ABCG2, menos expresión de RSK y menos fosforilación de ERK. El tratamiento con inhibidor de ABCG2, Ko143, induce los siguientes cambios: 1) más sensibilidad a 5-FU 500 mM, 2) proliferación aumentada y 3) menos fosforilación de ERK. Estos resultados sugieren que la autofagia protectora en células SNU-C5/5-FUR con mayor expresión de ABCG2 podría ser un mecanismo candidato para la resistencia a los medicamentos. Como las respuestas de ERK fueron diferentes de cada estímulo, los mecanismos factibles entre ERK-RSK- ABCG2 deberían investigarse más a fondo en células CCR resistentes a 5-FU.

Curcuma as an adjuvant in colorectal cancer treatment.

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide and mostly affects men. Around 20% of its incidence is by familiar disposition due to hereditary syndromes. The CRC treatment involves surgery and chemotherapy; however, the side effects of treatments and the fast emergence of drug resistance evidence the necessity to find more effective drugs. Curcumin is the main polyphenol pigment present in Curcuma longa, a plant widely used as healthy food with antioxidant properties. Curcumin has synergistic effects with antineoplastics such as 5-fluorouracil and oxaliplatin, as well anti-inflammatory drugs by inhibiting cyclooxygenase-2 and the Nuclear factor kappa B. Furthermore, curcumin shows anticancer properties by inhibition of the Wnt/ß-catenin, Hedgehog, Notch, and the phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways implicated in the progression of CRC. However, the consumption of pure curcumin is less suitable, as the absorption is poor, and the metabolism and excretion are high. Pharmacological formulations and essential oils of the plant improve the curcumin absorption, resulting in therapeutical dosages. Despite the evidence obtained in vitro and in vivo, clinical studies have not yet confirmed the therapeutic potential of curcumin against CRC. Here we reviewed the last scientific information that supports the consumption of curcumin as an adjuvant for CRC therapy.

Radioterapia y 5-fluorouracilo-cisplatino en el tratamiento del cáncer de cuello uterino de alto riesgo / Radiotherapy and 5-fluorouracil-cisplatin treatment for high-risk uterine cervical cancer

Objetivo: evaluar la eficacia de la combinación de radioterapia y 5-fluorouracilo-cisplatino en el tratamiento del cáncer de cuello uterino de alto riesgo. Materiales y métodos: estudio retrospectivo en el que se revisaron los datos de pacientes tratadas en el periodo enero 2009 a diciembre 2019 en el Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela. Se revisaron los registros clínicos de todas las pacientes sometidas a histerectomía radical y linfadenectomía pélvica bilateral que recibieron quimio-radioterapia concurrente adyuvante con 5-fluorouracilo-cisplatino (grupo de tratamiento) y se compararon con quienes no fueron manejadas con este régimen, las que no recibieron ningún tratamiento adyuvante o solo fueron tratadas con radioterapia (grupo control). Se evaluaron las características generales, efectos adversos del tratamiento, recurrencias de la enfermedad y supervivencia. Resultados: para el análisis final quedaron 164 pacientes, de las cuales 115 (70,1%) fueron del grupo de tratamiento y 49 (29,9%) del control. No se encontraron diferencias estadísticamente significativas en las características clínicas entre ambos grupos (p = ns); sí las hubo en la frecuencia de recurrencias a distancia (p = 0,0056). La supervivencia libre de progresión y la global de ambos grupos no mostraron diferencias significativas (p = 0,2678 y p = 0,3452). Conclusión: no existen beneficios evidentes del uso de 5-fluorouracilo-cisplatino desde el punto de vista de progresión o supervivencia general, en pacientes con carcinoma cuello uterino de alto riesgo.

Objective: to evaluate the efficacy of radiotherapy combined with 5-fluorouracil-cisplatin in the treatment of high-risk uterine cervical cancer. Materials and methods: Retrospective study, in which the data of patients treated between January 2009 and December 2019 at Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela, was analyzed. The clinical records of all patients who underwent radical hysterectomy and bilateral pelvic lymphadenectomy and received adjuvant concurrent chemoradiotherapy with 5-fluorouracil-cisplatin (treatment group) compared with those patients not managed with this regimen, those who did not receive any adjuvant treatment or received only radiotherapy (control group), were reviewed. The general characteristics, treatment adverse effects, disease recurrences and survival rate were evaluated. Results: 164 patients remained for the final analysis, of which 115 (70.1%) were in the treatment group and 49 (29.9%) in the control group. No statistically significant differences were found in the clinical characteristics of patients between the two groups (p = ns); while differences in the distant recurrence rate (p = 0.0056) were found. Progression-free survival and overall survival in both groups did not show significant differences (p = 0.2678 and p = 0.3452). Conclusion: there is no evident benefit of the use of 5-fluorouracil-cisplatin in terms of progression or overall survival in patients with high-risk cervical carcinoma.

