ABSTRACT
Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.
Subject(s)
Antineoplastic Agents , Benzimidazoles , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , TOR Serine-Threonine Kinases , Tubulin Modulators , Tubulin , Uterine Cervical Neoplasms , Zebrafish , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Tubulin/metabolism , Cell Proliferation/drug effects , Animals , Structure-Activity Relationship , Phosphatidylinositol 3-Kinases/metabolism , Female , Molecular Structure , Tubulin Modulators/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Apoptosis/drug effects , Dose-Response Relationship, Drug , Molecular Docking Simulation , Cell Line, Tumor , Signal Transduction/drug effectsABSTRACT
Objective@#The aim of this paper is to understand the prevalence of smoking behavior among middle school students and to analyze the impact of childhood abuse experience on smoking behavior of middle school students.@*Methods@#Stratified cluster sampling method was used to select 14 500 middle school students from Shenzhen, Zhengzhou, Nanchang and Guiyang as participants. A multivariate logistic regression model was established to analyze the effects of childhood abuse on smoking behavior among middle school students.@*Results@#The rate of smoking behavior among middle school students was 3.6%, male students (5.8%) were higher than female students (1.4%), senior high school (5.0%) was higher than junior high school (2.3%), and rural (6.0%) was higher than urban (2.8%). The differences were statistically significant(P<0.01). Those exposed to high-level of various types of childhood abuse had a higher rate of smoking behavior than those with low levels. Multivariate Logistic regression models showed that emotional abuse(OR=1.69, 95%CI=1.38-2.07), physical abuse(OR=2.17, 95%CI=1.78-2.64), sexual abuse(OR=2.56, 95%CI=2.10-3.12), emotional neglect(OR=2.27, 95%CI=1.89-2.74), physical neglect (OR=2.21, 95%CI=1.83-2.67) and childhood abuse experience (OR=2.66, 95%CI=2.21-3.21) increased the risk of smoking among middle school students independently(P<0.01).@*Conclusion@#Childhood abuse is closely assoliated with smoking behavior among middle school students. Strengthening the importance and intervention of childhood abuse is beneficial to the prevention and control of smoking behavior among middle school students.
