The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Michihiko Kuwano - One of the best experts on this subject based on the ideXlab platform.
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enhanced expression of gamma glutamylcysteine synthetase and glutathione s transferase genes in cisplatin resistant bladder cancer cells with multiDrug resistance phenotype
The Journal of Urology, 1997Co-Authors: Shuji Kotoh, Akira Yokomizo, Kimitoshi Kohno, Michihiko Kuwano, Seiji Naito, Joichi KumazawaAbstract:ABSTRACTPurpose: To elucidate the mechanisms of cisplatin resistance in human bladder cancer.Materials and Methods: After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various Drug resistance-related genes was examined.Results: KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multiDrug resistance. Decreased intracellular Drug Accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines.Conclusions: Multiple mechanisms, including decreased Drug Accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cispl...
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Enhanced Expression of gamma/Glutamylcysteine Synthetase and Glutathione S-transferase Genes in Cisplatin-Resistant Bladder Cancer Cells with MultiDrug Resistance Phenotype
The Journal of Urology, 1997Co-Authors: Shuji Kotoh, Akira Yokomizo, Kimitoshi Kohno, Michihiko Kuwano, Seiji Naito, Joichi KumazawaAbstract:ABSTRACTPurpose: To elucidate the mechanisms of cisplatin resistance in human bladder cancer.Materials and Methods: After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various Drug resistance-related genes was examined.Results: KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multiDrug resistance. Decreased intracellular Drug Accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines.Conclusions: Multiple mechanisms, including decreased Drug Accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cispl...
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A Human Canalicular Multispecific Organic Anion Transporter (cMOAT) Gene Is Overexpressed in Cisplatin-resistant Human Cancer Cell Lines with Decreased Drug Accumulation
Cancer research, 1996Co-Authors: Ken Taniguchi, Kimitoshi Kohno, Shin-ichi Akiyama, Morimasa Wada, Takanori Nakamura, T Kawabe, Mina Kawakami, Kazuhiro Kagotani, Katsuzumi Okumura, Michihiko KuwanoAbstract:By targeting the ATP binding conserved domain in three ATP binding cassette superfamily proteins (P-glycoprotein, multiDrug resistance protein, and cystic fibrosis transmembrane regulator), we isolated the cDNA of a new ATP binding cassette superfamily that was specifically enhanced in a cisplatin-resistant human head and neck cancer KB cell line. A human clone homologous to rat canalicular multispecific organic anion transporter (cMOAT) was found and designated human cMOAT. Fluorescence in situ hybridization demonstrated the chromosomal locus of the gene on chromosome 10q24. The human cMOAT cDNA hybridized a 6.5-kb mRNA that was expressed 4- to 6-fold higher by three cisplatin-resistant cell lines derived from various human tumors exhibiting decreased Drug Accumulation. Human cMOAT may function as a cellular cisplatin transporter.
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Reduction of Drug Accumulation in Cisplatin-Resistant Variants of Human Prostatic Cancer PC-3 Cell Line
The Journal of urology, 1993Co-Authors: Masayuki Nakagawa, Kimitoshi Kohno, Yoshio Nomura, Mayumi Ono, Hiroaki Mizoguchi, Jiro Ogata, Michihiko KuwanoAbstract:Abstract We have isolated cis-diamminedichloroplatinum (II) (CDDP)-resistant variants, P/CDP4 and P/CDP5, from human prostatic cancer PC-3 cells after a stepwise exposure to CDDP. P/CDP4 and P/CDP5 showed 11-fold and 23-fold higher resistance to CDDP than did PC-3. P/CDP5 was cross-resistant to carboplatin, mitomycin C, etoposide, m-AMSA, bleomycin and UV irradiation. Alkaline elution of DNA showed an increased amount of DNA interstrand cross-links in PC-3 but not in P/CDP5 when PC-3 and P/CDP5 were cultured with CDDP. Flameless atomic absorption spectrophotometry revealed that intracellular Accumulation of CDDP in P/CDP4 and P/CDP5 was decreased to 18 to 34% and 9 to 18% of that of PC-3, respectively, when PC-3 and its CDDP-resistant counterparts were incubated with 5 and 10 μ g./ml. of CDDP for 24 hours. These data suggest that decreased Drug Accumulation is involved in the development of CDDP-resistance in the PC-3 cell line.
