Cross-talk between Bcr-Abl tyrosine kinase, protein kinase C and telomerase-a potential reason for resistance to Glivec in chronic myelogenous leukaemia.
To prevent the resistance to Glivec in patients with chronic myelogenous leukaemia (CML), it is necessary to get a good understanding of its potential mechanisms. The present hypothesis accents on the mechanisms whereby Bcr-Abl tyrosine kinase remains inhibited by Glivec, but alternative signalling pathways become activated-the potential reason associates with activation of telomerase after long-term treatment with Glivec and recovery of cell proliferation and immortality. The hypothesis is based on the observations about differences in telomere dynamics and telomerase activity between chronic and blast phases of CML patients, as well as about the potential effect of Glivec on the cross-talk between telomerase, Bcr-Abl tyrosine kinase and protein kinase C family-key enzymes in CML. It proceeds from recently published data, demonstrating that protein kinase C activates and c-Abl tyrosine kinase inhibits telomerase. During optimization of chemical structure, Glivec loose its effect on protein kinase C and enhances the effect on Bcr-Abl tyrosine kinase, resulting in a high potential to activate telomerase indirectly through its effect on both kinases. Experimental preclinical data are given in confirmation of this hypothesis.
National Institute of Advanced Industrial Science and Technology, AIST-Shikoku, 2217-14 Hayashi-cho, 761-0395 Takamatsu, Japan.
Rumiana
R
Bakalova
Hideki
H
Ohba
Zhivko
Z
Zhelev
Mitsuru
M
Ishikawa
Yasuo
Y
Shinohara
Yoshinobu
Y
Baba
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D019098:Telomerase / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D011493:Protein Kinase C; D019098:Telomerase