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Cholesterol-rich nanoemulsion (LDE) can carry chemotherapeutic agents in the circulation and can concentrate those agents in the neoplastic and inflammatory tissues. This method improves the biodistribution of the drug and reduces toxicity. However, the structural stability of LDE particles, without or with associated drugs, has not been extensively investigated. The aim of the present study is to investigate the structural stability of LDE and LDE associated to paclitaxel, etoposide or methotrexate in aqueous solution over time by small-angle X-ray scattering (SAXS and Ultra SAXS) and dynamic light scattering (DLS). The results show that LDE and LDE associated with those chemotherapeutic agents had reproducible and stable particle diameter, physical structure, and aggregation behavior over 3-month observation period. As estimated from both DLS and Ultra-SAXS methods, performed at pre-established intervals, the average particle diameter of LDE alone was approx. 32 nm, of LDE-paclitaxel was 31 nm, of LDE-methotrexate was 35 nm and of LDE-etoposide was 36 nm. Ultra-SAXS analysis showed that LDE nanoparticles were quasi-spherical, and SAXS showed that drug molecules inside the particles showed a layered-like organization. Formulations of LDE with associated PTX, ETO or MTX were successfully tested in animal experiments and in patients with cancer or with cardiovascular disease, showing markedly low toxicity, good tolerability and possible superior pharmacological action. Our results may be useful for ensuing clinical trials of this novel Nanomedicine tool, by strengthening the knowledge of the structural aspects of those LDE formulations.

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SUMMARY: Etoposide is an effective antimitotic and antineoplastic agent used to treat various human malignancies. In the present study, Etoposide was injected intraperitoneally into the rats at 1 mg/kg/day for 52 days (52 doses). The control animals received physiological saline (0.5 ml) intraperitoneally daily for 52 doses. The body weight of etoposide-treated rats was significantly reduced compared to control rats. Lipid peroxidation demonstrated an insignificant rise in hepatic tissue, a non-significant decline in renal tissue, and a significant reduction in cardiac tissue. The levels of GSH in hepatic and renal tissue were found to be non-significantly increased but significantly increased in cardiac tissue compared to controls. GR activity was found to be considerably decreased in the treated group. G-S-T levels increased significantly in all treated group. Etoposide injections caused a non-significant change in the GPX level of hepatic tissue, whereas renal and cardiac tissues showed a significant increase. The activity of CAT in hepatic tissue was significantly increased, while CAT activity in renal tissue showed a non-significant decrease, whereas in cardiac tissue, significantly lower levels were observed than in control group. The level of CYTp450 in hepatic and cardiac tissues showed a significant increase; however, renal tissue showed non-significant depletion, whereas CYTb5 in hepatic, renal, and cardiac tissues was significantly lower than controls. The protein content in the hepatic tissue was not significantly increased, whereas the total protein in the renal and cardiac tissues was increased significantly. The research finding is indicative of detoxification activity in the etoposide model.

El etopósido es un agente antimitótico y antineoplásico eficaz que se utiliza para tratar diversas neoplasias malignas humanas. En el presente estudio, se inyectó etopósido por vía intraperitoneal a las ratas a razón de 1 mg/kg/día durante 52 días (52 dosis). Los animales control recibieron solución salina fisiológica (0,5 ml) por vía intraperitoneal diariamente por 52 dosis. El peso corporal de las ratas tratadas con etopósido se redujo significativamente en comparación con las ratas del grupo control. La peroxidación lipídica demostró un aumento insignificante del tejido hepático, una disminución no significativa del tejido renal y una reducción significativa del tejido cardíaco. Se encontró que los niveles de GSH en el tejido hepático y renal no aumentaron significativamente, pero sí aumentaron significativamente en el tejido cardíaco en comparación con los controles. Se encontró que la actividad de GR disminuyó considerablemente en el grupo tratado. Los niveles de G-S-T aumentaron significativamente en todos los grupos tratados. Las inyecciones de etopósido provocaron un cambio no significativo en el nivel de GPX del tejido hepático, mientras que los tejidos renal y cardíaco mostraron un aumento significativo. La actividad de CAT en el tejido hepático aumentó significativamente, mientras que la actividad de CAT en el tejido renal mostró una disminución no significativa, mientras que en el tejido cardíaco se observaron niveles significativamente más bajos que en el grupo de control. El nivel de CYTp450 en los tejidos hepático y cardíaco mostró un aumento significativo; sin embargo, el tejido renal mostró un agotamiento no significativo, mientras que CYTb5 en los tejidos hepático, renal y cardíaco fue significativamente menor que los controles. El contenido de proteínas en el tejido hepático no aumentó significativamente, mientras que la proteína total en los tejidos renal y cardíaco aumentó significativamente. El hallazgo de la investigación es indicativo de la actividad de desintoxicación en el modelo de etopósido.

