The new iodoacetamidobenzofuran derivative TR120 decreases STAT5 expression and induces antitumor effects in imatinib-sensitive and imatinib-resistant BCR-ABL-expressing leukemia cells.
The identification of novel compounds modulating the expression/activity of molecular targets downstream to BCR-ABL could be a new approach in the treatment of chronic myeloid leukemias (CMLs) resistant to imatinib or other BCR-ABL-targeted molecules. Recently, we synthesized a new class of substituted 2-(3,4,5-trimethoxybenzoyl)-2-N,N-dimethylamino-benzo[b]furans, and among these 3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone (TR120) showed marked cytotoxic activity in BCR-ABL-expressing cells. Interestingly, TR120 was more potent than imatinib in cell growth inhibition and apoptosis induction in both BCR-ABL-expressing K562 and KCL22 cells. Moreover, it showed antitumor activity in imatinib-resistant K562-R and KCL22-R cells at concentrations similar to those active in the respective sensitive cells. Further, TR120 induced a marked decrease in signal transducer and activator of transcription 5 (STAT5) expression in K562 cells. Consistent with this effect, it determined a block of cells in the G0-G1 phase of the cell cycle, a decrease in the level of cyclin D1, and a reduction in Bcl-xL expression; however, it did not cause modifications in the Bcl-2 level. Of interest, TR120 had synergistic effects when used in combination with imatinib in both sensitive and resistant cells. Considering that STAT5 is a BCR-ABL molecular target that plays a key role in the pathogenesis of CML as well as in BCR-ABL-mediated resistance to apoptosis, TR120 could potentially be a useful novel agent in the treatment of imatinib-resistant CML.
Department of Biomedical Internal and Specialized Medicine, University of Palermo, Palermo, Italy.
Stefania
S
Grimaudo
Maria
M
Meli
Antonietta
A
Di Cristina
Arianna
A
Ferro
Maria R
MR
Pipitone
Romeo
R
Romagnoli
Daniele
D
Simoni
Francesco
F
Dieli
Manlio
M
Tolomeo
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D001572:Benzofurans; D001577:Benzophenones; D001854:Bone Marrow Cells / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003114:Colony-Forming Units Assay; D019938:Cyclin D1 / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019940:Genes, bcl-1; D019254:Genes, bcl-2; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D009336:Necrosis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
C582797:3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001549:Benzamides; D001572:Benzofurans; D001577:Benzophenones; C530104:CCND1 protein, human; D009363:Neoplasm Proteins; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D051020:bcl-X Protein; D019938:Cyclin D1; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl