Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia

Styczyński, Jan; Wysocki, Mariusz; Dębski, Robert; Czyżewski, K; Kołodziej, Beata; Rafinska, Beata; Kubicka, Małgorzata; Kołtan, Sylwia; Kołtan, Andrzej; Pogorzała, Monika; Kurylak, Andrzej; Olszewska−Słonina, Dorota; Balwierz, Walentyna; Juraszewska, Edyta; Wieczorek, Maria; Olejnik, Igor; Krawczuk‐Rybak, Maryna; Kuzmicz, Marta; Kowalczyk, Jerzy; Stefaniak, Jolanta; Badowska, Wanda; Sońta-Jakimczyk, D; Szczepanski, Tomasz; Matysiak, Michał; Malinowska, Iwona; E, Stańczak; Wachowiak, Jacek; Konatkowska, Benigna; Gil, Lidia; Balcerska, Anna; Maciejka-Kapuścińska, Lucyna

doi:10.1007/s00432-007-0299-5

Cited by 10 publications

(13 citation statements)

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“…Expression of ABC transporters in the tumor cells has been reported to be responsible for drug resistance in acute lymphoblastic leukemia (21), breast cancer (22), and nonsmall cell lung cancer (23). With regard to PCNSL, Kunishio et al proposed that expression of MDR1 Pgp and MRP1 in tumor cells is associated with resistance to MTX (24).…”

Section: Discussionmentioning

confidence: 99%

ATP-binding cassette transporters in primary central nervous system lymphoma: Decreased expression of MDR1 P-glycoprotein and breast cancer resistance protein in tumor capillary endothelial cells

Sakata

Fujiwara

Ohtsuka³

et al. 2011

Oncol Rep

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Abstract. Most tumors in the central nervous system are drug resistant partly because of the presence of the bloodbrain barrier (BBB) between circulating blood and tumor tissues. Primary central nervous system lymphoma (PCNSL) is one of the exceptions, as it is highly sensitive to high-dose methotrexate (MTX)-based chemotherapy. The aim of this study was to evaluate the BBB function of tumor capillary endothelial cells in PCNSL. Expression of three major drug efflux transporters that belong to the ATP-binding cassette (ABC) superfamily, P-glycoprotein encoded by the human multidrug resistance gene (MDR1 Pgp; ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance-associated protein 1 (MRP1; ABCC1), was evaluated. Immunohistochemistry was performed in capillary endothelial cells of 30 tumor areas from 22 PCNSL cases and compared with that of 30 gliomas. The microenvironment around tumor capillaries was assessed by examining the distribution of astrocytes and by counting the number of macrophages and T-cells, the principal cytokine producers. In PCNSL, expression of MDR1 Pgp and BCRP in tumor capillary endothelial cells was decreased in 63 and 93% of tumor areas examined, respectively, and these reduction levels differed significantly from those of gliomas (P<0.05). When the PCNSLs were further segregated by way of infiltration of tumor cells into three patterns (dense, perivascular and sparse), decreased MDR1 Pgp and BCRP in tumor capillary endothelial cells were much more prominent in dense and perivascular patterns. In all tumors and non-tumor areas of the brain, MRP1 was undetected on capillary endothelial cells. Assessment of the microenvironment around the tumor capillaries suggested that dissociation from astrocytes and infiltration of macrophages and T-cells was involved in the down-regulation of MDR1 Pgp and BCRP in capillary endothelial cells. In conclusion, we report that expression of the major ABC transporters of the BBB, MDR1 Pgp and BCRP, decreases in tumor capillary endothelial cells of PCNSL. Thus, decreased expression may permit delivery of chemotherapeutic agents to the tumor tissues.

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Section: Discussionmentioning

confidence: 99%

ATP-binding cassette transporters in primary central nervous system lymphoma: Decreased expression of MDR1 P-glycoprotein and breast cancer resistance protein in tumor capillary endothelial cells

Sakata

Fujiwara

Ohtsuka³

et al. 2011

Oncol Rep

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“…The redox mediator ferrocenemethanol (FcCH 2 OH) is used to quantify MRP1 activity of these two cell lines through its unique interaction with glutathione, a peptide molecule involved in MRP1-related transport. Tracking the evolution of MRP1 activity and expression is important because direct clinical implications make MRP1 a relatively unique molecular marker in comparison with other prognostic variables identified for several cancer types (27,28). …”

mentioning

confidence: 99%

Assessment of multidrug resistance on cell coculture patterns using scanning electrochemical microscopy