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Research on the relationships between oligoelements (OE) and the development of cancer or its prevention is a field that is gaining increasing relevance. The aim was to evaluate OE and their interactions with oncology treatments (cytarabine or etoposide) to determine the effects of this combination on biogenic amines and oxidative stress biomarkers in the brain regions of young Wistar rats. Dopamine (DA), 5-Hydroxyindoleacetic acid (5-Hiaa), Glutathione (Gsh), Tiobarbituric acid reactive substances (TBARS) and Ca+2, Mg+2 ATPase enzyme activity were measured in brain regions tissues using spectrophometric and fluorometric methods previously validated. The combination of oligoelements and cytarabine increased dopamine in the striatum but decreased it in cerebellum/medulla-oblongata, whereas the combination of oligoelements and etoposide reduced lipid peroxidation. These results suggest that supplementation with oligoelements modifies the effects of cytarabine and etoposide by redox pathways, and may become promising therapeutic targets in patients with cancer.

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The present work was showed to assess the effect of administration of rosemary extract on etoposide-induced toxicity, injury and proliferation in male rats were investigated. Forty male albino rats were arranged into four equal groups. 1st group, control; 2nd group, etoposide; 3rd group, co-treated rosemary & etoposide; 4th group, rosemary alone. In comparison to the control group, etoposide administration resulted in a significant increase in serum ALT, AST, ALP, total bilirubin, total protein, and gamma GT. In contrast; a significant decrease in albumin level in etoposide group as compared to G1. G3 revealed a significant decrease in AST, ALT, ALP, total protein and total bilirubin levels and a significant rise in albumin level when compared with G2. Serum levels of urea, creatinine, potassium ions, and chloride ions significantly increased; while sodium ions were significantly decreased in G2 when compared with G1. Also, there was an increase of MDA level for etoposide treated group with corresponding control rats. However, there was a remarkable significant decrease in SOD, GPX and CAT levels in G2 as compared to G1. There was a significant increase in serum hydrogen peroxide (H2O2) and Nitric oxide (NO) levels in group treated with etoposide when compared to control group. It was noticeable that administrated by rosemary alone either with etoposide had not any effect on the levels of H2O2 and Nitric oxide. Serum level of T3 and T4 was significantly increased in etoposide-administered rats in comparison with G1. The administration of rosemary, either alone or with etoposide, increased the serum levels of T3 and T4 significantly when compared to control rats. The gene expression analysis showed significant downregulation of hepatic SOD and GPx in (G2) when compared with (G1). The treatment with rosemary extract produced significant upregulation of the antioxidant enzymes mRNA SOD and GPx. MDA gene was increased in (G2) when contrasted with (G1). Treatment of the etoposide- induced rats with rosemary extract delivered significant decrease in MDA gene expression when compared with etoposide group. Rats treated with etoposide showed significant decline in hepatic Nrf2 protein expression, when compared with G1. While, supplementation of Etoposide- administered rats with the rosemary produced a significant elevation in hepatic Nrf2 protein levels. Additionally, the liver histological structure displayed noticeable degeneration and cellular infiltration in liver cells. It is possible to infer that rosemary has a potential role and that it should be researched as a natural component for etoposide-induced toxicity protection.

