ABSTRACT
Multidrug resistance (MDR) has been considered as a huge challenge to the effective chemotherapy. Therefore, it is necessary to develop new strategies to effectively overcome MDR. Here, based on the previous research of -(2-hydroxypropyl)methacrylamide (HPMA) polymer-drug conjugates, we designed an effective system that combined drug-efflux circumvention and mitochondria targeting of anticancer drug doxorubicin (Dox). Briefly, Dox was modified with mitochondrial membrane penetrating peptide (MPP) and then attached to (HPMA) copolymers (P-M-Dox). Our study showed that macromolecular HPMA copolymers successfully bypassed drug efflux pumps and escorted Dox into resistant MCF-7/ADR cells endocytic pathway. Subsequently, the mitochondria accumulation of drugs was significantly enhanced with 11.6-fold increase by MPP modification. The excellent mitochondria targeting then resulted in significant enhancement of reactive oxygen species (ROS) as well as reduction of adenosine triphosphate (ATP) production, which could further inhibit drug efflux and resistant cancer cell growth. By reversing Dox resistance, P-M-Dox achieved much better suppression in the growth of 3D MCF-7/ADR tumor spheroids compared with free Dox. Hence, our study provides a promising approach to treat drug-resistant cancer through simultaneous drug efflux circumvention and direct mitochondria delivery.
ABSTRACT
BACKGROUND: Qiangji jianli liquid plays a key role in prevention and cure of myasthenia gravis; however, whether changes of nucleic acid and protein are related to its mechanism or not should be studied further.OBJECTIVE: To observe the effect of qiangji jianli liquid on synthesis of nucleic acid and protein in mice with experimental spleen deficiency syndrome, and investigate the effect on myasthenia gravis and the molecular biological basis.DESIGN: Randomized controlled animal study.SETTING: Testing Center and Basic Medical College of Guangzhou University of Traditional Chinese Medicine.MATERIALS: Healthy male NIH mice, aged 4 weeks, of clean grade, weighing 17-21 g, were provided by Medical Experimental Animal Center of Guangdong Province. Qiangji jianli liquid (Guangdong Dongfang Shencao Pharmaceutical Factory); serpate solution (Guangdong Bangmin Pharmaceutical Factory); [5-methyl-3H] TdR, [5-3H] uridine and L-[4,5-3H]leucine (Atom High-nuclear Technology Application Limited Company).METHODS: The experiment was carried out in the Laboratory of Nuclear Medicine of Guangzhou University of Traditional Chinese Medicine from June to November 2005. A total of 180 healthy male NIH mice were randomly divided into normal control group, model group, 26 g/kg qiangji jianli liquid group, 13 g/kg qiangjijianli liquid group and sijunzi decoction group with 36 in each group. Except normal control group, serpate was used to establish animal models of spleen deficiency syndrome. 0.2 mg/(kg ·d) serpate was intraperitoneally injected into mice. ① 0.1 mL/(mouse·d) saline was intraperitoneally injected into mice in normal control group. ② 26 g/kg and 13 g/kg were perfused into mice in 26 g/kg and 13 g/kg qiangji jianli liquid groups, respectively, once a day. Qiangji jianli liquid consisted of beiqi, dangshen, shengma,baizhu, gaicao, etc., with 1.204 g raw drugs a milliliter. ③ 26 g/kg sijunzi decoction, which consisted of dangshen,baizhu, fuling, jiugancao, etc., was perfused into mice with the dosage of 0.5 mL/mouse in si junzi decoction group once a day. After 16 successive days, contents of DNA, RNA and protein were measured in spleen and kidney tissue; meanwhile, body mass, ratio between spleen mass and body mass, and ratio between kidney mass and body mass were also measured before modeling and after administration.MAIN OUTCOME MEASURES: ① Changes of body mass before modeling and at 16 days after administration; ② changes of mass of spleen and kidney tissues; ③ Comparisons of DNA, RNA and protein in spleen and kidney tissues at 16 days after administration.RESULTS: All 180 mice were involved in the final analysis without any loss. ① There was no significant difference of body mass (17.4-21 g) among groups before experiment (P =0.993); however, after experiment, body mass in model group was lower than that in normal control group (Q =22.84, P ＜ 0.01); 16 days after administration, body mass was higher in qiangji jianli liquid groups (26 g/kg, 13 g/kg) and sijunzi decoction group than that in model group (Q =8.66-10.24, P ＜ 0.01). ② Values of spleen mass/body mass and kidney mass/body mass were decreased in model group as compared with those in normal control group (Q =4.02-12.93, P ＜ 0.01); masses of spleen and kidney tissues were increased in qiangji jianli liquid groups (26 g/kg, 13 g/kg) and sijunzi decoction group as compared with those in model group (Q =3.21-9.69, P ＜ 0.05-0.01); ratios in 13 g/kg qiangji jianli liquid group were higher than those in model group (Q =4.07, 5.92; P ＜ 0.05, 0.01). ③ Contents of DNA, RNA and protein in spleen tissue and contents of RNA and protein in kidney tissue were lower in model group than those in normal control group (Q =7.15-19.2, P＜ 0.01); however, content of DNA in kidney tissue was higher in model group than that in normal control group (Q =4.19, P ＜ 0.05). Contents of DNA, RNA and protein in spleen tissue and contents of RNA and protein in kidney tissue were higher in 26 g/kg qiangji jianli liquid group and sijunzi decoction group than those in model group (Q =2.91-14.12, P ＜ 0.05-0.01 ).CONCLUSION: Qiangji jianli liquid can accelerate synthesis of nucleic acid and protein; additionally, onset of spleen deficiency syndrome may be related to decreasing synthesis of nucleic acid and protein.
ABSTRACT
[Objective] To observe levels of plasma endothelin (ET) and calcitonin gene - related peptide (CGRP) in rats with myocardial hypertrophic heart failure affected by Yang Xin Kang (composed of Radix Ginseng, Radix Ophio-pogonis, Radix flicis Pubescetis, etc.) and its mechanism. [Methods] Rat models with myocardial hypertrophic heart failure was established by subcutaneous injection of isoprenaline for 13 days. Fifty rats were allocated to five groups: normal control (Group A), model (Group B), digoxin (Group C), high dosage of Yang Xin Kang (Group D) and low dosage of Yang Xin Kang (Group E). ET and CGRP levels were measured by radioimmunoassay method. [Results] ET level in Group B was higher and CGRP level lower than those in Group A (P
ABSTRACT
[Objective] To investigate the effect of Bao Xin Kang (BXK) on levels of cyclic adenosine monophosphate (cGMP) and cyclic guanosine monophosphate (cAMP) in vascular smooth muscle of rats with myocatdial hypertrophic heart failure and to explore its mechanism. [Methods] Fifty rats were randomly allocated to five groups: normal control group (Group A) , model group (Group B) , digoxin group (Group C), large - dose BXK group (Group D) and small - dose BXK group (Group E). Rat models with myocardial hypertrophic heart failure were established by subcutaneous injection of isoprenaline for 13 days. Radioimmunoassay was used to measure the levels of cAMP, cGMP and the ratio of cAMP/cGMP in vascular smooth muscle. The body weight and the weight of heart, liver and lung were measured and his-tomorphologic features of heart, liver and lung also examined. [Results] The levels of cAMP and cGMP and the heart index (heart weight /body weight) and the liver index (liver weight/body weight) in Group B were increased as compared with those in Group A (P