NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function

Background and purpose

Increased expression of P‐glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients.

Experimental Approach

In an effort to search for new chemical entities targeting PGP1‐associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies.

Key Results

After screening 500+ kinase inhibitors, we identified NVP‐TAE684 as the most effective MDR reversing agent. NVP‐TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET‐743 or mitoxantrone. NVP‐TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1‐overexpressing cell lines. NVP‐TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors.

Conclusions and Implications

The application of NVP‐TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1‐mediated MDR in human cancer and may ultimately benefit cancer patients.

Abbreviations

ABC

ATP‐binding cassette

ALK

anaplastic lymphoma kinase

CsA

cyclosporin A

MDR

multidrug resistance

MTT

3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide

PGP1

P‐glycoprotein

Rh123

rhodamine 123

     

Whole-brain changes in white matter microstructure after radiotherapy for nasopharyngeal carcinoma: a diffusion tensor imaging study

Radiation-induced local white matter (WM) damage has been observed by diffusion tensor imaging (DTI) within a priori-defined regions of interest following radiotherapy (RT) for nasopharyngeal carcinoma (NPC). In this study, we aimed to detect WM changes throughout the brain of NPC patients by DTI. Tract-based spatial statistics (TBSS) was used to analyze DTI data from 81 NPC patients. Fractional anisotropy (FA) and mean diffusivity (MD) were quantified across the whole brain in separate groups: pre-RT, and <6, 6–12, and >12 months post-RT. We found that fractional anisotropy values were significantly lower in the right frontal, parietal, and occipital WM <6 months post-RT compared with pre-RT and remained significantly lower in the right frontal and parietal WM at >12 months. MD values were significantly higher in the right occipital, bilateral temporal, right occipital–temporal junction, left parietal, left centrum semiovale, and left frontal–parietal junction WM <6 months post-RT and remained higher in the right occipital WM at >12 months. This study suggests that changes in white matter microstructure following RT for NPC were widespread, complex, and dynamic. Diffusion tensor imaging with TBSS analysis allows for early non-invasive detection of RT-induced WM damage.     

糖尿病患者的前庭功能变化特点与分析

目的分析糖尿病患者的前庭温度试验结果与特点,探讨糖尿病对外周前庭器官的影响。方法纳入符合2型糖尿病诊断标准的患者51例(2014年1月至2015年12月期间,在首都医科大学附属北京同仁医院就诊;男性27例,女性24例;年龄56.1±10.1岁)和对照组43例(男性12例,女性31例;年龄50.4±7.2岁,无耳科疾病史,无糖尿病史者,其中含有高血压病13例、高脂血症8例)。全部受试者接受体格检查、实验室检查及温度试验检查。结果 1 51例糖尿病患者中前庭功能损害的有36例,占70.6%;相对于对照组(43例中出现前庭功能损害22例,比率为51.2%)有统计学差异(P=0.043);2 36例前庭功能损害的糖尿病患者中双侧损害16例,比率44.4%,相对于对照组(22例前庭功能损害的对照组成员中双侧损害4例,比率22.2%)有统计学意义(P=0.037);3糖尿病患者病程≥10年组对比病程<10年组,前庭功能损害无明显差异(P>0.05);4糖尿病患者中Hb A1C≥7组对比Hb A1C<7组前庭功能损害无明显差异(P>0.05)。结论 1.糖尿病患者前庭功能损害发生率增高,且糖尿病更容易导致双侧前庭功能损害;2.糖尿病患者病程长短、血糖控制水平可能对前庭功能无显著影响。     

维拉帕米和仙茅苷在大鼠体内药物相互作用研究

目的：研究维拉帕米联用仙茅苷之后,维拉帕米和仙茅苷在大鼠体内可能发生的药物相互作用。方法：24只雄性SD大鼠,随机分为单药组和联用药组,单药组灌胃仙茅苷20 mg· kg-1,联用药组灌胃维拉帕米和仙茅苷,其给药剂量分别为10 mg·kg-1和20 mg·kg-1。在不同时间点取血,采用LC-MS测定仙茅苷的的血药浓度,计算并比较仙茅苷的药代动力学参数。结果：与单药组相比,联用药组仙茅苷药代动力学参数发生明显变化,其中仙茅苷最大血药浓度从189.13 ng·mL-1增加到277.53 ng·mL-1,血浆曲线下面积从949.18 ng·h·mL-1增加到1728.08 ng·h·mL-1。结论：维拉帕米联合仙茅苷用药之后,维拉帕米能明显增强仙茅苷在大鼠体内的血药浓度。     

Minimal diameter of the fistula vein defines a significant stenosis in an autologous arteriovenous fistula

Objective To define a parameter of autologous arteriovenous fistula stenosis that limits the fistula function for hemodialysis in our country. Methods Retrospectively study the doppler ultrasound of patients who accepted the percutaneous transluminal angioplasty (PTA) therapy due to autogenous arteriovenous fistula dysfunction; identify the least diameter of the fistula vein and compare it with the corresponding data of well-functioned fistula. Determine which absolute diameter constitutes a hemodynamically significant stenosis in a radiocephalic autologous arteriovenous fistula by receiver operating characteristic curve (ROC curve). Result Forty-two patients were enrolled in the study. The average age of those patients was 54.63±2.44 years old. Twenty-one patients were female. Twenty-six fistula located on the left arm. The minimal diameter of the dysfunction fistula averaged 1.57±0.07 mm, while the average forearm fistula vein diameter was 4.04±0.23 mm, significantly smaller than those in the compare group - an average minimal fistula vein diameter of 3.34±0.11 mm and a forearm vein diameter of 5.36(4.52, 6.45) mm (P﹤0.05). The control group contained sixty-eight patients. The average age of those patients was 52.56±2.00 years old. Thirty-one patients were female. Forty-nine fistula located on the left arm. It was quiet appropriate in using minimal diameter of the fistula vein to indicate the dysfunction istula with an under-curve area of 0.979, 95%CI 0.959-0.998. The under-curve area would be at the largest level when meeting the cutoff point at 2.40mm, in which it could achieve the area of 0.853. Conclusions The minimal diameter of the dysfunction wrist autogenous arteriovenous fistula was much smaller than the functioned ones. Minimal diameter of the fistula vein may serve as an effective parameter in detecting dysfunction fistula.