O presente trabalho foi apresentado para avaliar o efeito da administração de extrato de alecrim na toxicidade, lesão e proliferação induzidas por etoposídeos em ratos machos. Quarenta ratos albinos machos foram organizados em quatro grupos iguais: 1º grupo, controle; 2º grupo, etoposídeo; 3º grupo, alecrim e etoposídeo cotratados; 4º grupo, alecrim sozinho. Em comparação com o grupo controle, a administração de etoposídeo resultou em aumento significativo da ALT, AST, ALP, bilirrubina total, proteína total e gama GT séricas. Em contraste, houve diminuição significativa do nível de albumina no grupo etoposídeo em relação ao G1. O G3 revelou diminuição significativa dos níveis de AST, ALT, ALP, proteína total e bilirrubina total e aumento significativo do nível de albumina quando comparado ao G2. Os níveis séricos de ureia, creatinina, íons potássio e íons cloreto aumentaram significativamente, enquanto os íons sódio diminuíram significativamente no G2 quando comparado ao G1. Além disso, houve um aumento do nível de MDA para o grupo tratado com etoposídeo com os ratos controle correspondentes. No entanto, houve uma notável diminuição nos níveis de SOD, GPX e CAT no G2 em relação ao G1. Houve aumento significativo dos níveis séricos de peróxido de hidrogênio (H2O2) e óxido nítrico (NO) no grupo tratado com etoposídeo quando comparado ao grupo controle. Foi perceptível que a administração de alecrim isoladamente ou com etoposídeo não teve efeito sobre os níveis de H2O2 e NO. O nível sérico de T3 e T4 foi significativamente aumentado em ratos administrados com etoposídeo em comparação com o G1. A administração de alecrim, isoladamente ou com etoposídeo, aumentou significativamente os níveis séricos de T3 e T4 quando comparada aos ratos controle. A análise da expressão gênica mostrou desregulação significante da SOD e GPx hepática em G2 quando comparado com o G1. O tratamento com extrato de alecrim produziu aumento significativo das enzimas antioxidantes mRNA SOD e GPx. O gene MDA estava aumentado em G2 quando contrastado com o G1. O tratamento dos ratos induzidos por etoposídeo com extrato de alecrim proporcionou diminuição significativa na expressão do gene MDA quando comparado ao grupo etoposídeo. Ratos tratados com etoposídeo apresentaram declínio significativo na expressão da proteína Nrf2 hepática quando comparados ao G1. Enquanto isso, a suplementação de ratos administrados com etoposídeo e alecrim produziu uma elevação significativa nos níveis de proteína hepática Nrf2. Além disso, a estrutura histológica do fígado apresentou degeneração perceptível e infiltração celular nas células hepáticas. É possível inferir que o alecrim tem um papel potencial e que deve ser pesquisado como um componente natural para proteção da toxicidade induzida por etoposídeos.

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Resumen ANTECEDENTES: Durante el embarazo es más común el linfoma de Hodking que el no Hodking; afecta, en promedio, a mujeres de 30 años (18-44 años) y más. Suele diagnosticarse alrededor de las 28 semanas de embarazo y está documentado que puede llegarse al término. Los esquemas de tratamiento pueden iniciarse en el posparto inmediato o, incluso, antes. La incidencia mundial del linfoma no Hodking es de 0.8 por cada 100,000 mujeres; se desconoce la supervivencia durante el embarazo. CASO CLINICO: Paciente de 34 años, con antecedentes obstétricos de tres embarazos, una cesárea y un aborto y el embarazo actual en curso de las 29 semanas, referida de la ciudad de Colima debido a un reporte de BI-RADS 3 en el ultrasonido de mama y un nódulo mamario palpable, con evidencia de múltiples tumoraciones en la zona hepática, esplénica y peripancreática. La biopsia tomada de las zonas de la lesión reportó: linfoma de células B de alto grado de malignidad, con morfología blastoide y expresión de C-MYC y BCL2. Además, la paciente se encontró con: anemia, dolor abdominal, múltiples nódulos hepáticos y adenopatías abdominales. Se decidió la interrupción del embrazo a las 30 semanas, con la obtención de un recién nacido, sin complicaciones. Enseguida se inició el tratamiento con rituximab-etopósido-prednisolona-vincristina-ciclofosfamida-doxorrubicina (R-EPOCH) con adecuada adaptación por la paciente. CONCLUSION: Puesto que la información bibliográfica de linfoma y embarazo es escasa el caso aquí reportado es relevante por su aporte. La atención multidisciplinaria favorecerá siempre el pronóstico de las pacientes.

