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STAUROSPORINE: A PKC INHIBITOR

 STAUROSPORINE PROPERTIES AND ORIGIN:
The discovery of Staurosporine was done during the research on a bacterium Streptomyces staurosporeus in 1977, this compound was identified as an antibiotic and now this molecules has been studied thoroughly [1]. Another alternate name of this molecule is STS or Staurosporine AM-2282, its configuration and structure was identified by certain physical techniques such as analysis of X-ray [2]. Staurosporine PKC inhibitor is also found as active against a good number of protein kinases (PKs), Staurosporine IC50 for PKA, PKC and PKG is 7.0 nM, 0.7 nM and 8.5 nM respectively. When Staurosporine is stored at -20 oC it’s stability remains un-affected for two years. This compound is soluble in DMSO. Molecular weight of Staurosporine is 466.53 and it is expensive as Staurosporine price for 1 mg is more than $500, however the price is variable from one Staurosporine supplier to other. Staurosporine PKC inhibitor is available easily and if someone wants to purchase Staurosporine for laboratory and research use one can buy Staurosporine easily.
Staurosporine owes multiple kinase inhibitory effects and many of the kinases are checked in wide number of pathways, therefore this molecule is having broad spectrum uses and is being employed in various studies. Analogues of Staurosporine are designed and found as active for the NOS expression enhancement in endothelial cells [4]. In cancer studies Staurosporine is important as it overcome the chemoresistance by the cancer cells [5]. Apoptosis induced by this molecule can be caspase independent or caspase dependent [6] as different research groups reported this and in cells of melanoma this was also noted [7] though before these findings it was thought Staurosporine induces apoptosis by affecting all major caspases [8].
STAUROSPORINE MODE OF ACTION AND ITS ANALOGS:
Extensive studies are done for the development of Staurosporine analogs with more effective and safe functions and these analogs have different effects on cell cycle from each other [9] and also on cell cycle check [10]. Among these analogs many of these are designed in such a way to act as anti-cancer agents with full potential [11], some of these have been employed against NSCLC (non small cell lung cancer) in combination with other agents during phase I studies [12]. Almost all the analogs are found as PKC inhibitors [13] and many are reported as anti-proliferative in cell signaling [14].
Various research groups have done Staurosporine PKC inhibition in details [15]. It is reported that Staurosporine can induce apoptosis human endothelial corneal cells [16] and is noted as dephosphorylation agent Focal Adhesion Kinases or FAKs in these endothelial corneal cells [17]. As discussed earlier it can affect various caspases and in some of the cases it acts via caspase-1 [18] and some in cases via caspase-9 without Apaf-1 [19]. Caspase-3 is activated in osteoblasts and hepatocytes [20][21] and also inhibits topoisomerase II like other PKIs [22]. It is reported that the T-cells treated with Staurosporine are found to have the Ca2+ inhibition involvement [23], in a separate research group role of PAR-1 was deemed which resisted the apoptosis induced by Staurosporine [24].
STAUROSPORINE IN CLINICAL STUDIES:
In various in vivo and in vitro studies during preclinical studies Staurosporine along with its analogs have been analyzed, though these studies are needed to be shifted at clinical level. In clinical studies phase I this compound has been used against patients having solid and malignant tumors [25] alone and in combination, NSCLC patients generated remarkable results [12]. It was also used to treat the refractory neoplasms and it its analog UCN01 was used in combination [26]. Staurosporine’s analogs are currently undergoing clinical trials phase I and II and are promising as potential anticancer agents because of their ability to check cell cycle [27].

