Utilizing the Hippo pathway as a therapeutic target for combating endocrine-resistant breast cancer

Abstract Drug resistance is always a great obstacle in any endocrine therapy of breast cancer. Although the combination of endocrine therapy and targeted therapy has been shown to significantly improve prognosis, refractory endocrine resistance is still common. Dysregulation of the Hippo pathway is often related to the occurrence and the development of many tumors. Targeted therapies of this pathway have played important roles in the study of triple negative breast cancer (TNBC). Targeting the Hippo pathway in combination with chemotherapy or other targeted therapies has been shown to significantly improve specific antitumor effects and reduce cancer antidrug resistance. Further exploration has shown that the Hippo pathway is closely related to endocrine resistance, and it plays a “co-correlation point” role in numerous pathways involving endocrine resistance, including related pathways in breast cancer stem cells (BCSCs). Agents and miRNAs targeting the components of the Hippo pathway are expected to significantly enhance the sensitivity of breast cancer cells to endocrine therapy. This review initially explains the possible mechanism of the Hippo pathway in combating endocrine resistance, and it concludes by recommending endocrine therapy in combination with therapies targeting the Hippo pathway in the study of endocrine-resistant breast cancers

Image2_In silico mechanisms of arsenic trioxide-induced cardiotoxicity.TIF

It has been found that arsenic trioxide (ATO) is effective in treating acute promyelocytic leukemia (APL). However, long QT syndrome was reported in patients receiving therapy using ATO, which even led to sudden cardiac death. The underlying mechanisms of ATO-induced cardiotoxicity have been investigated in some biological experiments, showing that ATO affects human ether-à-go-go-related gene (hERG) channels, coding rapid delayed rectifier potassium current (IKr), as well as L-type calcium (ICaL) channels. Nevertheless, the mechanism by which these channel reconstitutions induced the arrhythmia in ventricular tissue remains unsolved. In this study, a mathematical model was developed to simulate the effect of ATO on ventricular electrical excitation at cellular and tissue levels by considering ATO’s effects on IKr and ICaL. The ATO-dose-dependent pore block model was incorporated into the IKr model, and the enhanced degree of ATO to ICaL was based on experimental data. Simulation results indicated that ATO extended the action potential duration of three types of ventricular myocytes (VMs), including endocardial cells (ENDO), midmyocardial cells (MCELL), and epicardial cells (EPI), and exacerbated the heterogeneity among them. ATO could also induce alternans in all three kinds of VMs. In a cable model of the intramural ventricular strand, the effects of ATO are reflected in a prolonged QT interval of simulated pseudo-ECG and a wide vulnerable window, thus increasing the possibility of spiral wave formation in ventricular tissue. In addition to showing that ATO prolonged QT, we revealed that the heterogeneity caused by ATO is also an essential hazard factor. Based on this, a pharmacological intervention of ATO toxicity by resveratrol was undertaken. This study provides a further understanding of ATO-induced cardiotoxicity, which may help to improve the treatment for APL patients.</p

Video2_In silico mechanisms of arsenic trioxide-induced cardiotoxicity.MP4

It has been found that arsenic trioxide (ATO) is effective in treating acute promyelocytic leukemia (APL). However, long QT syndrome was reported in patients receiving therapy using ATO, which even led to sudden cardiac death. The underlying mechanisms of ATO-induced cardiotoxicity have been investigated in some biological experiments, showing that ATO affects human ether-à-go-go-related gene (hERG) channels, coding rapid delayed rectifier potassium current (IKr), as well as L-type calcium (ICaL) channels. Nevertheless, the mechanism by which these channel reconstitutions induced the arrhythmia in ventricular tissue remains unsolved. In this study, a mathematical model was developed to simulate the effect of ATO on ventricular electrical excitation at cellular and tissue levels by considering ATO’s effects on IKr and ICaL. The ATO-dose-dependent pore block model was incorporated into the IKr model, and the enhanced degree of ATO to ICaL was based on experimental data. Simulation results indicated that ATO extended the action potential duration of three types of ventricular myocytes (VMs), including endocardial cells (ENDO), midmyocardial cells (MCELL), and epicardial cells (EPI), and exacerbated the heterogeneity among them. ATO could also induce alternans in all three kinds of VMs. In a cable model of the intramural ventricular strand, the effects of ATO are reflected in a prolonged QT interval of simulated pseudo-ECG and a wide vulnerable window, thus increasing the possibility of spiral wave formation in ventricular tissue. In addition to showing that ATO prolonged QT, we revealed that the heterogeneity caused by ATO is also an essential hazard factor. Based on this, a pharmacological intervention of ATO toxicity by resveratrol was undertaken. This study provides a further understanding of ATO-induced cardiotoxicity, which may help to improve the treatment for APL patients.</p