Abstract BACKGROUND: Hodking's lymphoma is more common during pregnancy than non-Hodking's lymphoma; it affects, on average, women aged 30 years (18-44 years) and older. It is usually diagnosed around 28 weeks of pregnancy and is documented to be carried to term. Treatment regimens can be initiated in the immediate postpartum period or even earlier. The worldwide incidence of non-Hodking's lymphoma is 0.8 per 100,000 women; survival during pregnancy is unknown. CLINICAL CASE: 34-year-old patient, with obstetric history of three pregnancies, one cesarean section and one abortion and the current pregnancy in progress at 29 weeks, referred from the city of Colima due to a report of BI-RADS 3 on breast ultrasound and a palpable breast nodule, with evidence of multiple tumors in the hepatic, splenic and peripancreatic area. Biopsy taken from the lesion areas reported: high grade malignant B-cell lymphoma, with blastoid morphology and expression of C-MYC and BCL2. In addition, the patient was found to have: anemia, abdominal pain, multiple hepatic nodules and abdominal adenopathies. It was decided to terminate the pregnancy at 30 weeks, with the delivery of an uncomplicated newborn. Rituximab-Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin (R-EPOCH) therapy was started immediately with adequate adaptation by the patient. CONCLUSION: Since bibliographic information on lymphoma and pregnancy is scarce, the case reported here is relevant for its contribution. Multidisciplinary care will always favor the prognosis of patients.

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ATM and DNA-PKcs coordinate the DNA damage response at multiple levels following the exposure to chemotherapy. The Topoisomerase II poison etoposide (ETO) is an effective chemotherapeutic agent that induces DNA double-strand breaks (DSB), but it is responsible from the chromosomal rearrangements frequently found in therapy-related secondary tumors. Targeted inhibition of DNA-PKcs in ATM-defective tumors combined with radio- or chemotherapy has been proposed as relevant therapies. Here, we explored the DNA repair mechanisms and the genetic consequences of targeting the non-oncogenic addiction to DNA-PKcs of ATM-defective tumor cells after exposure to ETO. We demonstrated that chemical inhibition of DNA-PKcs followed by treatment with ETO resulted in the accumulation of chromatid breaks and decreased mitotic index in both A-T cells and ATM-knocked-down (ATMkd) tumor cells. The HR repair process in DNA-PKcs-inhibited ATMkd cells amplified the RAD51 foci number, with no correlated increase in sister chromatid exchanges. The analysis of post-mitotic DNA lesions presented an augmented number of persistent unresolved DSB, without alterations in the cell cycle progression. Long-term examination of chromosome aberrations revealed a strikingly high number of chromatid and chromosome exchanges. By using genetic and pharmacological abrogation of PARP-1, we demonstrated that alternative end-joining (alt-EJ) repair pathway is responsible for those chromosome abnormalities generated by limiting c-NHEJ activities during directed inhibition of DNA-PKcs in ATM-deficient cells. Targeting the non-oncogenic addiction to DNA-PKcs of ATM-defective tumors stimulates the DSB repair by alt-EJ, which is liable for the origin of cells carrying stable chromosome aberrations that may eventually restrict the therapeutic strategy.

