[Study on the mechanisms of imatinib-resistance of cancer stem-like cells in K562/Vp16 cell line].
OBJECTIVE
To elucidate the mechanisms of imatinib resistance involved in some chronic myeloid leukemia (CML) cells overexpressing P-glycoprotein (P-gp).


METHODS
Generation of resistant K562 cell line K562/Vp16 overexpressing P-gp was achieved by exposure of K562 cells to stepwise increase of concentrations of Vp16. A small set of side population (SP) with the characteristics of stem cells being capable of efflux fluorescent dye Hoechst 33342 in the cell line was isolated by flow cytometry. The mechanisms involved in K562/Vp16 SP cells resistant to imatinib were studied.


RESULTS
The levels of BCR/ABL and ABL proteins in K562 cells were similar to those in K562/Vp16 non-SP and K562/Vp16 SP cells. The 170 KDa P-gp was detected in K562/Vp16 and K562/Vp16 SP cells at similar levels but not in K562 cells. Compared with K562/Vp16 non-SP cells, K562/Vp16 SP cells were more resistant to imatinib, which could hardly be reversed by many multidrug resistance inhibitors. In addition, in vivo study showed that the malignancy of K562/Vp16 cells was largely attributed to the SP cells.


CONCLUSIONS
Bcr/Abl gene amplification and multidrug-resistant gene 1 (mdr1) overexpression might not be an important clinical mechanism in the diversity of resistance to imatinib treatment, and the development of drug resistance by leukemia cells may be at least partly due to a rare SP of tumor stem-like cells which drives leukemia occurrence and maintenance. These SP cells might be targeted for effective cancer therapy.
Song
Yong-ping
YP
Cancer Institute, Second Affiliated Hospital, Zhejiang University, Hangzhou 310009, China.
Fang
Bai-jun
BJ
Wei
Xu-dong
XD
Zheng
Shu
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D005047:Etoposide; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl