Novel 2'-substituted, 3'-deoxy-phosphatidyl-myo-inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3-kinase/Akt pathway.
Activation of the phosphoinositide 3-kinase (PI3-K)/Akt signalling pathway has been linked with resistance to chemotherapeutic drugs, and its down-regulation, by means of pharmacological inhibitors of PI3-K, considerably lowers resistance to various types of therapy in cell lines derived from solid tumours. Recently, a new class of Akt inhibitors, referred to as phosphatidylinositol ether lipids (PIAs), have been synthesized. We tested whether two new PIAs could lower the sensitivity threshold to chemotherapeutic drugs of human leukaemia cell lines with an activated PI3-K/Akt network. We used HL60AR (for apoptosis resistant), K562 and U937 cells. The two pharmacological inhibitors, used at 5 micromol/l, down-regulated Akt kinase activity and phosphorylation. Neither of the two chemicals affected the activity of other signalling proteins in the Akt pathway, such as phosphoinositide-dependent protein kinase-1 or PTEN. When employed at 5 micromol/l, the Akt inhibitors markedly reduced the resistance of the leukaemic cell lines to etoposide or cytarabine. Remarkably, a 5 micromol/l concentration of the inhibitors did not negatively affect the survival rate of human cord blood CD34(+) cells. Overall, our results indicate that new selective Akt pharmacological inhibitors might be used in the future for overcoming Akt-mediated resistance to therapeutic treatments of acute leukaemia cells.
Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signaling Laboratory, Università di Bologna, Bologna, Italy.
Giovanna
G
Tabellini
Pier Luigi
PL
Tazzari
Roberta
R
Bortul
Anna Maria
AM
Billi
Roberto
R
Conte
Lucia
L
Manzoli
Lucio
L
Cocco
Alberto M
AM
Martelli
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010716:Phosphatidylinositols / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010742:Phospholipid Ethers / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003561:Cytarabine; D004791:Enzyme Inhibitors; D005047:Etoposide; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010742:Phospholipid Ethers; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human