Galangin increases the cytotoxic activity of imatinib mesylate in imatinib-sensitive and imatinib-resistant Bcr-Abl expressing leukemia cells.
Resistance to imatinib mesylate is an emergent problem in the treatment of Bcr-Abl expressing myelogenous leukemias and additional therapeutic strategies are required. We observed that galangin, a non-toxic, naturally occurring flavonoid was effective as anti-proliferative, and apoptotic agent in Bcr-Abl expressing K562 and KCL22 cells and in imatinib mesylate resistant K562-R and KCL22-R cells. Galangin induced an arrest of cells in G0-G1phase of cell cycle and a decrease in pRb, cdk4, cdk1, cycline B levels; moreover, it was able to induce a monocytic differentiation of leukemic Bcr-Abl+ cells. Of note, galangin caused a decrease in Bcl-2 levels and markedly increased the apoptotic activity of imatinib both in sensitive or imatinib-resistant Bcr-Abl+ cell lines. In contrast, flavonoids unable to modify the Bcl-2 intracellular levels, such as fisetin and chrysin, did not increase the apoptotic effect of imatinib. These data suggest that galangin is an interesting candidate for a combination therapy in the treatment of imatinib-resistant leukemias.
Tolomeo
Manlio
M
Centro Interdipartimentale di Ricerca in Oncologia Clinica, Università di Palermo, Palermo, Italy. mtolomeo@hotmail.com
Grimaudo
Stefania
S
Di Cristina
Antonietta
A
Pipitone
Rosaria M
RM
Dusonchet
Luisa
L
Meli
Maria
M
Crosta
Lucia
L
Gebbia
Nicola
N
Invidiata
Francesco Paolo
FP
Titone
Lucina
L
Simoni
Daniele
D
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000627:therapeutic use*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects
D001549:Benzamides; D005419:Flavonoids; D010879:Piperazines; D011743:Pyrimidines; C037032:galangin; D000068877:Imatinib Mesylate