Kimitoshi Kohno - One of the best experts on this subject based on the ideXlab platform.
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enhanced expression of gamma glutamylcysteine synthetase and glutathione s transferase genes in cisplatin resistant bladder cancer cells with multiDrug resistance phenotype
The Journal of Urology, 1997Co-Authors: Shuji Kotoh, Akira Yokomizo, Kimitoshi Kohno, Michihiko Kuwano, Seiji Naito, Joichi KumazawaAbstract:ABSTRACTPurpose: To elucidate the mechanisms of cisplatin resistance in human bladder cancer.Materials and Methods: After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various Drug resistance-related genes was examined.Results: KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multiDrug resistance. Decreased intracellular Drug Accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines.Conclusions: Multiple mechanisms, including decreased Drug Accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cispl...
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Enhanced Expression of gamma/Glutamylcysteine Synthetase and Glutathione S-transferase Genes in Cisplatin-Resistant Bladder Cancer Cells with MultiDrug Resistance Phenotype
The Journal of Urology, 1997Co-Authors: Shuji Kotoh, Akira Yokomizo, Kimitoshi Kohno, Michihiko Kuwano, Seiji Naito, Joichi KumazawaAbstract:ABSTRACTPurpose: To elucidate the mechanisms of cisplatin resistance in human bladder cancer.Materials and Methods: After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various Drug resistance-related genes was examined.Results: KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multiDrug resistance. Decreased intracellular Drug Accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines.Conclusions: Multiple mechanisms, including decreased Drug Accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cispl...
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A Human Canalicular Multispecific Organic Anion Transporter (cMOAT) Gene Is Overexpressed in Cisplatin-resistant Human Cancer Cell Lines with Decreased Drug Accumulation
Cancer research, 1996Co-Authors: Ken Taniguchi, Kimitoshi Kohno, Shin-ichi Akiyama, Morimasa Wada, Takanori Nakamura, T Kawabe, Mina Kawakami, Kazuhiro Kagotani, Katsuzumi Okumura, Michihiko KuwanoAbstract:By targeting the ATP binding conserved domain in three ATP binding cassette superfamily proteins (P-glycoprotein, multiDrug resistance protein, and cystic fibrosis transmembrane regulator), we isolated the cDNA of a new ATP binding cassette superfamily that was specifically enhanced in a cisplatin-resistant human head and neck cancer KB cell line. A human clone homologous to rat canalicular multispecific organic anion transporter (cMOAT) was found and designated human cMOAT. Fluorescence in situ hybridization demonstrated the chromosomal locus of the gene on chromosome 10q24. The human cMOAT cDNA hybridized a 6.5-kb mRNA that was expressed 4- to 6-fold higher by three cisplatin-resistant cell lines derived from various human tumors exhibiting decreased Drug Accumulation. Human cMOAT may function as a cellular cisplatin transporter.
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Reduction of Drug Accumulation in Cisplatin-Resistant Variants of Human Prostatic Cancer PC-3 Cell Line
The Journal of urology, 1993Co-Authors: Masayuki Nakagawa, Kimitoshi Kohno, Yoshio Nomura, Mayumi Ono, Hiroaki Mizoguchi, Jiro Ogata, Michihiko KuwanoAbstract:Abstract We have isolated cis-diamminedichloroplatinum (II) (CDDP)-resistant variants, P/CDP4 and P/CDP5, from human prostatic cancer PC-3 cells after a stepwise exposure to CDDP. P/CDP4 and P/CDP5 showed 11-fold and 23-fold higher resistance to CDDP than did PC-3. P/CDP5 was cross-resistant to carboplatin, mitomycin C, etoposide, m-AMSA, bleomycin and UV irradiation. Alkaline elution of DNA showed an increased amount of DNA interstrand cross-links in PC-3 but not in P/CDP5 when PC-3 and P/CDP5 were cultured with CDDP. Flameless atomic absorption spectrophotometry revealed that intracellular Accumulation of CDDP in P/CDP4 and P/CDP5 was decreased to 18 to 34% and 9 to 18% of that of PC-3, respectively, when PC-3 and its CDDP-resistant counterparts were incubated with 5 and 10 μ g./ml. of CDDP for 24 hours. These data suggest that decreased Drug Accumulation is involved in the development of CDDP-resistance in the PC-3 cell line.