Image3_In silico mechanisms of arsenic trioxide-induced cardiotoxicity.TIF

It has been found that arsenic trioxide (ATO) is effective in treating acute promyelocytic leukemia (APL). However, long QT syndrome was reported in patients receiving therapy using ATO, which even led to sudden cardiac death. The underlying mechanisms of ATO-induced cardiotoxicity have been investigated in some biological experiments, showing that ATO affects human ether-à-go-go-related gene (hERG) channels, coding rapid delayed rectifier potassium current (IKr), as well as L-type calcium (ICaL) channels. Nevertheless, the mechanism by which these channel reconstitutions induced the arrhythmia in ventricular tissue remains unsolved. In this study, a mathematical model was developed to simulate the effect of ATO on ventricular electrical excitation at cellular and tissue levels by considering ATO’s effects on IKr and ICaL. The ATO-dose-dependent pore block model was incorporated into the IKr model, and the enhanced degree of ATO to ICaL was based on experimental data. Simulation results indicated that ATO extended the action potential duration of three types of ventricular myocytes (VMs), including endocardial cells (ENDO), midmyocardial cells (MCELL), and epicardial cells (EPI), and exacerbated the heterogeneity among them. ATO could also induce alternans in all three kinds of VMs. In a cable model of the intramural ventricular strand, the effects of ATO are reflected in a prolonged QT interval of simulated pseudo-ECG and a wide vulnerable window, thus increasing the possibility of spiral wave formation in ventricular tissue. In addition to showing that ATO prolonged QT, we revealed that the heterogeneity caused by ATO is also an essential hazard factor. Based on this, a pharmacological intervention of ATO toxicity by resveratrol was undertaken. This study provides a further understanding of ATO-induced cardiotoxicity, which may help to improve the treatment for APL patients.</p

Video1_In silico mechanisms of arsenic trioxide-induced cardiotoxicity.MP4

It has been found that arsenic trioxide (ATO) is effective in treating acute promyelocytic leukemia (APL). However, long QT syndrome was reported in patients receiving therapy using ATO, which even led to sudden cardiac death. The underlying mechanisms of ATO-induced cardiotoxicity have been investigated in some biological experiments, showing that ATO affects human ether-à-go-go-related gene (hERG) channels, coding rapid delayed rectifier potassium current (IKr), as well as L-type calcium (ICaL) channels. Nevertheless, the mechanism by which these channel reconstitutions induced the arrhythmia in ventricular tissue remains unsolved. In this study, a mathematical model was developed to simulate the effect of ATO on ventricular electrical excitation at cellular and tissue levels by considering ATO’s effects on IKr and ICaL. The ATO-dose-dependent pore block model was incorporated into the IKr model, and the enhanced degree of ATO to ICaL was based on experimental data. Simulation results indicated that ATO extended the action potential duration of three types of ventricular myocytes (VMs), including endocardial cells (ENDO), midmyocardial cells (MCELL), and epicardial cells (EPI), and exacerbated the heterogeneity among them. ATO could also induce alternans in all three kinds of VMs. In a cable model of the intramural ventricular strand, the effects of ATO are reflected in a prolonged QT interval of simulated pseudo-ECG and a wide vulnerable window, thus increasing the possibility of spiral wave formation in ventricular tissue. In addition to showing that ATO prolonged QT, we revealed that the heterogeneity caused by ATO is also an essential hazard factor. Based on this, a pharmacological intervention of ATO toxicity by resveratrol was undertaken. This study provides a further understanding of ATO-induced cardiotoxicity, which may help to improve the treatment for APL patients.</p

Image1_In silico mechanisms of arsenic trioxide-induced cardiotoxicity.TIF

It has been found that arsenic trioxide (ATO) is effective in treating acute promyelocytic leukemia (APL). However, long QT syndrome was reported in patients receiving therapy using ATO, which even led to sudden cardiac death. The underlying mechanisms of ATO-induced cardiotoxicity have been investigated in some biological experiments, showing that ATO affects human ether-à-go-go-related gene (hERG) channels, coding rapid delayed rectifier potassium current (IKr), as well as L-type calcium (ICaL) channels. Nevertheless, the mechanism by which these channel reconstitutions induced the arrhythmia in ventricular tissue remains unsolved. In this study, a mathematical model was developed to simulate the effect of ATO on ventricular electrical excitation at cellular and tissue levels by considering ATO’s effects on IKr and ICaL. The ATO-dose-dependent pore block model was incorporated into the IKr model, and the enhanced degree of ATO to ICaL was based on experimental data. Simulation results indicated that ATO extended the action potential duration of three types of ventricular myocytes (VMs), including endocardial cells (ENDO), midmyocardial cells (MCELL), and epicardial cells (EPI), and exacerbated the heterogeneity among them. ATO could also induce alternans in all three kinds of VMs. In a cable model of the intramural ventricular strand, the effects of ATO are reflected in a prolonged QT interval of simulated pseudo-ECG and a wide vulnerable window, thus increasing the possibility of spiral wave formation in ventricular tissue. In addition to showing that ATO prolonged QT, we revealed that the heterogeneity caused by ATO is also an essential hazard factor. Based on this, a pharmacological intervention of ATO toxicity by resveratrol was undertaken. This study provides a further understanding of ATO-induced cardiotoxicity, which may help to improve the treatment for APL patients.</p

Dendrobium Nobile Alcohol Extract Extends the Lifespan of <i>Caenorhabditis elegans</i> via <i>hsf-1</i> and <i>daf-16</i>

Dendrobium nobile is a traditional Chinese herb with anti-inflammatory, antioxidant, and neuroprotective properties. However, its antiaging effects are unclear. Herein, we studied the aging-related functions and the mechanism of action of the alcohol extract of Dendrobium nobile (DnAE) in the model organism Caenorhabditis elegans. The results indicated that 1 mg/mL DnAE slowed lipofuscin accumulation, decreased the levels of reactive oxygen species, elevated superoxide dismutase activity, enhanced oxidative and heat stress resistance, extended the lifespan of nematodes, protected their dopamine neurons from 6-hydroxydopamine-induced neurodegeneration, and reduced Aβ-induced neurotoxicity. DnAE upregulated the mRNA expression of the transcription factors DAF-16 and HSF-1, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2. However, it had no effect on the lifespan of DAF-16 mutants. Thus, DnAE can significantly extend lifespan, enhance heat stress tolerance, and delay age-related diseases through a DAF-16-dependent pathway