Reversal effect of PI3-K inhibitor LY294002 on P-glycoprotein-mediated multidrug resistance of human leukemia cell line K562/DNR and gastric cancer cell line SGC7901/ADR.
OBJECTIVE
Phosphatidylinositol-3-kinase/protein kinase B (PI3-K/Akt) signaling pathway plays an important role in cell survival. This study was to explore the reversal effect of PI3-K inhibitor LY294002 on p-glycoprotein (P-gp)-mediated multidrug resistance in human leukemia cell line K562/DNR and gastric cancer cell line SGC7901/ADR.


METHODS
The cells were divided into simple drug-treated groups and LY294002 pretreated groups: the former groups received treatment of daunorubicin (DNR), adriamycin (ADR), vincristine (VCR) and etoposide (VP-16), respectively; the latter groups received pretreatment of LY294002 before drug treatment. Trypan blue dye exclusion method and MTT assay were used to detect the drug sensitivity of K562/DNR and SGC7901/ADR cells, and the effect of LY294002 on the drug resistance. The expression of P-gp and phosphorylated Akt (p-Akt) in K562/DNR, SGC7901/ADR and their parental cell lines K562 and SGC7901 was detected by Western blot. Intracellular drug accumulation was measured by flow cytometry (FCM).


RESULTS
LY294002 pretreatment significantly decreased the 50% inhibition concentration (IC(50)) of DNR, ADR, VCR and VP-16 for K562/DNR cells, with reverse efficiencies of 72.4%, 64.9%, 60.4% and 52.8%. In SGC7901/ADR cells, the similar result was obtained with a reverse efficiency of 31.0%. LY294002 pretreatment partially inhibited the expression of p-Akt and P-gp, and promoted the intracellular accumulation of DNR and ADR in K562/DNR and SGC7901/ADR cells, respectively.


CONCLUSIONS
LY294002 could partially reverse multidrug resistance in K562/DNR and SGC7901/ADR cells in vitro via inhibiting PI3-K/Akt pathway.
Zhang
Ye
Y
Department of Medical Oncology, Shengjing Hospital, China Medical University, Shenyang, Liaoning, PR China.
Qu
Xiu-Juan
XJ
Liu
Yun-Peng
YP
Yang
Xiang-Hong
XH
Hou
Ke-Zuo
KZ
Teng
Yue-E
YE
Zhang
Jing-Dong
JD
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D003630:Daunorubicin