Suppression of proline-directed protein kinase F-A potentiates apoptotic induction and greatly enhances chemosensitivity in human acute lymphoblasticleukemia cells
Cp. Hsu et al., Suppression of proline-directed protein kinase F-A potentiates apoptotic induction and greatly enhances chemosensitivity in human acute lymphoblasticleukemia cells, CANCER, 92(7), 2001, pp. 1753-1758
BACKGROUND. Previously, the authors reported that specific antisense suppre
ssion 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 wi
th drug resistance in human malignancies.
METHODS. In this report, by using a similar approach, the authors demonstra
te further that the suppression of PDPK FA enhances even more dramatically
the chemosensitivity of clinically used anticancer drugs in various types o
f human acute lymphoblastic leukemia (ALL) cells.
RESULTS. Compared with parental and control transfected cells, transduced A
LL cells (both Jurkat and CCRF-CEM cells) with low levels of PDPK F-A displ
ayed an enhanced sensitivity to vincristine, vinblastine, paclitaxel, metho
trexate, doxorubicin, and daunorubicin. Estimation of the 50% inhibitory co
ncentration (IC50) index further revealed that the transduced cells display
ed up to > 3000-fold drug sensitivity, and there was a correlation between
suppressed levels of PDPK F-A and drug sensitivity. A mechanistic study fur
ther revealed that the enhanced chemosensitivity in transduced ALL cells wa
s due mainly to the potentiation of apoptotic induction.
CONCLUSIONS. Taken together, the results demonstrate that the suppression o
f overexpressed PDPK F-A greatly enhances the chemosensitivity of various c
linical anticancer drugs in both types of human ALL cells, providing initia
l evidence for an important role of this PDPK in controlling multidrug resi
stance of ALL. (C) 2001 American Cancer Society.