REFERENCES:
1. Omura, S.e.a., A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J Antibiot (Tokyo), 1977.
2. Funato, N.e.a., Absolute Configuration of Staurosporine By X-Ray Analysis. Tetrahedron Letters, 1994.
3. Tamaoki, T.a.N., H., Potent and Specific Inhibitors of Protein Kinase C of Microbial Origin. Nature Biotechnology, 1990.
4. LI, H.a.F., U., Structure-Activity Relationship of Staurosporine Analogs in Regulating Expression of Endothelial Nitric-Oxide Synthase Gene. MOLECULAR PHARMACOLOGY, 2000.
5. Stepczynska, A.e.a., Staurosporine and conventional anticancer drugs induce overlapping, yet distinct pathways of apoptosis and caspase activation. Oncogene, 2001.
6. Belmokhtar, C.A.e.a., Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene, 2001.
7. Zhang, X.D.e.a., Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways. Mol Cancer Ther, 2004.
8. Bertrand, R.e.a., Induction of a common pathway of apoptosis by staurosporine. Exp Cell Res., 1994.
9. Akiyama, T.e.a., Differential effects of UCN-01, staurosporine and CGP 41 251 on cell cycle progression and CDC2/cyclin B1 regulation in A431 cells synchronized at M phase by nocodazole. Anticancer Drugs, 1999.
10. Lee, S.I.e.a., Comparison of the efficacy of 7-hydroxystaurosporine (UCN-01) and other staurosporine analogs to abrogate cisplatin-induced cell cycle arrest in human breast cancer cell lines. Biochemical Pharmacology, 1999.
11. Gescher, A.e.a., Analogs of Staurosporine: Potential Anticancer Drugs? General Pharmacology: The Vascular System, 1998.
12. Monnerat, C.e.a., Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer. Ann Oncol, 2004.
13. Gani, O.A.e.a., Protein kinase inhibition of clinically important staurosporine analogues. Nat Prod Rep., 2010.
14. Schupp, P.e.a., Anti-proliferative effects of new staurosporine derivatives isolated from a marine ascidian and its predatory flatworm. Cancer Letters, 2001.
15. Ward, N.E.a.O.B., C.A., Kinetic analysis of protein kinase C inhibition by staurosporine: evidence that inhibition entails inhibitor binding at a conserved region of the catalytic domain but not competition with substrates. Molecular Pharmacology, 1992.
16. Thuret, G.e.a., Mechanisms of staurosporine induced apoptosis in a human corneal endothelial cell line. Br J Ophthalmol, 2003.
17. Kabir, J.e.a., Staurosporine induces endothelial cell apoptosis via focal adhesion kinase dephosphorylation and focal adhesion disassembly independent of focal adhesion kinase proteolysis. Biochemical Journal, 2002.
18. Krohn, A.J.e.a., Staurosporine-Induced Apoptosis of Cultured Rat Hippocampal Neurons Involves Caspase-1-Like Proteases as Upstream Initiators and Increased Production of Superoxide as a Main Downstream Effector. The Journal of Neuroscience, 1998.
19. Manns, J.e.a., Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1. FASEB, 2011.
20. Chae, H.e.a., Molecular mechanism of staurosporine-induced apoptosis in osteoblasts. Pharmacological Research, 2000.
21. Feng, G.a.K., N. , Mechanism of staurosporine-induced apoptosis in murine hepatocytes. American Journal of Physiology  - Gastrointestinal and Liver Physiology, 2002.
22. Lassota, P.e.a., Mechanism of Topoisomerase II Inhibition by Staurosporine and Other Protein Kinase Inhibitors. The Journal of Biological Chemistry, 1996.
23. Kubbies, M.e.a., Complex Ca2+ flux inhibition as primary mechanism of staurosporine-induced impairment of T cell activation. European Journal of Immunology, 1989.
24. Mosnier, L.O.a.G., J.H., Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor. Biochem J., 2003.
25. Eder, J.P.e.a., A Phase I Trial of Daily Oral 4′-N-Benzoyl-Staurosporine in Combination with Protracted Continuous Infusion 5-Fluorouracil in Patients with Advanced Solid Malignancies. Investigational New Drugs, 2004.
26. Sausville, E.A.e.a., Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms. . Journal of Clinical Oncology, 2001.
27. Senderowicz, A.M., The Cell Cycle as a Target for Cancer Therapy: Basic and Clinical Findings with the Small Molecule Inhibitors Flavopiridol and UCN-01. Journal of Clinical Oncology, 2002. The Oncologist.
 

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S1421 Staurosporine Staurosporine is a potent PKC inhibitor for PKCα, PKCγ and PKCη with IC50 of 2 nM, 5 nM and 4 nM, less potent to PKCδ (20 nM), PKCε (73 nM) and little active to PKCζ (1086 nM) in cell-free assays. Also shows inhibitory activities on other kinases, such as PKA, PKG, S6K, CaMKII, etc. Phase 3. (17) (4)

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PKC