Resistance of Nonmelanoma Skin Cancer to Nonsurgical Treatments. Part I: Topical Treatments. / Resistencias al tratamiento no quirúrgico en cáncer cutáneo no melanoma. Parte I: tratamientos tópicos.

A wide range of treatments is now available for nonmelanoma skin cancer (NMSC), including 5-fluorouracil, ingenol mebutate, imiquimod, diclofenac, photodynamic therapy, methotrexate, cetuximab, vismodegib, and radiotherapy. All are associated with high clinical and histologic response rates. However, some tumors do not respond due to resistance, which may be primary or acquired. Study of the resistance processes is a broad area of research that aims to increase our understanding of the nature of each tumor and the biologic features that make it resistant, as well as to facilitate the design of new therapies directed against these tumors. In this article we review resistance to the authorized topical treatments for NMSC.

In vitro effect of 5-fluorouracil and paclitaxel on Echinococcus granulosus larvae and cells.

Human cystic echinococcosis is a zoonosis caused by the metacestode stage of the tapeworm Echinococcus granulosus. Although benzimidazole compounds such as albendazole and mebendazole have been the cornerstone of chemotherapy for the disease, there is often no complete recovery after treatment. Hence, in searching for novel treatment options, we examined the in vitro efficacies of 5-fluorouracil (5-FU) and paclitaxel (PTX) against E. granulosus germinal cells, protoscoleces and cysts. 5-FU or PTX inhibited the growth of E. granulosus cells in a time dependent manner. Although both treatments had a protoscolicidal effect, 5-FU had a considerably stronger effect than PTX. 5-FU produced a dose- and time-dependent effect, provoking the complete loss of viability after 24 days of incubation. Moreover, cysts did not develop following the inoculation of treated protoscoleces into mice. The loss of viability was slower in PTX treated protoscoleces, reaching to approximately 60% after 30 days. The results of the in vitro treatment with 5-FU and PTX were similar in secondary murine cysts. The employment of SEM and TEM allowed us to examine, at an ultrastructural level, the effects induced by 5-FU and PTX on E. granulosus germinal cells, protoscoleces and murine cysts. In conclusion, the data obtained clearly demonstrated that 5-FU and PTX at clinically achievable concentrations inhibit the survival of larval cells, protoscoleces and metacestodes. In vivo studies to test the antiparasitic activities of 5-FU and PTX are currently being undertaken on the murine model of cystic echinococcosis.

Conjunctival intraepithelial neoplasia. Interferon as a rescue therapy after failure of mitomycin C.

CLINICAL CASE: The case of a 60 year-old male with a conjunctival lesion diagnosed as conjunctival intraepithelial neoplasia (CIN), who was treated with mitomycin-C for 3 weeks with minimal improvement. The therapy was change to interferon 2B. Six month later, and after a complete remission of the lesion, the treatment was suspended, with no signs of relapse. DISCUSSION: The treatment of these lesions is currently made with chemotherapy and immunotherapy agents, such as mitomycin-C, 5-fluorouracil, and interferon alfa 2B. The latter, even although is the least used, gives excellent results with fewer secondary effects than mitomycin-C, resulting in an optimal therapy for the non-invasive treatment of CIN lesions.

Revisión por aguja de la bula de filtración, una alternativa terapÚutica en pacientes trabeculectomizados / Needle review of the filtering bleb as an alternative in the treatment of patients undergoing trabeculectomy

La trabeculectomía es generalmente un procedimiento exitoso para reducir la presión intraocular en pacientes con glaucoma. Sin embargo, el fallo de la ampolla de filtración puede ocurrir y provocar un incremento de la presión intraocular. Esto conllevaría a una intervención médica o quirúrgica adicional. Se realiza una revisión bibliográfica sobre la cistitomía transconjuntival, asociada al uso de antimetabolitos (mitomicina C o 5-fluorouracilo) o no. Se demuestra que es mínimamente invasiva, con escasas complicaciones y que constituye un método eficaz, fácil y barato para restablecer el drenaje acuoso y disminuir la presión intraocular

