Suppression of proline-directed protein kinase F(A) potentiates apoptotic induction and greatly enhances chemosensitivity in human acute lymphoblastic leukemia cells.
BACKGROUND
Previously, the authors reported that specific antisense suppression of overexpressed proline-directed protein kinase (PDPK) F(A) enhances the chemosensitivity of various clinical anticancer drugs up to > 100-fold in human prostate carcinoma cells, suggesting an association of PDPK F(A) with drug resistance in human malignancies.


METHODS
In this report, by using a similar approach, the authors demonstrate further that the suppression of PDPK F(A) enhances even more dramatically the chemosensitivity of clinically used anticancer drugs in various types of human acute lymphoblastic leukemia (ALL) cells.


RESULTS
Compared with parental and control transfected cells, transduced ALL cells (both Jurkat and CCRF-CEM cells) with low levels of PDPK F(A) displayed an enhanced sensitivity to vincristine, vinblastine, paclitaxel, methotrexate, doxorubicin, and daunorubicin. Estimation of the 50% inhibitory concentration (IC(50)) index further revealed that the transduced cells displayed up to > 3000-fold drug sensitivity, and there was a correlation between suppressed levels of PDPK F(A) and drug sensitivity. A mechanistic study further revealed that the enhanced chemosensitivity in transduced ALL cells was due mainly to the potentiation of apoptotic induction.


CONCLUSIONS
Taken together, the results demonstrate that the suppression of overexpressed PDPK F(A) greatly enhances the chemosensitivity of various clinical anticancer drugs in both types of human ALL cells, providing initial evidence for an important role of this PDPK in controlling multidrug resistance of ALL.
Hsu
C P
CP
Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.
Yang
C C
CC
Hsueh
S F
SF
Peng
C C
CC
Fu
H H
HH
Yang
S D
SD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology*; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases