Induction of Multidrug Resistance in Human Cells by Transient Exposure to Different Chemotherapeutic Drugs

Chaudhary, Preet M.; Roninson, Igor B.

doi:10.1093/jnci/85.8.632

Cited by 327 publications

(197 citation statements)

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“…anthracyclines, vinca alkaloids, podophylotoxins, colchicine) structurally dissimilar and having different intracellular targets constitutes the major problem in cancer therapy (Chaudhary and Roninson, 1993). The MDR transporters (e.g.…”

Section: Discussionmentioning

confidence: 99%

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

et al. 2005

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Clinical usefulness of doxorubicin (DOX) is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1) responsible for the active efflux of drugs out of resistant cells. Doxorubicin is a well-known bioreductive antitumour drug. Its ability to undergo a one-electron reduction by cellular oxidoreductases is related to the formation of an unstable semiquionone radical and followed by the production of reactive oxygen species. There is an increasing body of evidence that the activation of bioreductive drugs could result in the alkylation or crosslinking binding of DNA and lead to the significant increase in the cytotoxic activity against tumour cells. The aim of this study was to examine the role of reductive activation of DOX by the human liver NADPH cytochrome P450 reductase (CPR) in increasing its cytotoxic activity especially in regard to MDR tumour cells. It has been evidenced that, upon CPR catalysis, DOX underwent only the redox cycling (at low NADPH concentration) or a multistage chemical transformation (at high NADPH concentration). It was also found, using superoxide dismutase (SOD), that the first stage undergoing reductive activation according to the mechanism of the redox cycling had the key importance for the metabolic conversion of DOX. In the second part of this work, the ability of DOX to inhibit the growth of human promyelocytic-sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. Our assays showed that the presence of CPR catalysing only the redox cycling of DOX had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of DOX after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells.

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Section: Discussionmentioning

confidence: 99%

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

et al. 2005

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“…This method of detection, therefore, is not sufficiently sensitive to detect gene expression in the majority of clinical osteosarcoma specimens which express the gene in lower levels more similar to KB8 cells. In (Chaudhary and Roninson, 1993). Induction of MDR1 mRNA was evaluated in the present study by determining expression levels before and after the administration of adjuvant multidrug regimes that invariably included doxorubicin.…”

Section: Resultsmentioning

confidence: 99%

“…We have used this assay to address the question of whether MDR1 expression varies with location within the tumour by determining the level of MDR1 mRNA expression in multiple specimens collected from different sites of the same primary tumour. It has been shown that MDR1 expression may be induced in cell lines following transient exposure to chemotherapeutic agents (Chaudhary and Roninson, 1993). To investigate whether MDR1 levels in osteosarcoma specimens could be increased by chemotherapy, we analysed specimens collected from tumours both before and after chemotherapy.…”

mentioning

confidence: 99%

Quantitative analysis of multidrug resistance gene expression in human osteosarcomas

Lee

Noble-Topham²,

Bell³

et al. 1996

Br J Cancer

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Summary We evaluated the MDR1 expression levels in 77 osteosarcomas and investigated whether MDR1 mRNA expression in osteosarcomas varies with location within the tumour, following chemotherapy, or after metastasis. We modified the semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assay to determine accurately the levels of MDR1 mRNA expression in clinical specimens. We show that specimens collected from multiple locations in six tumours revealed very little variation in MDR1 expression suggesting that the levels of MDR1 in these tumours do not vary greatly with location within the tumour mass. In a comparison of pre and post-chemotherapy specimens it was found that MDR1 levels did not change appreciably following chemotherapy in 16 of 20 cases. In addition, in eight of ten specimens obtained before and after metastasis, the amount of MDR1 mRNA was found to remain relatively constant despite metastatic spread. Thus, many osteosarcomas exhibited intrinsic expression of MDRI mRNA before multidrug regimens which invariably included doxorubicin and, in most cases, MDR1 expression was not induced following chemotherapeutic treatment. Our results suggest that some osteosarcoma patients may have primary tumours which are resistant to doxorubicin. These individuals may benefit from different chemotherapeutic regimens, e.g. the addition of MDR reversal agents.

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Section: Discussionmentioning

confidence: 99%

“…YB-1 plays a significant role in the mediation of chemoresistance in many cancers, primarily by mechanisms involving mdr1 expression 13,27,28 and increased potential of DNA repair by molecules such as DNA topoisomerase. 28 There is also evidence that YB-1 binds specifically to RNA containing 8-oxoguanine, cisplatin-modified and apurinic DNA and interacts with proliferating cell nuclear antigen and p53, enhancing DNA repair. [29][30][31] Recent biomarkers evaluated for predicting radiosensitivity and chemosensitivity in nasopharyngeal cancer include heat-shock protein Gp96 (HSP Gp96), growth differentiation factor 15 (GDF15), basic helixloop-helix transcription factor TWIST, cytokeratin 8 (CK 8), latent membrane protein-1 (LMP-1) and inhibitor of differentiation/DNA-binding 1 (Id-1).…”

Section: Discussionmentioning

confidence: 99%

Y-Box-binding protein-1 is a promising predictive marker of radioresistance and chemoradioresistance in nasopharyngeal cancer

et al. 2009

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The Y-Box-binding protein-1, a member of the cold-shock domain DNA-and RNA-binding protein superfamily, is known to mediate chemoresistance. The aim of this study was to determine the expression of Y-Box- Y-Box-binding protein-1 immunostaining was observed to be predominantly cytoplasmic. A higher recurrence of nasopharyngeal cancer was found in patients whose tissues had increased Y-Box-binding protein-1 expression (Po0.001). The Cox proportionate hazard regression model also established that high Y-Box-binding protein-1 immunoreactivity was significantly correlated with increased risk (2.13 times) of recurrence as compared to low Y-Box-binding protein-1 immunoreactivity (P ¼ 0.01). Within groups of patients treated by radiotherapy or chemoradiotherapy, recurrent cases had significantly higher Y-Box-binding protein-1 expression than nonrecurrent cases (Po0.001 and P ¼ 0.0035, respectively). These data suggest that Y-Box-binding protein-1 expression has clinicopathological significance with potential as a predictive marker of recurrence in nasopharyngeal cancer patients who undergo radiotherapy or chemoradiotherapy.

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Induction of Multidrug Resistance in Human Cells by Transient Exposure to Different Chemotherapeutic Drugs

Abstract: Induction of MDR1 expression in response to cellular damage may account for increased MDR1 expression in treated human tumors. Protein kinase inhibitors may be useful in preventing the emergence of multidrug resistance during cancer chemotherapy.

Cited by 327 publications

References 0 publications

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

Quantitative analysis of multidrug resistance gene expression in human osteosarcomas

Y-Box-binding protein-1 is a promising predictive marker of radioresistance and chemoradioresistance in nasopharyngeal cancer

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