Radicicol

Radicicol is an inhibitor of the ATPase/kinase with IC50 values of ＜1μM, 100μM and 400μM, respectively for Hsp90, Topo VI and PDK3 [1].

Radicicol inhibits the activities of Hsp90, Topo VI and PDK3 by blocking ATP binding to them. Radicicol binds to the ATP-binding site in the C-terminal domain of PDK3 and competes with ATP. The inhibition does not cause the structure change of PDK3. Radicicol also shows a weak inhibition of PDK1 and PDK2 with IC50 value of 230mM and Ki value of 23μM, respectively [1].

As an inhibitor of Hsp90, radicicol is reported to downregulate the expression of PPARγ, C/EBPα , FAS and FABP4 results in the inhibition of lipid accumulation in 3T3-L1 adipocytes. Radicicol also has effects on cell cycle arrest and the PDK1/Akt pathway, thus causing the inhibition of the differentiation of 3T3-L1 preadipocytes. In addition, it is shown that radicicol increases the activation of the caspase-8- and Bid-dependent pathway and then enhances TRAIL-induced apoptosis in ovarian carcinoma cell lines [2, 3].

References:
[1] Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007 Aug;15(8):992-1004.
[2] He Y, Li Y, Zhang S, Perry B, Zhao T, Wang Y, Sun C. Radicicol, a heat shock protein 90 inhibitor, inhibits differentiation and adipogenesis in 3T3-L1 preadipocytes. Biochem Biophys Res Commun. 2013 Jun 28;436(2):169-74.
[3] Kim YJ, Lee SA, Myung SC, Kim W, Lee CS. Radicicol, an inhibitor of Hsp90, enhances TRAIL-induced apoptosis in human epithelial ovarian carcinoma cells by promoting activation of apoptosis-related proteins. Mol Cell Biochem. 2012 Jan;359(1-2):33-43.

Radicicol-Mediated Inhibition of Topoisomerase VIB-VIA Activity of the Human Malaria Parasite Plasmodium falciparum.[Pubmed:27303712]

mSphere. 2016 Jan 6;1(1). pii: mSphere00025-15.

Plasmodium falciparum topoisomerase VIB (TopoVIB)-TopoVIA (TopoVIB-VIA) complex can be potentially exploited as a drug target against malaria due to its absence from the human genome. Previous work in our laboratory has suggested that P. falciparum TopoVIB (PfTopoVIB) might be a target of Radicicol since treatment of parasite cultures with this antibiotic is associated with upregulation of Plasmodium TopoVIB at the transcript level as well as at the protein level. Further studies demonstrated that Radicicol treatment impaired mitochondrial replication of human malaria parasite P. falciparum. However, the technical challenge associated with the expression of the above protein complex hampered its functional characterization. Using Saccharomyces cerevisiae as a heterologous system, we expressed PfTopoVIB (Myc-tagged) and PfTopoVIA (Flag-tagged) (PfTopoVIB-VIA) proteins. Yeast two-hybrid analysis showed the formation of PfTopoVIB homodimers and PfTopoVIB/PfTopoVIA heteromers. Our study demonstrated that PfTopoVIB and PfTopoVIA together can rescue the lethal phenotype of yeast DeltatopoII mutants, whereas Plasmodium topoisomerase VIB alone cannot. Using yeast cell-free extracts harboring the PfTopoVIB-VIA protein complex, we have performed a decatenation assay and observed that PfTopoVIB-VIA can decatenate DNA in an ATP- and Mg(2+)-dependent manner. The specificity of this enzyme is established by abrogation of its activity in the presence of PfTopoVIB-specific antibody. Our study results show that Radicicol and etoposide can specifically inhibit PfTopoVIB-VIA decatenation activity whereas the gyrase inhibitor novobiocin cannot. Such a yeast-based assay system can be employed in screening specific inhibitors against Plasmodium VIB-VIA. IMPORTANCE In this study we characterize topoisomerase VI from Plasmodium falciparum using genetic and biochemical approaches. We use various inhibitors and identify Radicicol as a specific inhibitor of its decatenation activity. We establish a very simple and economical biochemical assay system that can be exploited to screen inhibitors of PfTopoVI.

