title: Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) exert their anti-proliferative activity by interfering with Akt-mTOR signaling and bax:bcl-2 ratio modulation in cells from chronic myeloid leukemic patients.
abstract: In our study we found that pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) mediated apoptosis in primary leukemia cells from 27 chronic myelogenous leukemia (CML) patients at onset through the activation of the caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP). The bax:bcl-2 ratio was increased as a consequence of down-regulation of bcl-2 and up-regulation of bax proteins in response to treatment with PBTDs. In addition, PBTDs were able to induce cell death in primary leukemia cells derived from 23 CML-chemoresistant patients. Furthermore, the effects of PBTDs on the Akt-mTOR (mammalian target of rapamycin) pathway were determined by Western blot. PBTDs possessed inhibitory activity against mTOR and also impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. The results presented in this study demonstrate that we have identified the PBTDs as restoring the apoptotic pathways both in primary leukemia cells derived from CML patients at onset and in primary leukemia cells derived from CML-chemoresistant patients, thus showing their ability to undergo apoptosis. These compounds constitute a promising therapeutic approach for patients with leukemia. They provide the basis for new strategies for an additional anticancer drug in leukemia therapies, especially when conventional ones fail.
authors: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
authors: Carla
authors: C
authors: Di Stefano
authors: Gabriella
authors: G
authors: Marfe
authors: Malgorzata Monika
authors: MM
authors: Trawinska
authors: Paola
authors: P
authors: Sinibaldi-Salimei
authors: Romano
authors: R
authors: Silvestri
authors: Sergio
authors: S
authors: Amadori
authors: Elisabetta
authors: E
authors: Abruzzese
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D001582:Benzothiepins / Q000494:pharmacology; D053453:Caspase 9 / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001582:Benzothiepins; D003499:Cyclic S-Oxides; D047908:Intracellular Signaling Peptides and Proteins; C552371:RS 2630; C527487:RS 678; C527488:RS 779; D051028:bcl-2-Associated X Protein; D001569:Benzodiazepines; D000246:Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9