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The Function of Kinase Inhibitor Staurosporine in Healthy and Disease States Essay

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Updated: Apr 14th, 2022

Activation of intrinsic cell death pathway

Previous studies had alluded to the fact that Staurosporine and its derivative (7-hydroxystaurosporine) activate the intrinsic cell death pathway. Known anticancer agents trigger apoptosis through the intrinsic pathway in cancer cells. In an experiment carried out to elucidate the specific signaling pathways activated by staurosporine, it was found that staurosporine activates apoptosis via two pathways. First, it triggers apoptosis via the classical mitochondrial pathway in which activation requires the formation of an apoptosome. Second, it triggers apoptosis via a new pathway that is not dependent on the formation of an apoptosome.

Known pathways were blocked before studying the new pathway. This was a way of eliminating confounding factors. Immunoblotting for Apaf-1 and caspase-9 was then carried out.

The data showed that staurosporine and 7-hydroxystaurosporine can elicit programmed cell death through a new pathway. The pathway does not depend on the known death receptor pathways. Staurosporine and its derivative can trigger the mitochondrial pathway directly. In addition, staurosporine has a rapid onset of action. It elicits apoptosis in one to two hours. Other anticancer agents elicit apoptosis after approximately eight hours. The results further indicate that staurosporine and 7-hydroxystaurosporine-induced apoptosis is not prevented by anti-apoptotic proteins. Anti-apoptotic proteins such as Bcl-2 and Bcl-xL block other intrinsic apoptotic pathways. It is thought that anti-apoptotic proteins do not inhibit the extrinsic death pathway. However, caspace-9 deficient cell lines (Jurkat T lymphoma cells, MCF7 breast cancer cells, and SH-EP neuroblastoma cells) were resistant to staurosporine-triggered apoptosis. This implies that staurosporine-induced apoptosis requires activation of caspace-9. However, results indicate that staurosporine does not achieve its effect through inhibition of the known and putative caspce-9 kinases (Akt,ERK1/2,PKC+, PKA, CDK1/cyclin B1, CK2, cAbl, DYRK , ATM, CK1, PKC, GSK3, and DNA-PK). Therefore, it is evident that staurosporine achieves its effect by inhibiting other kinases that are yet to be described.

In conclusion, it is evident that staurosporine induces mitochondrial-mediated apoptosis via two pathways. First, it induces apoptosis via the cytochrome c/Apaf-1 pathway, which is sensitive to anti-apoptotic protein Bcl-2. Second, it triggers cell death via an intrinsic pathway, which is resistant to anti-apoptotic agent Bcl-2 and free from Apaf-1.

Microparticles (MPs) release in disease state by cells exposed to staurosporine

Microparticles may be defined as membrane vesicles originating from dying and activated cells. These particles have demonstrated a great range of physiologic properties. The particles are beginning to attract attention due to these properties. This study was designed to investigate microparticle release induced by staurosporine and 7-hydroxystaurosprine. This finding had been reported by earlier studies. The current study found that staurosporine and its analogue induce microparticle formation at various stages of cell death. Early signs of microparticle formation appear two hours after treatment with staurosporine.

The experiment was carried out using Jurkat cells treated with staurosporine and 7-hydroxystaurosporine. Untreated cell lines were included in the study to provide a basis for comparison. Microparticles were isolated using a two-step centrifugation process. Cells were centrifuged at room temperature. Flow cytometry was then used to describe the microparticles. Microparticles were analyzed based on dose response and onset of action.

The results indicate that staurosporine and 7-hydroxystaurosporine induce microparticle formation as early as two hours. Late microparticle formation was also observed. Staurosporine and its analogue demonstrated a linear relationship between microparticle formation and the dose. In contrast, other kinase inhibitors did not exhibit increase in microparticle formation with increase in dose. This implies that staurosporine and its analogue induce microparticle formation via more than one pathway. Further tests showed that the microparticles exhibited phenotypic changes after they were formed. Permeability and phospholipid distribution appear to be altered over time. The data indicates that staurosporine–induced microparicles undergo some form of maturation after their formation. The maturation renders the microparticles annexin V and PI positive. Annexin V and PI binding is an indicator used to demonstrate presence of intracellular particles on the surface of the cell. Presence of these particles on the surface of the cell is a sign of apoptosis. Microparticles are thought to mediate internal cell processes in disease.

In conclusion, these results indicate that stausporine and its analogue induce microparticle formation in cells. This suggests that stourosporine-induced micropaarticles may be used as biomarkers in assays. Clinically, quantifying microparticles may be used to identify certain malignancies in blood and other body fluids. In addition, phenotypic characterization of microparticles may be used clinical settings to describe the cytotoxic effects of kinase inhibitors.

Taken together, the two studies show a great potential clinically. The first study indicated that staurosporine and its analogue could induce apoptosis through a novel pathway that had not been described previously. The ability of staurosporine and its analogue to trigger apoptosis without involving Apaf-1 and in the presence of anti-apoptotic proteins such Bcl-2 and Bcl-xL can be exploited clinically to deal with anti-cancer drug resistant malignancies. The second study indicates that staurosporine-induced apoptosis may be tracked using microparticles released during apoptosis. The two processes may be exploited independently even though they occur concurrently.

References

Manns J, Daubrawa M, Driessen S, Paasch F, Hoffmann N, Lo¨ffler A et al. Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1. FASEB J [serial online]. 2011.

Seifert A, Allan L A and Clarke PR. DYRK1A phosphorylates caspase 9 at an inhibitory site and is potently inhibited in human cells by harmine. FEBS J. 2008; 275: 6268–6280.

Ullal AJ and Pisetsky DS. The release of microparticles by Jurkat leukemia T cells treated with staurosporine and related kinase inhibitors to induce apoptosis. Apoptosis [serial online]. 2010.

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