Trabeculectomy is usually a successful procedure to reduce intraocular pressure in glaucoma patients. However, the failure of the filtering bleb can occur, leading to increased intraocular pressure and to a further medical or surgical intervention. A literature review on transconjunctival cystotomy, with or without the use of mitomycin C or 5-fluorouracil, was made. It was demonstrated that this method is minimally invasive with few complications, effective, easy-to-apply and inexpensive to restore aqueous drainage and lowering intraocular pressure

Efectividad de cistotomía de cápsula de Tenon con aguja fina en fallo de ampolla de filtración / Effectiveness Tenon capsule cystotomy with Fine needle on bleb failure

La trabeculectomía es generalmente un procedimiento exitoso parareducir la presión intraocular en pacientes con glaucoma. Sin embargo,el fallo de la ampolla de filtración puede ocurrir, provocando unincremento de la presión intraocular; lo que conlleva a una intervenciónmédica o quirúrgica adicional. Se realiza una breve revisión bibliográficasobre la cistotomía transconjuntival, asociada o no al uso deantimetabolitos (mitomicina C o 5-fluorouracilo), demostrando que esun procedimiento mínimamente invasivo, con escasas complicaciones;que constituye un método eficaz, fácil, de bajo costo para restablecer eldrenaje acuoso y disminuir la presión intraocular(AU)

Trabeculectomy is a successful method in reducing intraocular pressure in glaucoma patients. However, the failure of the filtration bleb can occur, leading to increased intraocular pressure, which leads to a surgical intervention. A brief bibliographical review is done on the transconjunctival cystotomy, with or without the use of antimetabolites (mitomycin C or 5-fluorouracil), showing that it is a minimally invasive procedure with few complications, which is an effective, easy and inexpensive method to re-establish the aqueous drainage and reduce intraocular pressure(AU)

Revisión por aguja de la bula de filtración, una alternativa terapÚutica en pacientes trabeculectomizados / Needle review of the filtering bleb as an alternative in the treatment of patients undergoing trabeculectomy

La trabeculectomía es generalmente un procedimiento exitoso para reducir la presión intraocular en pacientes con glaucoma. Sin embargo, el fallo de la ampolla de filtración puede ocurrir y provocar un incremento de la presión intraocular. Esto conllevaría a una intervención médica o quirúrgica adicional. Se realiza una revisión bibliográfica sobre la cistitomía transconjuntival, asociada al uso de antimetabolitos (mitomicina C o 5-fluorouracilo) o no. Se demuestra que es mínimamente invasiva, con escasas complicaciones y que constituye un método eficaz, fácil y barato para restablecer el drenaje acuoso y disminuir la presión intraocular(AU)

Trabeculectomy is usually a successful procedure to reduce intraocular pressure in glaucoma patients. However, the failure of the filtering bleb can occur, leading to increased intraocular pressure and to a further medical or surgical intervention. A literature review on transconjunctival cystotomy, with or without the use of mitomycin C or 5-fluorouracil, was made. It was demonstrated that this method is minimally invasive with few complications, effective, easy-to-apply and inexpensive to restore aqueous drainage and lowering intraocular pressure(AU)

Efecto inmunomodulador de la solución CM-95 tratada magnéticamente en ratones Balb/c inoculados con 5-fluorouracilo / Immunomodulator effect of the CM-95 Solution treated magnetically in Balb/c mouse with 5- fluorouracil inoculated

El 5-fluorouracilo es un antineoplásico usado en la terapia del cáncer y posee acción inmunosupresora al inhibir la proliferación de células del tejido hematopoyético. En este trabajo se evaluó el efecto inmunomodulador de la solución CM-95 tratada magnéticamente en ratones Balb/c inoculados con 5-fluorouracilo a través de su acción protectora rehabilitadora sobre parámetros celulares y tisulares del tejido hematopoyético. A los ratones, entre 20-22 g de peso y 6 semanas de nacidos, se les administró esta solución CM-95 tratada magnéticamente por vía intraperitoneal en un esquema de dos inoculaciones; luego se administró por la misma vía el 5_fluorouracilo a una dosis de 150 mg/m2 de superficie corporal de cada ratón. Se evaluó el conteo total y diferencial de leucocitos antes de inocular el 5-fluorouracilo, y a los tres y siete días de aplicado este. La celularidad de médula ósea y bazo y la observación microscópica del corte histológico de hígado y bazo por la técnica de inclusión en parafina y tinción con eosina hematoxilina al 10 por ciento se evaluaron a los siete días de haber aplicado el 5- fluorouracilo. La solución CM-95, tratada magnéticamente, logró modular los efectos del 5-fluorouracilo con una actividad protectora rehabiltadora, para los parámetros evaluados en médula ósea, sangre periférica, bazo e hígado. Estos resultados abren nuevas perspectivas para la aplicación del sistema acuoso tratado magnéticamente como inmunomodulador(AU)