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DNA damage induces the activation of many different signals associated with repair or cell death, but it is also connected with physiological events, such as adult neurogenesis and B-cell differentiation. DNA damage induces different signaling pathways, some of them linked to important metabolic changes. The mTORC1 pathway has a central role in the regulation of growth processes and cell division in response to environmental changes and also controls protein synthesis, lipid biogenesis, nucleotide synthesis, and expression of glycolytic genes. Here, we report that double-strand breaks induced with etoposide affect the expression of genes encoding different enzymes associated with specific metabolic pathways in Ramos cells. We also analyzed the role of mTOR signaling, demonstrating that double-strand breaks induce downregulation of mTOR signaling. Specific inhibition of mTORC1 using rapamycin also induced changes in the expression of metabolic genes. Finally, we demonstrated that DNA damage and rapamycin can regulate glucose uptake. In summary, our findings show that etoposide and rapamycin affect the expression of metabolic genes as well as apoptotic and proliferation markers in Ramos cells, increasing our understanding of cancer metabolism.

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The catastrophe of the coronavirus continues from one part of the world to another, and hardly a country is left without its devastations. Millions of people were infected and several hundred thousand died of the COVID-19 pandemic across the world. There is no clear targeted drug therapy available for the treatment of the patients. The discovery of vaccines is not enough to curtail its spread and disastrous implications. An instantly qualifying approach is needed to utilize the current drugs and isolated compounds. The purpose of this work is to determine potent inhibitors against the target proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For this purpose, molecular docking study of pathogenic spike glycoproteins (S), nucleocapsid phosphoprotein (N), an envelope protein (E), two drugs i.e., cefixime, etoposide, and a previously isolated compound nebrodenside A is performed. Promising results were obtained via complimentary analysis of molecular dynamics (MD) simulations performed for the complexes of three proteins with etoposide drug. Minimum values were recorded for the docking scores and binding energies of the complexes. These results were further supported by the RMSD, RMSF data for the stability of proteins and ligands. Additionally, ligand properties and ligand-protein contacts were also explained with histograms of every simulation trajectory. The computational studies confirmed that cefixime, etoposide, and nebrodenoside A can be used as potent inhibitors of COVID-19. Nevertheless, additional experimental investigations and validation of the selected candidates are mandatory to confirm their applicability for clinical trials.

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Therapy-related acute myeloid leukemia (t-AML) following treatment with topoisomerase-II inhibitors has been increasingly reported. These compounds (e.g. etoposide) promote DNA damage and are associated with KMT2A rearrangements. They are widely used as first-line treatment in hemophagocytic lymphohistiocytosis (HLH). Here we describe a newborn who developed t-AML after HLH treatment. We provide detailed clinical, cytogenetic, and molecular characteristics of this patient, including the identification of a novel gene fusion - KMT2A-SNX9 - in t-AML. Considering the dismal outcome of this case, we discuss the side-effects of etoposide administration during HLH treatment in infants.

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DNA topoisomerase II enzymes maintain DNA stability during vital processes, such as genome replication, transcription and chromosomal segregation during mitosis and meiosis. In the present work, we analyzed functional aspects of the DNA topoisomerase II (AeTopII) enzyme of the mosquito Aedes aegypti. Here, we show that AeTopII mRNA is expressed at all stages of mosquito development. By in situ hybridization, we found that the AeTopII mRNA is concentrated along the ovarian follicular cells as well as in the region of the follicles. The observed expression profiles likely reflect increased topoisomerase II cellular requirements due to the intense ovarian growth and egg production following blood feeding in Ae. aegypti females. The drug etoposide, a classic inhibitor of topoisomerase II, was used for in vivo testing with 2nd stage larvae, in order to investigate the functional importance of this enzyme in Ae. aegypti survival and development. Inhibition of topoisomerase II activity with etoposide concentrations ranging from 10 to 200 µM did not leads to the immediate death of larvae. However, after 10 days of observation, etoposide treatments resulted in 30-40% decrease in survival, in a dose dependent manner, with persisting larvae and pupae presenting incomplete development, as well as morphological abnormalities. Also, approximately 50% of the treated larvae did not reach the pupal stage. Thus, we conclude that AeTopII is a vital enzyme in the development of Ae. aegypti and its sensitivity to inhibitors should be explored for potential chemical agents to be used in vector control.

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