The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy.

DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments.

Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy.

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2-DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

Discovery of New Catalytic Topoisomerase II Inhibitors for Anticancer Therapeutics.

Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.

Alteración de la percepción del estado nutricional por parte de padres de preescolares: un factor de riesgo para obesidad y sobrepeso / Altered perception of the nutritional status of preschoolers by their parents: A risk factor for overweight and obesity

Introducción. Muchos padres de familia tienen una percepción inadecuada del tamano de su hijo; en general, subestiman el sobrepeso y la obesidad. Objetivo. Identificar la diferencia entre la percepción de los padres del estado nutricional del niño y el índice de masa corporal medido. Población y métodos. Se realizó un estudio analítico, descriptivo y transversal entre padres de niños de 2 a 6 años de edad. Se determinó el índice de masa corporal de los niños y se evaluó la percepción de los padres mediante una escala visual de imágenes corporales en forma de pictogramas (dibujos de siluetas equivalentes a percentiles del índice de masa corporal). Resultados. Fueron evaluados 605 niños y sus padres. Se encontró sobrepeso en 74 casos (12,2%) y obesidad en 87 casos (14,3%). De 161 niños con sobrepeso u obesidad, 98,8% (159) de los padres subestimaron el estado nutricional de sus hijos. Tener una imagen paterna de la figura del cuerpo infravalorada presentó un OR= 2,1 ± 0,5, p= 0,002 (IC 95%: 1,32-3,32) para obesidad y un OR= 4,42 ± 1,2, p < 0,001 (IC 95%: 2,631-7,439) para sobrepeso. Conclusiones. El 98,8% (159) de los padres de niños con sobrepeso u obesidad subestimaron el peso de sus hijos. Esta subestimación por parte de los padres puede considerarse un factor de riesgo significativo para el desarrollo y/o mantenimiento del sobrepeso y la obesidad en sus hijos.

Introduction. Many parents have a misperception of their children's body size; in general, they underestimate overweight and obesity. Objective. To identify the difference between parents' perception of their children's nutritional status and measured body mass index. Population and methods. An analytical, descriptive and cross-sectional study was conducted among parents of children aged 2 to 6 years old. Children's body mass index was measured, and parents' perception was assessed using a visual scale of body size pictograms (drawings of body figures equivalent to body mass index percentiles). Results. A total of 605 children and their parents were assessed. Seventy-four (12.2%) were overweight and 87 were obese (14.3%). There were 161 overweight or obese children, but 98.8% (159) of parents underestimated their children's nutritional status. Parents' underperception of their children's body size accounted for an OR= 2.1 ± 0.5, p= 0.002 (95% confidence interval [CI]: 1.32-3.32) for obesity and an OR = 4.42 ± 1.2, p < 0.001 (95% CI: 2.631-7.439) for overweight. Conclusions. Among parents of overweight and obese children, 98.8% (159) underestimated their children's weight status. Such underestimation by parents may be a significant risk factor for the development and/or persistence of overweight and obesity in their children.

Altered perception of the nutritional status of preschoolers by their parents: A risk factor for overweight and obesity. / Alteración de la percepción del estado nutricional por parte de padres de preescolares: un factor de riesgo para obesidad y sobrepeso.

INTRODUCTION: Many parents have a misperception of their children's body size; in general, they underestimate overweight and obesity. OBJECTIVE: To identify the difference between parents' perception of their children's nutritional status and measured body mass index. POPULATION AND METHODS: To identify the difference between parents' perception of their children's nutritional status and measured body mass index. RESULTS: A total of 605 children and their parents were assessed. Seventy-four (12.2%) were overweight and 87 were obese (14.3%). There were 161 overweight or obese children, but 98.8% (159) of parents underestimated their children's nutritional status. Parents' underperception of their children's body size accounted for an OR= 2.1 ± 0.5, p= 0.002 (95% confidence interval [CI]: 1.32-3.32) for obesity and an OR = 4.42 ± 1.2, p < 0.001 (95% CI: 2.631-7.439) for overweight. CONCLUSIONS: Among parents of overweight and obese children, 98.8% (159) underestimated their children's weight status. Such underestimation by parents may be a significant risk factor for the development and/or persistence of overweight and obesity in their children.

INTRODUCCIÓN: Muchos padres de familia tienen una percepción inadecuada del tamano de su hijo; en general, subestiman el sobrepeso y la obesidad. OBJETIVO: Identificar la diferencia entre la percepción de los padres del estado nutricional del niño y el índice de masa corporal medido. POBLACIÓN Y MÉTODOS: Se realizó un estudio analítico, descriptivo y transversal entre padres de niños de 2 a 6 anos de edad. Se determinó el índice de masa corporal de los niños y se evaluó la percepción de los padres mediante una escala visual de imágenes corporales en forma de pictogramas (dibujos de siluetas equivalentes a percentiles del índice de masa corporal). RESULTADOS: Fueron evaluados 605 niños y sus padres. Se encontró sobrepeso en 74 casos (12,2%) y obesidad en 87 casos (14,3%). De 161 niños con sobrepeso u obesidad, 98,8% (159) de los padres subestimaron el estado nutricional de sus hijos. Tener una imagen paterna de la figura del cuerpo infravalorada presentó un OR= 2,1 ± 0,5, p= 0,002 (IC 95%: 1,32-3,32) para obesidad y un OR= 4,42 ± 1,2, p < 0,001 (IC 95%: 2,631-7,439) para sobrepeso. CONCLUSIONES: El 98,8% (159) de los padres de niños con sobrepeso u obesidad subestimaron el peso de sus hijos. Esta subestimación por parte de los padres puede considerarse un factor de riesgo significativo para el desarrollo y/o mantenimiento del sobrepeso y la obesidad en sus hijos.