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

Julio   R.   Caceres-Cortes

doi:10.2174/187152008785914752

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.

Keywords: Tyrphostins, AG490, Tyr B42, tyrosine kinases, cervical carcinoma, acute myeloblastic leucemia

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