A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia.
p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
D Y
DY
Xia
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
L
L
Liu
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
M W
MW
Hao
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Q
Q
Liu
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
R A
RA
Chen
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Y M
YM
Liang
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000187:drug effects / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004338:Drug Combinations; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D051358:Cyclin-Dependent Kinase 4