A Potent Anti-Carcinoma and Anti-Acute Myeloblastic Leukemia Agent, AG490

Abstract

Proteins with tyrosine kinase activity are recognized as key regulators of cellular processes including growth and differentiation. Tyrosine kinase receptors e.g. EGFR and soluble tyrosine kinase proteins e.g. JAK-2, have emerged as essentials in cell survival for cervical carcinoma and acute myeloblastic leukemia, respectively. These receptors and soluble cytoplasm networks have been studied in detail and finally pharmacological agents, targeted at key molecules, could be produced. Tyrphostins are kinases inhibitors synthesized on the basic structure of erbstatin a natural kinase inhibitor. The JAK-2 specific inhibitor, Tyrphostin AG490 is used to inhibit phosphorylation of EGFR and signal transducer and activator of transcription 3 [STAT-3], and subsequently reduce invasion and adhesion potential of malignant cells. This review summarizes experiments providing a detailed picture of how hematopoietic cancer c-Kit+, Jak-2+ and non hematopoietic tumors c-Kit+, HER-2+, JAK-2+ can be inhibited by the chemosensitizing agent AG490 causing programmed cell death. Furthermore, studies presented herein analyzed several cellular targets that can be modified by the same death effector. The highly conserved JAK-2/STAT-3, c-Kit, and HER-2 signaling pathways play pleiotropic roles during embryonic development and are important for the regulation of self-renewing tissues. The physiological functions of these signaling cascades range from stem cell maintenance and influencing cell fate decisions of progenitor cells, to the induction of terminal differentiation processes, all of which have been found to be recapitulated in different forms of cancers. Inhibiting their action by AG490 represents a therapeutic approach for the treatment of individual types of cancer and several broad-spectrum.

The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway

“…Additionally, in vitro studies have demonstrated that STAT3 potentiates anti-apoptotic signals through the induction of Bcl2 and the inhibition of Caspase3 protein expression [15,16,51]. AG, a JAK2-specific inhibitor, has been used to inhibit the phosphorylation of STAT3 in many experimental studies [8,35]. We used 1-lM AG to investigate the role of the JAK2/STAT3 pathway in mediating Cur posttreatment protection against myocardial IR injury.…”

IL-15 as a potential target in leukemia

“…75 IL-15 can lower the proapoptotic Bid protein in LGL leukemia, which was shown to result from increased proteasomal degradation, whereas the induction of Bid by the proteasome inhibitor bortezomib increased leukemic cell death, suggesting that proteasome inhibitors could be an effective treatment option for this disease. 36 Furthermore, a formulation of a proteasomal inhibitors provides long-term disease-free survival in leukemic mice, 49 thus offering a new approach to treating patients with aggressive LGL leukemia.…”

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T Cells and Th17 Cells

“…Recently, the JAK2 inhibitors CEP-33779 and SB1578 were investigated in an RA model (22,23). AG490 has been widely used as a JAK2 inhibitor in various settings, and it appears to specifically suppress JAK2/STAT3 signaling (24)(25)(26)(27). However, its therapeutic potential in autoimmune arthritis has never been addressed.…”