Effect of D, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol and tetrandrine on the reversion of multidrug resistance in K562/A02 cells.
In this study, we applied D, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) hydrochloride as a chemical inhibitor for glucosylceramide synthase (GCS) and tetrandrine (Tet) for P-glycoprotein (P-gp) to reverse daunorubicin (DNR) resistance of human leukemia cell line K562/A02. Cytotoxicity assays showed that either PDMP or Tet enhanced cytotoxic effect of DNR on K562/A02 cells, while cotreatment of these two drugs had a more significant effect on chemosensitization. Using flow cytometric analysis, we confirmed that the enhancement effect was accompanied by elevated cellular DNR accumulation and DNR-induced apoptosis. According to reverse transcription-polymerase chain reaction and western blot, the reversal effect of that composite might owe to the significant downregulation of mdr1 and GCS gene expressions. Importantly, PDMP diminished mdr1 gene expression and Tet also downregulated GCS gene expression. Moreover, a positive correlation was observed between GCS and P-gp. Thus, our results suggest that a potential clinical application of PDMP in combination with Tet may enhance chemosensitivity in leukemia.
Department of Hematology, Zhongda Hospital affiliated to Southeast University, Nanjing, China. cba8888@hotmail.com
Baoan
B
Chen
Li
L
Yin
Jian
J
Cheng
Jiahua
J
Ding
Chong
C
Gao
Yunyu
Y
Sun
Gang
G
Zhao
Jun
J
Wang
Wen
W
Bao
Guohua
G
Xia
Feng
F
Gao
Xuemei
X
Wang
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*
D044182:Benzylisoquinolines; D009025:Morpholines; C009438:tetrandrine; C033110:RV 538; D003630:Daunorubicin