Jan Lankelma - One of the best experts on this subject based on the ideXlab platform.
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P-Glycoprotein-independent decrease in Drug Accumulation by phorbol ester treatment of tumor cells
Biochemical pharmacology, 1997Co-Authors: Peter R. Wielinga, Marc Heijn, Henk J. Broxterman, Jan LankelmaAbstract:The effect of a change in the phosphorylation state of the Drug transporter P-glycoprotein (P-gp) on its Drug transport activity was studied for the substrates daunorubicin (DNR), etoposide (VP-16), and calcein acetoxymethyl ester (Cal-AM). Phorbol ester (PMA), added to stimulate phosphorylation of P-gp by protein kinase C (PKC), caused a decrease in the cellular Accumulation of DNR and VP-16, both in multiDrug-resistant (MDR) P-gp-overexpressing cells and in wild-type cells. Since treatment of cells with kinase inhibitor staurosporine (ST) reversed this effect of PMA and the non-PKC-stimulating phorbol ester 4alpha-phorbol, 12,13-didecanoate (4alphaPDD) did not result in a decreased DNR Accumulation, we conclude that this effect is the result of kinase activity. The concentration dependence of the inhibition of P-gp by verapamil (Vp) was not influenced by PMA. Accumulation of the P-gp substrate Cal-AM was not influenced by PMA in wild-type cells. Therefore, Cal-AM was used to study the effect of PMA-induced phosphorylation of P-gp on its transport activity. Activation of PKC with PMA or inhibition of protein phosphatase 1/2A (PP1/PP2A) with okadaic acid (OA) did not affect the Accumulation of Cal-AM in the MDR cells or wild-type cells. The kinase inhibitor ST increased the Cal-AM Accumulation only in the MDR cells. Neither stimulating PKC with PMA nor inhibiting PP1/PP2A with OA led to a decreased inhibition of P-gp by ST, indicating that ST inhibits P-gp directly. From these experiments, we conclude that PKC and PP1/PP2A activity do not regulate the Drug transport activity of P-gp. However, these studies provide evidence that PMA-induced PKC activity decreases cellular Drug Accumulation in a P-gp-independent manner.
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Genistein modulates the decreased Drug Accumulation in non-P-glycoprotein mediated multiDrug resistant tumour cells
British journal of cancer, 1993Co-Authors: C. H. M. Versantvoort, Gerrit Jan Schuurhuis, H.m. Pinedo, C.a. Eekman, C. M. Kuiper, Jan Lankelma, H.j. BroxtermanAbstract:In tumour cells the pharmacological basis for multiDrug resistance (MDR) often appears to be a reduced cellular cytostatic Drug Accumulation caused by the Drug efflux protein, P-glycoprotein (Pgp MDR), or by other Drug transporters (non-Pgp MDR). Here we report the reversal of the decreased daunorubicin (DNR) Accumulation in five non-Pgp MDR cell lines (GLC4/ADR, SW-1573/2R120, HT1080/DR4, MCF7/Mitox and HL60/ADR) by genistein. Genistein inhibited the enhanced DNR efflux in the GLC4/ADR cells. In these cells the decreased VP-16 Accumulation was also reversed by genistein. Three other (iso)flavonoids biochanin A, apigenin and quercetin also increased the DNR Accumulation in the GLC4/ADR cells. In contrast to the effects on non-Pgp MDR cells, 200 microM genistein did not increase the reduced DNR Accumulation in three Pgp MDR cell lines (SW-1573/2R160, MCF7/DOX40 and KB8-5) or in the parental cell lines. In conclusion the use of genistein provides a means to probe non-Pgp related Drug Accumulation defects.
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Energy-dependent processes involved in reduced Drug Accumulation in multiDrug-resistant human lung cancer cell lines without P-glycoprotein expression.