Kuss

Polcari

Geißler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The emergence of resistance to multiple unrelated chemotherapeutic drugs impedes the treatment of several cancers. Although the involvement of ATP-binding cassette transporters has long been known, there is no in situ method capable of tracking this transporter-related resistance at the single-cell level without interfering with the cell's environment or metabolism. Here, we demonstrate that scanning electrochemical microscopy (SECM) can quantitatively and noninvasively track multidrug resistance-related protein 1-dependent multidrug resistance in patterned adenocarcinoma cervical cancer cells. Nonresistant human cancer cells and their multidrug resistant variants are arranged in a side-by-side format using a stencil-based patterning scheme, allowing for precise positioning of target cells underneath the SECM sensor. SECM measurements of the patterned cells, performed with ferrocenemethanol and [Ru(NH 3 ) 6 ] 3+ serving as electrochemical indicators, are used to establish a kinetic "map" of constant-height SECM scans, free of topography contributions. The concept underlying the work described herein may help evaluate the effectiveness of treatment administration strategies targeting reduced drug efflux.ancer cells, such as lung cancer or leukemia, acquire resistance to multiple unrelated drugs in response to treatment with chemotherapeutic agents (1, 2). Resistance impedes therapeutic effectiveness, which in turn, reduces the long-term survival rate of cancer patients (2). The emergence of multidrug resistance (MDR) involves the overexpression of transmembrane proteins P-glycoprotein (P-gp) and MDR-related protein 1 (MRP1), which both belong to the family of 5′-triphosphatebinding cassette transporters (known as ABC transporters). P-gp and MRP1 act as molecular "pumps," actively removing therapeutic agents from the cancer cells, thereby preventing the drug from inducing the desired effect on the cell nucleus or cytoplasm. MDR based on P-gp is relatively well understood and involves binding of hyaluronan to the cell surface glycoprotein CD44. The resulting up-regulation of the transcriptional cofactor p300 expression and therefore the NFkappaB-specific transcriptional up-regulation lead to the production of P-gp, and with that chemoresistance in cells (3). However, the mechanism that causes MRP1-mediated MDR remains unclear.Currently, quantification of MDR relies on immunohistochemical analyses, such as real-time PCR, focusing mostly on P-gp or other members of ABC transporters (4-9). Fluorescent MRP1-specific studies were also conducted, revealing that resistant and nonresistant cancer cells have differential intracellular content of glutathione and GST, which affect their cell death mechanism during hyperthermia (10). Microvoltammetry was also used to measure the efflux of chemotherapeutic drugs from normal and MDR cancer cells on the single-cell level, with detection limits in the nanomolar range (11). Finally, flow cytometry has routinely been used to quantify and compare expression levels and activity of dif...

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“…To our knowledge, this is the first study to show this relationship. Since PGP, MRP1 and LRP proteins play an important role in multidrug resistance of leukemic cells through decreasing the intracellular drug concentration, overcoming this mechanism may have an important role in circumvention of resistance [23].…”

Section: Discussionmentioning

confidence: 99%

Imatinib is a substrate for various multidrug resistance proteins

Czyżewski

Styczyński²

2009

neo

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an increasing resistance to imatinib is an emerging problem in patients with chronic myeloid leukemia (Cml). The aim of the study was to asses mechanisms related to cellular drug resistance in imatinib-resistant derivates of chronic myeloid leukemia K-562 cell line. a parental K-562 and its imatinib-resistant derivate cell lines were used. Cell lines were tested for cytotoxicity of imatinib, cytarabine, busulfan and etoposide by the mTT assay. The cytotoxicity was expressed as IC50, inhibitory concentration for 50% of cells. multidrug resistance proteins expression, rhodamine retention and daunorubicin accumulation were measured for each cell line. Continuous exposition of K-562 cell line to 0.01-0.02 mm imatinib resulted in development of resistance, while exposition to 0.1 µm imatinib increased cell sensitivity to this drug. There was a high correlation between pGp, mRp1 and lRp expression and IC50 values for imatinib and etoposide. all tested cell lines were highly resistant to cytarabine. Rhodamine retention alone and in the presence of cyclosporine was the lowest in imatinibresistant K-562R-0.1 cell line, what suggest high pGp activity in this cell line. The highest daunorubicin accumulation was observed in parental K-562 cell line, while it was lower in imatinib-resistant cell lines. These data suggest that imatinib is a substrate for multidrug resistance proteins, and an increased expression of pGp, mRp1 and lRp play a role in resistance to imatinib in Cml.

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Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia

Abstract: The names of the last five authors were mistakenly deleted during production. The full list of authors and their affiliations are given here.

Cited by 10 publications

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ATP-binding cassette transporters in primary central nervous system lymphoma: Decreased expression of MDR1 P-glycoprotein and breast cancer resistance protein in tumor capillary endothelial cells

ATP-binding cassette transporters in primary central nervous system lymphoma: Decreased expression of MDR1 P-glycoprotein and breast cancer resistance protein in tumor capillary endothelial cells

Assessment of multidrug resistance on cell coculture patterns using scanning electrochemical microscopy

Imatinib is a substrate for various multidrug resistance proteins

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