The synergistic reversal effect of multidrug resistance by quercetin and hyperthermia in doxorubicin-resistant human myelogenous leukemia cells.
OBJECTIVE
This study aimed to evaluate the multidrug resistance (MDR) reversal activity of quercetin (Que) in combination with hyperthermia (HT) in human myelogenous leukemia cells K562/A.


METHODS
The cytotoxicity of Que alone and the effect of Que and HT to doxorubicin (Dox) cytotoxicity were determined using MTT assay in K562 and K562/A cells. K562/A cells was heated with or without Que pretreatment, and the protein and mRNA levels of heat shock protein 70 (HSP70) and P-glycoprotein (P-gp) were determined by flow cytometry (FCM) and RT-PCR, respectively. Intracellular accumulation of Dox, cell cycle and apoptosis were monitored with FCM.


RESULTS
Que alone inhibited cell growth in a dose-dependent manner in K562 and K562/A cells. Either Que or HT alone had a weak reversal effect on Dox resistance, however, combination HT and Que showed a much more significant reversal effect on Dox resistance (reverse fold 9.49). The elevated protein expression and mRNA level of HSP70 and P-gp in response to HT were inhibited by Que. Pretreatment with Que caused the cells to accumulate Dox 8.3-fold higher than in control cells. In addition, Que induced apoptosis and G2/M arrest in a dose-dependent manner, and the combination of Que and HT was found to have a synergistic effect on apoptosis.


CONCLUSIONS
Que pretreatment could significantly enhance the MDR reversal activity of HT in resistant cell line, by sensitizing the cell to reversing MDR activity of HT.
Shen
Jing
J
Affiliated Hospital, Academy of Military Medical Sciences, Beijing, China.
Zhang
Weijing
W
Wu
Jun
J
Zhu
Yunfeng
Y
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004357:Drug Synergism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011794:Quercetin / Q000494:pharmacology / Q000627:therapeutic use*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D018840:HSP70 Heat-Shock Proteins; D004317:Doxorubicin; D011794:Quercetin