Reversal effect of haloperidol on doxorubicin resistance and chloride channel inhibition in erythroleukemic cell K562/Dox.
- Author:
Jing-hong ZHOU
1
;
De-zheng WU
Author Information
- Publication Type:Journal Article
- MeSH: ATP-Binding Cassette, Sub-Family B, Member 1; biosynthesis; genetics; Antibiotics, Antineoplastic; pharmacology; Chloride Channels; drug effects; Doxorubicin; pharmacology; Drug Resistance, Multiple; drug effects; Drug Resistance, Neoplasm; drug effects; Glutathione S-Transferase pi; Glutathione Transferase; biosynthesis; genetics; Haloperidol; pharmacology; Humans; Isoenzymes; biosynthesis; genetics; K562 Cells; Multidrug Resistance-Associated Proteins; biosynthesis; genetics; RNA, Messenger; biosynthesis; genetics
- From: Chinese Journal of Oncology 2005;27(2):81-85
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo investigate the reversal effect of haloperidol (Hal) on doxorubicin (Dox) resistance and its inhibition effect on P-glycoprotein and swelling-activated chloride channel in Dox-resistant erythro-leukemic cell line K562/Dox.
METHODSTumor cell proliferation was measured by LDH assay. mRNA expressions of P-glycoprotein (MDR1), glutathione S-transferase Pi (GSTpi) and MDR-associated protein (MRP) of K562/Dox treated with Hal were assayed by RT-PCR. Chloride-sensitive dye MQAE was loaded into K562/Dox cells and the intracellular fluorescence intensity was measured to evaluate the effect of Hal on chloride channel in swelling-activated K562/Dox cells. Coulter counter ZM and Channelyzer 256 were used to measure cell volume regulation.
RESULTSHal significantly reversed Dox resistance in K562/Dox cells after 12.50, 6.25 and 3.12 micromol/L Hal treatment, the chemosensitivity to Dox increased by 8.61, 4.35 and 2.25 times respectively. After treatment with Hal 12.50 micromol/L, MDR1 and MRP mRNA expression were gradually down-regulated in a time-dependent manner on d1-d3, reducing to 76.3% and 64.6% of the control level on d3 (P < 0.05), while GSTpi mRNA expression decreased by 66.1% (P < 0.05) on d1-d2, and began to recover on d3. The swelling-activated chloride channel and cell regulatory volume decreased (RVD) in K562/Dox cells were also inhibited by Hal. Under hypotonic challenge the cellular fluorescence intensity which represented chloride concentration declined by (34.46 +/- 5.91)%. After adding 6.25 micromol/L and 18.75 micromol/L Hal, the hypotonic challenge only caused decrease in fluorescence intensity by (24.43 +/- 3.25)% and (16.63 +/- 4.98)% (P < 0.01). RVD in hypotonic condition was (84.95 +/- 5.69)%. RVD under hypotonic condition with 6.25 micromol/L and 18.75 micromol/L Hal were (51.12 +/- 6.01)% and (39.51 +/- 4.79)% respectively (P < 0.01).
CONCLUSIONA nontoxic concentration of haloperidol can significantly reverse drug resistance through a multi-pathway effect, including down-regulating mRNA expressions of MDR, GSTpi and MRP, inhibition of swelling-activated chloride channel and RVD in K562/Dox cells.
