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United States Biological
March 2009 Issue 1| Subscribe   www.usbio.net

Newsletter


Breast tumor
Antibiotics:

In addition to having low prices on such commonly used antibiotics as Tetracycline, Ampicillin, and Kanamycin, United States Biological provides a wide range of more novel antibiotics. Recent research has recognised fumitremorgin C as a potent and specific inhibitor of the breast cancer resistance protein (BCRP/ABCG2) multidrug transporter. Concanamycin A inhibits the acidification of organelles and blocks cell surface expression of viral envelope glycoproteins without affecting their synthesis. Oligomycin B makes cells more susceptible to cell death and also leads to a switch in the death mode from apoptosis to necrosis.


UNC-01Newsletter bonus discount:

10% off A2297-39 Antibiotic UCN-01 (7-Hydroxystaurosporine, UCN-01) Antibiotic UCN-01 is a indolocarbazole isolated from a high staurosporine-producing Streptomyces culture. UCN-01 inhibits protein kinase C (PKC) and cyclin-dependant kinase 2 (CDK2) resulting in accumulation of cells in the G1 phase and induction of apoptosis. (mention March 2009, issue 2)

 


This month's Specials:

10% off selected adult, normal human frozen tissue sections

T5595-4775  Tissue, Section, Human Adult Normal, Brain (Frozen) 
T5595-4913 Tissue, Section, Human Adult Normal, Heart (Frozen)   
T5595-4967  Tissue, Section, Human Adult Normal, Kidney (Frozen)   
T5595-4971  Tissue, Section, Human Adult Normal, Liver (Frozen) 
T5595-5025 Tissue, Section, Human Adult Normal, Skeletal Muscle (Frozen)    
T5595-4995 Tissue, Section, Human Adult Normal, Pancreas (Frozen)  
T5595-5041   Tissue, Section, Human Adult Normal, Spleen (Frozen)  
T5595-4975 Tissue, Section, Human Adult Normal, Lung (Frozen)   

Geldanamycin: a Novel Antibiotic

Potent Anti-Cancer Activity
   Novel antibiotics are important tools both in research and medicine and are increasingly becoming better characterized as more is being discovered about their mechanisms. Geldanamycin is one such antibiotic. Produced by the Actinomycete Streptomyces hygroscopicus var. geldanus, it is structurally a benzoquinone ansamycin antibiotic. It has been shown to possess weak broad-spectrum antibiotic activity and potent anticancer activity.

geldanamycin

Fig. 1: Structure of Geldanamycin

  Geldanamycin was discovered by DeBoer et al.. (1) It was extracted from a filtrate of S. hygroscopicus culture medium with butanol to recover impure geldanamycin. It was subsequently purified by crystallization, dissolution of the crystals in chloroform, filtration, and finally an additional crystallization step. 

  Geldanamycin is useful in the study of the action of Heat Shock Proteins. It binds to Heat Shock Protein 90 (Hsp90) and alters its function. HSP90 client proteins are involved in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis. Hsp90 plays a major role in the folding and activation of several signaling proteins that promote the growth and survival of tumor cells. Geldanamycin, induces the degradation of these signaling proteins and, consequently, the death of malignant cells.

HSP90
Fig. 2: HSP90 in Complex with Geldanamycin

 

  Geldanamycin (in yellow) binds HSP90 (in blue, interacting side chains in red) in a well-defined deep pocket lined by residues conserved across different species expressing HSP90. Geldanamycin occupies the ATP-binding site on the protein. (2)

  Antitumor effects of geldanamycin can be partly explained by the inhibition of oncoproteins such as v-Src, mutant p53 proteins, Raf-1, p185erbB2 proteins, and EGFR. Geldanamycin downregulates such target proteins as tyrosine kinases, steroid receptors, transcription factors and cell cycle regulatory kinases1,2. It induces the inactivation, destabilization and eventual degradation of HIF-1a. It also represents a potent inhibitor of p60src tyrosine kinase and of c-myc gene expression in murine lymphoblastoma cells.

   Geldanamycin binds to Hsp90 and disrupts Raf-1- Hsp90 complex, leading to destabilization of Raf-14-7. It can inhibit conformational changes and stabilization by HSP90 which leads to target aggregation and ultimate degradation of these client proteins. Geldanamycin and its synthetic derivatives show higher affinity to HSP90 in tumor cells as compared to normal tissues and constitute a class of potential antitumor drugs. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate (namely, hepatotoxicity and minimal water solubility) that have led to the development of geldanamycin analogs such as 17-AAG (17-allylamino demethoxygeldanamycin) and 17-DMAG(17-dimethylaminoethylamino demethoxygeldanamycin hydrochloride).


(1) DeBoer, C., et al. (1970) J. Antibiot. 23, 442
(2) Stebbins C.E.et al. (1997) Cell 89, 239-250.

 

 

 

 

 

 

Colon Tissue
Tetracycline

Other notable antibiotics :
Antibiotic TPU-0037-A
TPU-0037A, a close structural analogue of lydicamycin, has been shown to be highly active against MRSA

Indolmycin (Antibiotic PA 155A)
Recent research has shown that indolmycin is active against Mycobacteria and Helicobacter pylori and can stimulate transcription in Escherichia coli.

Phosphotrienin
The antitumor potential of fostriecin has attracted considerable interest, focused on its mode of action as a topoisomerase II inhibitor.

Piericidin A
Piericidin A inhibits both mitochondrial and bacterial NADH-ubiquinone oxidoreductases, binding close to NUOD-NUOB interface.

Quinomycin A
Quiniomycin A has broad activity against bacteria, fungi and viruses and has found application as an antitumor agent.


Ristocetin A Sulphate
Ristocetin A induces platelet aggregation by binding to a factor absent in people suffering from von Willebrand's disease.


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