From fighting depression to conquering tumors: a novel tricyclic thiazepine compound as a tubulin polymerization inhibitor

A novel tricyclic thiazepine derivative, 6-(p-tolyl)benzo[f] pyrido[2,3-b][1,4] thiazepine 11,11-dioxide (TBPT), exhibits potent inhibitory effects in two non-small-cell lung cancer cell lines, H460 and its drug-resistant variant, H460_TaxR, while exhibiting much less toxic effects on normal human fibroblasts. After five injections of TBPT at a dose of 60 mg/kg, it inhibits H460_TaxR tumor growth in xenografted mouse models by 66.7% without causing observable toxicity to normal tissues. Based on gene perturbation data and a series of investigations, we reveal that TBPT is not a P-glycoprotein substrate and it inhibits microtubule formation by targeting tubulin, thereby causing cell cycle arrest at the G2/M stage and eventually inducing apoptosis. This redeployment of anti-depressant compound scaffold for anticancer applications provides a promising future for conquering drug-resistant tumors with fewer side effects.Drug resistance and nonselective toxicity have been two major clinical obstacles for cancer chemotherapy.^{1, 2, 3, 4, 5} Drug resistance is responsible for treatment failure in >90% of patients with metastatic cancers.⁶ A major cause of drug resistance is the overexpression of a 170-kDa transmembrane protein, P-glycoprotein (P-gp), on the cancer cell surface in response to drug treatment. P-gp acts as an ATP-dependent drug efflux pump.^{7, 8, 9} Many drugs, including paclitaxel (PTX), taxanes, doxorubicin and vinca alkaloids are substrates of P-gp and are readily pumped out of cells, thereby leading to reduced drug accumulation inside cells.^{1, 10} Furthermore, anticancer drugs often elicit serious nonselective toxicity to normal organs. Patients who have undergone chemotherapy often suffer from treatment-related morbidity or mortality, such as leukopenia, hepatic toxicity and even death.^{11, 12, 13, 14} Therefore, potent and selective agents against multidrug-resistant cancers are urgently needed.Tricyclic azepine derivatives, such as tianeptine, clomipramine and quetiapine, have been used as anti-psychotic drugs. Other reports have demonstrated that tricyclic azepine derivatives such as nevirapine work as anti-human immunodeficiency virus agents.^{15, 16} A recent report has also demonstrated that tricyclic anti-depressants such as clomipramine exhibit anticancer activity.¹⁷ In this work, we report the good activity and superb selectivity of a tricyclic thiazepine compound, 6-(p-tolyl)benzo[f] pyrido[2,3-b][1,4] thiazepine 11,11-dioxide (TBPT) against drug-resistant non-small-cell lung cancer (NSCLC). TBPT inhibited the growth of both drug-sensitive and drug-resistant human lung cancer cells in vitro and drug-resistant tumors in vivo without obvious side effects. Further examination indicated that TBPT evaded the P-gp-mediated drug efflux and acted as a novel microtubule depolymerizing agent, thereby inducing cancer cell G2/M phase arrest and apoptosis.     

Extensive hydrolysis of raw rice starch by a chimeric α-amylase engineered with α-amylase (AmyP) and a starch-binding domain from Cryptococcus sp. S-2

Recombinant chimeric α-amylase (AmyP-Cr) was constructed by a catalytic core of α-amylase (AmyP) from a marine metagenomic library and a starch-binding domain (SBD_Cr) of α-amylase from Cryptococcus sp. S-2. The molecular fusion did not alter optimum pH, optimum temperature, hydrolysis products, and an ability of preferential and rapid degradation towards raw rice starch, but catalytic efficiency and thermostability were remarkably improved compared with those of the wild-type AmyP. AmyP-Cr achieved the final hydrolysis degree of 61.7 ± 1.2% for 10% raw rice starch and 47.3 ± 0.8% for 15% raw rice starch after 4 h at 40 °C with 1.0 U per mg of raw starch. The catalytic efficiency was very high, with 3.6–4.0 times higher than that of AmyP. The enhanced catalytic efficiency was attributed to the better thermostability and the higher adsorption and disruption to raw rice starch caused by SBD_Cr. The properties of AmyP-Cr open a new way in terms of a new design of raw rice starch processing.