Radicicol induces intracellular accumulation of glycan-deficient clusterin variant.[Pubmed:25680466]

Biochem Biophys Res Commun. 2015 Mar 13;458(3):555-560.

Proteostasis regulation using naturally occurring small molecules has been considered as a promising strategy for manipulating cancer sensitivity and therapy. Here, we identify a small molecule Hsp90 inhibitor Radicicol that induces intracellular accumulation of cytotoxic clusterin variant. In the mechanistic basis, this variant proved to be a product disposed from the stressed ER. During this process, inhibitory effect of Radicicol on protein degradation results in cytosolic accumulation of glycan-deficient clusterin variant that signals cell death. These results provide a therapeutic insight into the targeted proteostasis perturbation of clusterin as an anti-cancer strategy.

Development of a Selective Medium for the Fungal Pathogen Cylindrocarpon destructans Using Radicicol.[Pubmed:25506308]

Plant Pathol J. 2014 Dec;30(4):432-6.

The soil-borne ascomycete fungus Cylindrocarpon destructans causes ginseng root rot disease and produces various secondary metabolites such as brefeldin A and Radicicol. The slow growth of this fungus compared with other plant pathogenic and saprophytic fungi in soil disturbs isolation of this fungus from soil and infected ginseng. In this study, we developed a selective medium for C. destructans using Radicicol produced by this fungus. Supplementing 50 mg/L of Radicicol to medium inhibited the mycelia growth of other fungi including Botrytis cinerea, Rhizoctonia solani and Alternaria panax, but did not affect the growth of C. destructans. In addition, conidia germination of other fungal species except for C. destructans was inhibited in submerged culture supplemented with Radicicol. This medium provides a very efficient tool for isolating C. destructans and also can be used as an enrichment medium for this fungus.

Hsp70 inhibition potentiates radicicol-induced cell death in anaplastic thyroid carcinoma cells.[Pubmed:25202064]

Anticancer Res. 2014 Sep;34(9):4829-37.

BACKGROUND/AIM: The aim of the present study was to evaluate the effect of Radicicol, an inhibitor of heat shock protein (hsp) 90, alone or in combination with hsp70 inhibition on survival of anaplastic thyroid carcinoma (ATC) cells. MATERIALS AND METHODS: Antitumor activity of Radicicol-alone or in combination with the hsp70 inhibitor VER155008 was investigated in 8505C and CAL62 cells. RESULTS: Radicicol decreased cell viability and Akt protein levels, and increased the percentage of dead cells and hsp70 protein levels. In PIK3CA plasmid-transfected cells, compared to cells treated with Radicicol-alone, cell viability increased and cellular death decreased. In cells treated with both Radicicol and VER155008, compared to cells treated with Radicicol-alone, cell viability further decreased and the percentage of dead cells further increased, with a parallel decrease of the protein levels of heat shock cognate 70, Akt and survivin. CONCLUSION: Our results suggest that Radicicol induces cell death mediated through PI3K/Akt signaling with modulation of hsp90 client proteins and hsp70 inhibition enhances Radicicol-induced cell death with suppression of survivin in ATC cells.

Radicicol represses the transcriptional function of the estrogen receptor by suppressing the stabilization of the receptor by heat shock protein 90.[Pubmed:11911945]

Mol Cell Endocrinol. 2002 Feb 25;188(1-2):47-54.

The estrogen receptor (ER) is a hormone-dependent transcription factor that belongs to the steroid/thyroid hormone receptor superfamily. Since the ER contributes to development and progression in human breast cancer, a number of studies have explored ways to inactivate this receptor. Previous studies have suggested that the 90-kDa heat shock protein (Hsp90) interacts with the ER, thus stabilizing the receptor in an inactive state. Here, we report that Radicicol, an Hsp90-specific inhibitor, repressed estrogen-dependent transactivation of the ER as measured by pS2 gene transcription and a reporter gene encoding an estrogen-responsive element. Furthermore, we showed that Radicicol induced rapid degradation of ERalpha, while the amount of ubiquitinated ERalpha was increased. A proteasome inhibitor, LLnL, almost completely abrogated the Radicicol-induced decrease in expression level, as well as in transcriptional activity of ERalpha. These results suggest that Radicicol disrupts the ER-Hsp90 heterodimeric complex, thereby generating ERalpha that is susceptible to ubiquitin/proteasome-induced degradation.

Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones.[Pubmed:10478836]

Mol Endocrinol. 1999 Sep;13(9):1435-48.

The Hsp90 family of proteins in mammalian cells consists of Hsp90 alpha and beta, Grp94, and Trap-1 (Hsp75). Radicicol, an antifungal antibiotic that inhibits various signal transduction proteins such as v-src, ras, Raf-1, and mos, was found to bind to Hsp90, thus making it the prototype of a second class of Hsp90 inhibitors, distinct from the chemically unrelated benzoquinone ansamycins. We have used two novel methods to immobilize Radicicol, allowing for detailed analyses of drug-protein interactions. Using these two approaches, we have studied binding of the drug to N-terminal Hsp90 point mutants expressed by in vitro translation. The results point to important drug contacts with amino acids inside the N-terminal ATP/ADP-binding pocket region and show subtle differences when compared with geldanamycin binding. Radicicol binds more strongly to Hsp90 than to Grp94, the Hsp90 homolog that resides in the endoplasmic reticulum. In contrast to Hsp90, binding of Radicicol to Grp94 requires both the N-terminal ATP/ADP-binding domain as well as the adjacent negatively charged region. Radicicol also specifically binds to yeast Hsp90, Escherichia coli HtpG, and a newly described tumor necrosis factor receptor-interacting protein, Trap-1, with greater homology to bacterial HtpG than to Hsp90. Thus, the Radicicol-binding site appears to be specific to and is conserved in all members of the Hsp90 family of molecular chaperones from bacteria to mammals, but is not present in other molecular chaperones with nucleotide-binding domains.

Radicicol, a microbial cell differentiation modulator, inhibits in vivo angiogenesis.[Pubmed:7694864]

Eur J Pharmacol. 1993 Sep 14;241(2-3):221-7.

Angiogenesis plays a significant role in various pathological states, including the progressive growth of solid tumors, rheumatoid arthritis, psoriasis, and diabetic retinopathy, in addition to its crucial role in embryonic development. Recent studies have revealed that an angiogenesis inhibitor is efficacious for these so-called angiogenic diseases. In the previous studies, we found that retinoids and vitamin D3 analogs, which are known to exhibit cell differentiation-modulating activity, effectively inhibit angiogenesis in vivo, thus forming the basis of our working hypothesis that a modulator of cell differentiation is capable of affecting angiogenesis. In this study, to verify this hypothesis further, Radicicol (syn. monorden; 5-chloro-6-(7,8-epoxy-10-hydoxy-2-oxo-3,5-undecadienyl)-beta -resorcylic acid mu-lactone), a microbial cell differentiation modulator from a fungus, a strain of Neocosmospora tenuicristata, was examined for its anti-angiogenic activity in a bioassay system involving chorioallantoic membranes of growing chick embryos. The microbial cell differentiation modulator dose dependently inhibited embryonic angiogenesis, the ID50 value being 200 ng/egg. Radicicol also inhibited both the proliferation of and plasminogen activator production by vascular endothelial cells in the nM concentration range in a concentration-dependent manner, suggesting the possible involvement of these inhibitory effects in the anti-angiogenic action of the microbial product. These results indicate that Radicicol might be a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy.

Radicicol is an inhibitor of Hsp90 with an IC50 value of 1 μM. Radicicol binds to the ATPase domain of Hsp90 and prevents maturation of Hsp90 clients, leading to proteasomal degradation. Radicicol is an antifungal antibiotic with antimalarial activity, impairs mitochondrial replication by targeting P. falciparum topoisomerase VIB.

Radicicol,12772-57-5,Natural Products,HSP, buy Radicicol , Radicicol supplier , purchase Radicicol , Radicicol cost , Radicicol manufacturer , order Radicicol , high purity Radicicol