Variation of MDR proteins expression and activity levels according to clinical status and evolution of CML patients

Vasconcelos, Flavia da Cunha; Silva, Karina L.; Souza, Paloma Silva de; Silva, Luiz Felipe R.; Moellmann-Coelho, Arthur; Klumb, Claudete Esteves; Maia, Raquel Ciuvalschi

doi:10.1002/cyto.b.20580

Cited by 42 publications

(39 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, drug resistance can also be acquired during the course of chemotherapy by tumors that are initially sensitive to treatment (8,9). To support this notion, we have recently shown that modifications in Pgp status, caused by a diversity of drugs, can alter the desirable effect induced by a specific chemotherapeutic drug during the treatment of chronic myeloid leukemia (CML) patients (10).…”

Section: Introductionmentioning

confidence: 99%

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

Souza

Vasconcelos²,

Reis³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. Overexpression of P-glycoprotein (Pgp/ABCB1) in tumor cells is associated with a classic phenotype of multidrug resistance (MDR). Moreover, some members of the inhibitor of apoptosis protein (IAP) family, such as survivin, contribute to an apoptosis-resistant phenotype, by inhibiting chemotherapyinduced cell death and promoting MDR. By using Western blotting, qRT-PCR, Annexin V and immunofluorescence assays we have demonstrated a relationship between Pgp and survivin in a prior sensitive chronic myeloid leukemia (CML) cell line (K562). A high dose of vincristine induced a concomitant overexpression of Pgp and survivin, which was associated with a low apoptotic index in the K562 cell line. In addition, we observed a cytoplasmic co-localization of Pgp and survivin, suggesting a functional association between these two proteins in apoptosis control by a common mechanism. In summary, our data suggest that Pgp and survivin should be analyzed in aggregate because they may have significant impact on drug resistance in CML cells.

show abstract

Section: Introductionmentioning

confidence: 99%

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

Souza

Vasconcelos²,

Reis³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…13) Moreover, upregulation in the P-gp expression level in CML cells from patients has been reported to correlate with increased resistance to imatinib. 14,15) Very little information is available on the drug transporters involved in the disposition of nilotinib. In CML cells, the OCT inhibitor prazosin had no effect on the intracellular uptake of nilotinib.…”

mentioning

confidence: 99%

Distinct Interaction of Nilotinib and Imatinib with P-Glycoprotein in Intracellular Accumulation and Cytotoxicity in CML Cell Line K562 Cells

Yamakawa

Hamada²,

Uchida

et al. 2014

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for first-line chronic myeloid leukemia (CML) treatment. The improved clinical response of nilotinib over that of the first generation TKI, imatinib, has been thought to be a result of its high potency of inhibition of BCR-ABL kinase. This study aimed to characterize differences between nilotinib and imatinib in the intracellular accumulation and cytotoxic effect on the CML cell line K562. Accumulation of nilotinib in K562 cells was from 4.7-to 9.0-fold higher than that of imatinib. The cytotoxic effect of nilotinib on K562 cells was 14.2-fold higher than that of imatinib. Inhibition experiments in K562 cells, and examination of the cellular uptake using influx transporter-transfected human embryonic kidney (HEK) 293 cells, suggested that the influx transporters OCT1 and OATP1A2, which have been reported to mediate accumulation of imatinib in CML cells, contributed little to the uptake of nilotinib. Nilotinib was found to accumulate in imatinib-resistant K562 (K562/ IM) cells overexpressing the efflux transporter P-glycoprotein (P-gp), although cytotoxic assays showed that K562/IM cells displayed 20000-fold greater resistance to nilotinib over the parent K562 cells. In conclusion, the present findings suggest that intracellular accumulation of nilotinib in CML cells contributes to its clinical response and efficacy in CML patients. Although nilotinib has been reported to be effective against imatinib-resistant ABL kinase mutants, the drug could not overcome imatinib resistance acquired by P-gpoverexpression. These results imply that classification of mechanisms of drug resistance is important for suitable strategies to treat imatinib-resistant CML patients.

show abstract

“…MDR1/P-gp is expressed in almost all human tumor cells to different degrees, and its expression in tumors insensitive to chemotherapy or with poor efficacy is often high (25). Previous studies have reported that the sensitivity of some cancer patients to chemotherapy was increased following the administration of P-gp inhibitors (24,(26)(27)(28). In the present study, downregulation of P-gp protein by naringin was also observed, and therefore it was inferred that the ameliorating effect of naringin on cisplatin resistance of ovarian cancer cells was associated with the downregulation of P-gp.…”

Section: Discussionmentioning

confidence: 99%

Inï¿½vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway

et al. 2018

View full text Add to dashboard Cite

Abstract. The aim of the present study was to investigate the mechanism of action by which naringin reverses the resistance of ovarian cancer cells to cisplatin. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting assays were used to detect the effects of different concentrations of naringin on the expressions of nuclear factor (NF)-κB and P-glycoprotein (P-gp) in the SKOV3/CDDP cell line. Small interfering RNA (siRNA) targeting NF-κB was designed and synthesized to silence NF-κB, and recombinant plasmid vectors overexpressing NF-κB were constructed to transfect cells. RT-qPCR and western blotting assays were subsequently performed to detect the effects of NF-κB on the expression of P-gp at the mRNA and protein levels. Naringin was added to the NF-κB-overexpressing SKOV3/CDDP cells and cultured for 48 h, followed by the detection of the expression of P-gp. RT-PCR and western blotting results demonstrated that the gene and protein expressions of NF-κB and P-gp were significantly decreased in a dose-dependent manner by naringin treatment (P<0.05). In cells overexpressing NF-κB, P-gp expression was significantly elevated (P<0.05), and the expression of P-gp was significantly decreased when NF-κB was silenced (P<0.05). Treatment with naringin was able to significantly ameliorate the NF-κB-induced overexpression of P-gp (P<0.05). These results indicate that naringin is able to inhibit the expression of NF-κB and P-gp in SKOV3/CDDP cells. Such an inhibitory effect may increase gradually with concentration, and is associated with blockade of the NF-κB signaling pathway. This pathway may represent one of the mechanisms of action by which Naringin reverses resistance to platinum-based agents in ovarian cancer cells.

show abstract

Variation of MDR proteins expression and activity levels according to clinical status and evolution of CML patients

Cited by 42 publications

References 26 publications

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

Distinct Interaction of Nilotinib and Imatinib with P-Glycoprotein in Intracellular Accumulation and Cytotoxicity in CML Cell Line K562 Cells

Inï¿½vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway

Contact Info

Product

Resources

About