Cancer research, 1992Co-Authors: C. H. M. Versantvoort, C. M. Kuiper, H.j. Broxterman, Herbert M. Pinedo, E.g.e. De Vries, N. Feller, Jan LankelmaAbstract:Mechanisms contributing to reduced cytotoxic Drug Accumulation were studied in two multiDrug-resistant (MDR) human lung cancer cell lines without P-glycoprotein expression. In these (non-small cell) SW-1573/2R120 and (small cell) GLC4/ADR MDR cells, the steady-state Accumulation of [14C]daunorubicin was 30 and 12%, respectively, of that in the parent cells. When cells, at steady state, were permeabilized with digitonin, the amount of daunorubicin binding increased only in the resistant cells. The reduced Accumulation of daunorubicin in the SW-1573/2R120 and GLC4/ADR cells was accompanied by a lower initial (2 min) uptake rate of this Drug. No difference in initial efflux rate of daunorubicin from preloaded cells could be detected between sensitive and resistant SW-1573 cells. However, daunorubicin was extruded 5-fold faster from GLC4/ADR cells than from the parental cells. In the presence of the energy metabolism inhibitors sodium azide and deoxyglucose, the reduced daunorubicin Accumulations in the SW-1573/2R120 and GLC4/ADR MDR cells were (almost) completely reversed. The effects of these inhibitors on Drug uptake were already apparent during the earliest measured time points (
Joichi Kumazawa - One of the best experts on this subject based on the ideXlab platform.
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enhanced expression of gamma glutamylcysteine synthetase and glutathione s transferase genes in cisplatin resistant bladder cancer cells with multiDrug resistance phenotype
The Journal of Urology, 1997Co-Authors: Shuji Kotoh, Akira Yokomizo, Kimitoshi Kohno, Michihiko Kuwano, Seiji Naito, Joichi KumazawaAbstract:ABSTRACTPurpose: To elucidate the mechanisms of cisplatin resistance in human bladder cancer.Materials and Methods: After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various Drug resistance-related genes was examined.Results: KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multiDrug resistance. Decreased intracellular Drug Accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines.Conclusions: Multiple mechanisms, including decreased Drug Accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cispl...
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Enhanced Expression of gamma/Glutamylcysteine Synthetase and Glutathione S-transferase Genes in Cisplatin-Resistant Bladder Cancer Cells with MultiDrug Resistance Phenotype
The Journal of Urology, 1997Co-Authors: Shuji Kotoh, Akira Yokomizo, Kimitoshi Kohno, Michihiko Kuwano, Seiji Naito, Joichi KumazawaAbstract:ABSTRACTPurpose: To elucidate the mechanisms of cisplatin resistance in human bladder cancer.Materials and Methods: After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various Drug resistance-related genes was examined.Results: KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multiDrug resistance. Decreased intracellular Drug Accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines.Conclusions: Multiple mechanisms, including decreased Drug Accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cispl...
C. H. M. Versantvoort - One of the best experts on this subject based on the ideXlab platform.
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Altered MRP is associated with multiDrug resistance and reduced Drug Accumulation in human SW-1573 cells.