5-Fluorouracil is an antineoplastic drug used in cancer chemotherapy. It has immunosuppressant effects by inhibiting cell proliferation from the haematopoietic tissue. In this paper, the immunomodulating effect of the magnetically treated CM-95 solution in Balb/c mice inoculated with 5- fluorouracil by its rehabilitating protecting action on cell parameters of the haematopoietic tissue. Six-week old mice weighing 20-22 g were inoculated twice with magnetically treated CM-95 solution by intraperitoneal route. Then, they received 5-fluoracile in a dose of 150 mg/m2 of body surface by the same route. Haematopoietic parameters such as total and differential leukocyte count were evaluated before applying the antineoplastic drug and at the third and seventh days after the application. Bone marrow and spleen cellularity as well as the microscopic observation of the histological cut of the liver and of spleen, by the technique of inclusion in paraffin dyes with 10 percent eosin haematoxylin, were evaluated at seven days after the application of 5 fluorouracil. The magnetically treated CM-95 solution could modulate the effects of 5-fluorouracil with protecting and rehabilitating activity for the parameters evaluated in the bone marrow, peripheral blood, spleen and liver. These results open new perspectives for the application of the magnetically treated aqueous system as immunomodulator(AU)

Valor pronóstico y predictivo de la timidilato sintetasa (TS) en pacientes con cáncer de colon / Prognostic and predictive value of the thymidylate synthase (TS) in patients with colon cancer

El cáncer colo-rectal es uno de los cánceres más comunes en el mundo actual, para lo cual el 5-Fluorouracilo (5-FU) es usualmente parte importante del tratamiento quimioterapéutico. La Timidilato Sintetasa (TS), es la enzima blanco para el 5-FU. Estudios recientes sugieren que la TS puede predecir el pronóstico y el éxito de la terapia basada en el 5-FU. El propósito de este estudio retrospectivo fue determinar la expresión de la TS en muestras de biopsias de cáncer de colon incluidas en parafina, mediante la técnica de inmunohistoquímica y correlacionarla con factores de riesgo, antígeno carcinoembrionario (CEA), CA-19-9, evolución del paciente y respuesta al tratamiento con 5-FU. La población en estudio consistió en 34 muestras de biopsias de cáncer de colon obtenidas de pacientes quienes fueron tratados con 5-FU y Leucovorina. A las muestras de adenocarcinomas colónicas incluidas en parafina se les realizó la detección de TS a través de inmunohistoquímica. Los pacientes en cuyos tumores había una alta expresión de la TS, mostraron una sobrevida significativamente menor comparado son aquellos pacientes que mostraron baja expresión de la enzima en sus tumores (p=0,004). La expresión de la TS puede ser utilizada como un importante marcador pronóstico de sobrevida y de respuesta a la quimioterapia en pacientes con cáncer colo-rectal.

Colorectal cancer is one of the most common cancers in the world today, for which a 5-fluorouracil (5-FU) is usually an important part of the chemotherapeutic treatment. The thymidylate synthase (TS), is the target enzyme for 5-FU. Recent studies suggest that TS can predict the prognosis and the success of therapy based on 5-FU. The purpose of this retrospective study was to determine the expression of TS in samples from biopsies of colon cancer in paraffin, using the technique of immunohistochemistry and its correlation with risk factors, carcinoembryonic antigen (CEA), CA-19-9, patients evolution and response to treatment with 5-FU. The study population consisted of 34 biopsy samples obtained from colon cancer patients who were treated with 5-FU and Leucovorin. A sample of colonic adenocarcinoma in paraffin was performed to detect TS through immunohistochemistry. Patients whose tumours had a high expression of TS showed a significantly lower survival rate compared with those patients who showed low expression of the enzyme in their tumours (p = 0.004). The expression of TS can be used as an important marker of survival prognosis and response to chemotherapy in patients with colon cancer.