• Journal of Microbiology and Biotechnology
• /
• 제16권4호
• /
• pp.519-523
• /
• 2006

To improve epothilones production and the ratio of epothilone B/A, carbon sources were investigated in flask culture of Sorangium cellulosum. Depending on the initial concentration, starch significantly enhanced cell growth, but the maximum epothilones productivity and the maximum epothilones production (0.3 mg/l day and 2.6 mg/l at 15 g/l starch, respectively) were relatively low compared with cell growth. On the other hand, addition of glycerol did not stimulate cell growth, but epothilone production was increased from 2.81 mg/l to 7.59 mg/l. Addition of glycerol to culture medium resulted in more significant enhancement of the production of epothilone A, whereas epothilone B levels were relatively constant. Furthermore, when sodium propionate was added as a precursor of methylmalonyl-CoA, it resulted in increase of both total epothilones production and epothilone B/A resolution. Maximum epothilone A and B concentrations reached 10.9 mg/l and 8.58 mg/l, respectively, at 5 mM sodium propionate.

• Bulletin of the Korean Chemical Society
• /
• 제21권12호
• /
• pp.1177-1178
• /
• 2000

• Journal of Microbiology and Biotechnology
• /
• 제18권1호
• /
• pp.135-137
• /
• 2008

The metabolic engineering of epothilones, as secondary metabolites, was investigated using Sorangium cellulosum to achieve the selective production of epothilone B, a potent anticancer agent. Thus, the propionyl-CoA synthetase gene (prpE) from Ralstonia solanacearum was heterologously expressed in S. cellulosum to increase the production of epothilone B. Propionyl-CoA synthetase converts propionate into propionyl-CoA, a potent precursor of epothilone B. The recombinant S. celluloslim containing the prpE gene exhibited a significant increase in the resolution of epothilones B/A, with an epothilone B to A ratio of 127 to 1, which was 100 times higher than that of the wild-type cells, demonstrating its potential use for the selective production of epothilone B.

• The Korean Journal of Physiology and Pharmacology
• /
• 제18권2호
• /
• pp.109-120
• /
• 2014

The epothilones are a class of microtubule inhibitors that exhibit a strong antitumor activity. UTD2 is a novel epothilone analog generated by genetic manipulation of the polyketide biosynthetic gene cluster. This study investigated the effects of UTD2 on the actin cytoskeleton and its critical regulators, and the signaling pathways which are essential for cell motility, growth and survival in MCF-7 breast cancer cells. Results showed that UTD2 inhibited the cellular functions of actin cytoskeleton, such as wound-closure, migration and invasion, as well as adhesion. Our study further demonstrated that UTD2 suppressed Rac1 GTPase activation and reduced the activity of PAK1, which is a downstream effector of Rac1, while the activity of Cdc42 was not affected. Additionally, the phosphorylation of p38 and ERK were significantly inhibited, but the phosphorylation of JNK remained the same after UTD2 treatment. Moreover, UTD2 inhibited the activity and mRNA expression of MMP-2, which plays a key role in cell motility. UTD2 also reduced the phosphorylation of Akt, which is an important signaling kinase regulating the cell survival through Rac1. Furthermore, UTD2 interrupted the synergy between Rac1 and Raf in focus formation assays. Taken together, these results indicated that UTD2 exerted multiple effects on the actin cytoskeleton and signaling pathways associated with Rac1. This study provided novel insights into the molecular mechanism of the antineoplastic and antimetastatic activities of epothilones. Our findings also suggest that the signaling pathways regulated by Rac1 may be evaluated as biomarkers for the response to therapy in clinical trials of epothilones.

• Bulletin of the Korean Chemical Society
• /
• 제28권3호
• /
• pp.367-368
• /
• 2007

• 대한약학회:학술대회논문집
• /
• 대한약학회 2004년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
• /
• pp.138-139
• /
• 2004

• Bulletin of the Korean Chemical Society
• /
• 제34권7호
• /
• pp.1972-1984
• /
• 2013

Microtubules play an important role in intracellular transport, mobility, and particularly mitosis. Paclitaxel (Taxol$^{TM}$) and paclitaxel-like compounds have been shown to be anti-tumor agents useful for various human tumors. Paclitaxel-like compounds operate by stabilizing microtubules through interface binding at the interface between two ${\beta}$-tubulin monomers in adjacent protofilaments. In this paper we present the elucidation of the structural features of paclitaxel and paclitaxel-like compounds (e.g., epothilones) with microtubule stabilizing activities, and relate their activities to spatial and chemical features of the molecules. CATALYST program was used to generate three-dimensional quantitative structure activity relationships (3D-QSARs) resulting in 3D pharmacophore models of epothilone- and paclitaxel-derivatives. Pharmacophore models were generated from diverse conformers of these compounds resulting in a high correlation between experimental and predicted biological activities (r = 0.83 and 0.91 for epothilone and paclitaxel derivatives, respectively). On the basis of biological activities of the training sets, five- and four-feature pharmacophore hypotheses were generated in the epothilone and paclitaxel series. The validation of generated hypotheses was achieved by using twelve epothilones and ten paclitaxels, respectively, which are not in the training sets. The clustering (grouping) and merging techniques were used in order to supplement spatial restrictions of each of hypothesis and to develop more comprehensive models. This approach may be of use in developing novel inhibitor candidates as well as contributing a better understanding of structural characters of many compounds useful as anticancer agents targeting microtubules.

• 한국독성학회:학술대회논문집
• /
• 한국독성학회 2005년도 춘계 국제심포지엄 및 학술대회
• /
• pp.172-172
• /
• 2005