British journal of cancer, 1995Co-Authors: E. W. H. M. Eijdems, C. H. M. Versantvoort, Guido J.r. Zaman, M. De Haas, M. J. Flens, Rik J. Scheper, E. Kamst, P. Borst, Frank BaasAbstract:We have analysed the contribution of several parameters, e.g. Drug Accumulation, MDR1 P-glycoprotein (P-gp), multiDrug resistance-associated protein (MRP) and topoisomerase (topo) II, to Drug resistance in a large set of Drug-resistant variants of the human non-small-cell lung cancer cell line SW-1573 derived by selection with low concentrations of doxorubicin or vincristine. Selection with either Drug nearly always resulted in MDR clones. The resistance of these clones could be explained by reduced Drug Accumulation and was associated with a decrease rather than an increase in the low MDR1 mRNA level. To test whether a decrease in MDR1 mRNA indirectly affected resistance in these cells, we introduced a MDR1-specific hammerhead ribozyme into wild-type SW-1573 cells. Although this led to a substantial reduction in MDR1 mRNA, it did not result in resistance. In all resistant clones we found an altered form of the multiDrug resistance-associated protein (MRP), migrating slightly slower during SDS-polyacrylamide gel electrophoresis than MRP in parental cells. This altered MRP was also present in non-P-gp MDR somatic cell hybrids of the SW-1573 cells, demonstrating a clear linkage with the MDR phenotype. Treatment of crude cellular membrane fractions with N-glycanase, endoglycosidase H or neuraminidase showed that the altered migration of MRP on SDS-PAGE is due to a post-translational modification. There was no detectable difference in sialic acid content. In most but not all doxorubicin-selected clones, this MDR phenotype was accompanied by a reduction in topo II alpha mRNA level. No reduction was found in the clones selected with vincristine. We conclude from these results that selection of the SW-1573 cell line for low levels of doxorubicin or vincristine resistance, predominantly results in MDR with reduced Drug Accumulation associated with the presence of an altered MRP protein. This mechanism can be accompanied by other resistance mechanisms, such as reduced topo II alpha mRNA in case of doxorubicin selection.
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Genistein modulates the decreased Drug Accumulation in non-P-glycoprotein mediated multiDrug resistant tumour cells
British journal of cancer, 1993Co-Authors: C. H. M. Versantvoort, Gerrit Jan Schuurhuis, H.m. Pinedo, C.a. Eekman, C. M. Kuiper, Jan Lankelma, H.j. BroxtermanAbstract:In tumour cells the pharmacological basis for multiDrug resistance (MDR) often appears to be a reduced cellular cytostatic Drug Accumulation caused by the Drug efflux protein, P-glycoprotein (Pgp MDR), or by other Drug transporters (non-Pgp MDR). Here we report the reversal of the decreased daunorubicin (DNR) Accumulation in five non-Pgp MDR cell lines (GLC4/ADR, SW-1573/2R120, HT1080/DR4, MCF7/Mitox and HL60/ADR) by genistein. Genistein inhibited the enhanced DNR efflux in the GLC4/ADR cells. In these cells the decreased VP-16 Accumulation was also reversed by genistein. Three other (iso)flavonoids biochanin A, apigenin and quercetin also increased the DNR Accumulation in the GLC4/ADR cells. In contrast to the effects on non-Pgp MDR cells, 200 microM genistein did not increase the reduced DNR Accumulation in three Pgp MDR cell lines (SW-1573/2R160, MCF7/DOX40 and KB8-5) or in the parental cell lines. In conclusion the use of genistein provides a means to probe non-Pgp related Drug Accumulation defects.
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Energy-dependent processes involved in reduced Drug Accumulation in multiDrug-resistant human lung cancer cell lines without P-glycoprotein expression.
Cancer research, 1992Co-Authors: C. H. M. Versantvoort, C. M. Kuiper, H.j. Broxterman, Herbert M. Pinedo, E.g.e. De Vries, N. Feller, Jan LankelmaAbstract:Mechanisms contributing to reduced cytotoxic Drug Accumulation were studied in two multiDrug-resistant (MDR) human lung cancer cell lines without P-glycoprotein expression. In these (non-small cell) SW-1573/2R120 and (small cell) GLC4/ADR MDR cells, the steady-state Accumulation of [14C]daunorubicin was 30 and 12%, respectively, of that in the parent cells. When cells, at steady state, were permeabilized with digitonin, the amount of daunorubicin binding increased only in the resistant cells. The reduced Accumulation of daunorubicin in the SW-1573/2R120 and GLC4/ADR cells was accompanied by a lower initial (2 min) uptake rate of this Drug. No difference in initial efflux rate of daunorubicin from preloaded cells could be detected between sensitive and resistant SW-1573 cells. However, daunorubicin was extruded 5-fold faster from GLC4/ADR cells than from the parental cells. In the presence of the energy metabolism inhibitors sodium azide and deoxyglucose, the reduced daunorubicin Accumulations in the SW-1573/2R120 and GLC4/ADR MDR cells were (almost) completely reversed. The effects of these inhibitors on Drug uptake were already apparent during the earliest measured time points (