     

The Tumorgenicity of Glioblastoma Cell Line U87MG Decreased During Serial In Vitro Passage

Established cancer cell lines are routinely used to study cancer. Several factors such as serial passage may affect the reproducibility of experiments with cancer cell lines, but few researches focused on these changes. In the present study, different morphology and decreased tumorigenicity were observed in late passage U87MG cells. In vitro experiments further revealed that late passage U87MG cells possessed lower invasion properties than early passage, whereas no significant differences of proliferation and migration were found between early and late passage U87MG cells. In particular, we confirmed that late passage U87MG cells exhibited more epithelial phenotype with decreased PI3K/Akt pathway and TGF-β pathway expressions at protein level. In summary, our results focused on the changes of U87MG cells during serial in vitro passage, suggested that passage-induced changes may lead to notable changes of biological characteristics and several molecular transitions in cancer cell lines, indicating the necessity to shorten experiment-span and accomplish experiments with the same or similar passage cancer cell strains.     

Expression pattern of ABA metabolic and signalling genes during floral development and fruit set in sweet cherry

Abscisic acid plays a crucial role in the regulation of fruit development and ripening, however, its role in the floral development and the fruit set is still unclear. In the present study, the ABA accumulation and the expression patterns of genes related to ABA metabolism and signalling in sweet cherry were investigated. The results showed that ABA accumulation increased and peaked at stage V in ovary, at stage VI in stamen, and in young fruit it peaked at 7 days after full bloom. The expression pattern of ABA synthetase PaNCED1 was consistent with the changes of ABA accumulation. Among four ABA degradation enzymes PaCYP707As, PaCYP707A4 was highly expressed in ovary, PaCYP707A1 was mainly in stamen, and PaCYP707A2 was in young fruit, and their expressions were reversed to the trend of PaNCED1. With regard to ABA signalling genes, among three ABA receptors PaPYLs, PaPYL2 and PaPYL3 were high expression genes in ovary and in young fruit with similar expression patterns, while PaPYL3 was the high expression gene in stamen. Within six PaPP2Cs, PaPP2C1/2/3 were highly expressed in ovary and young fruit, while PaPP2C3/4 were mainly in stamen. The six PaSnRK2s showed different expression patterns: PaSnRK2.1/2.2/2.4 were highly expressed in ovary and young fruit, while PaSnRK2.1/2.3 were highly expressed in stamen. In situ hybridization results showed that PaPYL3, PaPP2C3 and PaSnRK2.4 were expressed in seed, pulp and fruit peel during fruit set. In conclusion, ABA and its signaling may play an important role in the regulation of floral development and fruit set.     

中国驴的地理生态和种群生态

一、驴的起源、驯养与生态环境的关系驴(Equus asinus Vulgaris)在动物分类学上与马是同属而异种。野生驴种有两种:(1)騑驴(E.asinus Taeniopus),亦称非洲野驴,它包括在中央撒哈拉生存的努比亚驴和从埃塞俄比亚到红海沿岸生存的索马驴,栖息在非洲东北部到南部;(2)骞驴(E.hemionus),亦称亚洲野驴,分布于中亚细亚、阿拉伯和中国西部。     

染色体端粒DNA与核骨架的结合关系(简报)

端粒是真核生物染色体的一种特化结构,对于染色体的稳定以及染色体的完全复制有着十分重要的意义。许多种生物的端粒DNA序列已被发现:四膜虫,草履虫为(G_4T_2)_n;人、锥虫、短膜虫为(AG_3T_2)_n;尖毛虫、棘尾虫、游仆虫为(T_4G_4)_n;拟蓝芥菜为(AG_3T_3)_n。