Manipulation of Drug Accumulation: Mechanisms to Overcome Resistance

Tapiero, Haïm; Boulé, Dominique; Ittah-Corcos, Nicole; Fourcade, A

doi:10.1016/b978-0-12-763362-6.50028-5

Cited by 3 publications

(4 citation statements)

References 24 publications

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“…R123 is a P-glycoprotein substrate, and the flow cytometric determination of R123 uptake can serve as a functional assay for P-glycoprotein activity. 30,31 As shown in Table 2, 32 none of these parameters revealed significant correlations with the log 10 IC 50 values for ursolic acid and pomolic acid, indicating that their cellular sensitivity was not related to the expression of MDR1/ABCB1 or the activity of P-glycoprotein. For comparison, the established anticancer drug daunorubicin was used as a positive control.…”

Section: ■ Results and Discussionmentioning

confidence: 93%

“…We used the mRNA expression as determined by microarray hybridization or RT-PCR of the P-glycoprotein-encoding MDR1/ABCB1 gene as well as gain of DNA at the chromosomal locus 7p21 (where the MDR1/ABCB1 gene is located) and the intracellular rhodamine 123 (R123) accumulation rates. R123 is a P-glycoprotein substrate, and the flow cytometric determination of R123 uptake can serve as a functional assay for P-glycoprotein activity. , As shown in Table , none of these parameters revealed significant correlations with the log 10 IC 50 values for ursolic acid and pomolic acid, indicating that their cellular sensitivity was not related to the expression of MDR1/ABCB1 or the activity of P-glycoprotein. For comparison, the established anticancer drug daunorubicin was used as a positive control.…”

Section: Resultsmentioning

confidence: 99%

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Pharmacogenomic Characterization of Cytotoxic Compounds from Salvia officinalis in Cancer Cells

Kadioglu

Efferth

2015

J. Nat. Prod.

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Salvia officinalis is used as a dietary supplement with diverse medicinal activity (e.g. antidiabetic and antiatherosclerotic effects). The plant also exerts profound cytotoxicity toward cancer cells. Here, we investigated possible modes of action to explain its activity toward drug-resistant tumor cells. Log10IC50 values of two constituents of S. officinalis (ursolic acid, pomolic acid) were correlated to the expression of ATP-binding cassette (ABC) transporters (P-glycoprotein/ABCB1/MDR1, MRP1/ABCC1, BCRP/ABCG2) and epidermal growth factor receptor (EGFR) or mutations in RAS oncogenes and the tumor suppressor gene TP53 of the NCI panel of cell lines. Gene expression profiles predicting sensitivity and resistance of tumor cells to these compounds were determined by microarray-based mRNA expressions, COMPARE, and hierarchical cluster analyses. Furthermore, the binding of both plant acids to key molecules of the NF-κB pathway (NF-κB, I-κB, NEMO) was analyzed by molecular docking. Neither expression nor mutation of ABC transporters, oncogenes, or tumor suppressor genes correlated with log10IC50 values for ursolic acid or pomolic acid. In microarray analyses, many genes involved in signal transduction processes correlated with cellular responsiveness to these compounds. Molecular docking indicated that the two plant acids strongly bound to target proteins of the NF-κB pathway with even lower free binding energies than the known NF-κB inhibitor MG-132. They interacted more strongly with DNA-bound NF-κB than free NF-κB, pointing to inhibition of DNA binding by these compounds. In conclusion, the lack of cross-resistance to classical drug resistance mechanisms (ABC-transporters, oncogenes, tumor suppressors) may indicate a promising role of the both plant acids for cancer chemotherapy. Genes involved in signal transduction may contribute to the sensitivity or resistance of tumor cells to ursolic and pomolic acids. Ursolic and pomolic acid may target different steps of the NF-κB pathway to inhibit NF-κB-mediated functions.

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Section: ■ Results and Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Pharmacogenomic Characterization of Cytotoxic Compounds from Salvia officinalis in Cancer Cells

Kadioglu

Efferth

2015

J. Nat. Prod.

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“…In favour of this approach is also the great difficulty in obtaining in vitro resistance to ACLA that has been described from different groups. Tapiero et al (1988) took 3 years to obtain a 6-fold ACLA resistant cell line, whereas a 100-fold ADR resistant cell line was obtained in a month. Likewise, Nishimura et al (1980) tried without success to isolate ACLA resistant cells in vitro.…”

Section: -65 -mentioning

confidence: 99%

In vitro evaluation of the potential of aclarubicin in the treatment of small cell carcinoma of the lung (SCCL)

Pb¹,

Vindeløv²,

Roed³

et al. 1989

Br J Cancer

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Summary The sensitivity of eight cell lines established from treated and untreated patients with small cell carcinoma of the lung (SCCL) was tested in the clonogenic assay with 1 h and continuous exposure to aclarubicin (ACLA), adriamycin (ADR), daunorubicin (DAU) and mitoxantrone (MITO). The sensitivity to ADR, DAU and MITO covariated, and varied with a factor of five. The sensitivity to ACLA was independent of the sensitivity to ADR and varied only within a factor of two. Only ACLA showed pronounced increased potency with continuous incubation, and ACLA was the most potent drug in the three cell lines least sensitive to ADR. Two resistant cell lines were selected by treating NCI-H69 in vitro with DAU. One cell line (9-fold resistant to DAU) expressed large amounts of P-glycoprotein, the other cell line (4-fold resistant to DAU) had barely detectable glycoprotein. Both lines acquired resistance to ADR, ACLA and MITO. The cross-resistance to ACLA and MITO was only partial and ACLA was still the most potent drug on these lines. The sensitivity to ACLA of the cell lines least sensitive to ADR suggest that ACLA partially circumvents mechanisms of multidrug resistance. Together with the pronounced increase in potency with prolonged exposure, these results suggest that ACLA has a mechanism of action different from the 'classical' anthracyclines. In this context mitoxantrone is more similar to the classical anthracyclines although its structure is more dissimilar.The anthracyclines are among the most potent drugs in the treatment of a wide range of human neoplasms. Development of resistance to the drugs is a major problem, and much effort is devoted to the search of new anthracyclines without cross-resistance to the parent drugs. The anthracycline aclarubicin (ACLA) was isolated in 1975 by Oki et al. (1975) and activitiy was found in acute myelogenic leukaemia (AML) refractory to treatment with daunorubicin (DAU) and cytarbine (Pedersen-Bjergaard et al., 1984; Warrel et al., 1982). Recently, a phase III trial has found ACLA to be superior to DAU in the treatment of de novo AML (Hansen et al., 1988). In a previous study on the inter-experimental variation in the clonogenic assay we observed that the sensitivity pattern to ACLA in a panel of small cell lung cancer (SCCL) cell lines was different from the sensitivity to adriamycin (ADR), DAU and mitoxantrone (MITO) after short time incubation (Jensen et al., 1989). The present investigations were initiated to further elucidate the differences between ACLA and the other analogues. A murine tumour has recently been described to be relatively more sensitive to MITO than the tested human tumours (Hill et al., 1989). The murine tumour cells P388 and Ehrlich were included in the present study for comparision to the human cell lines and the in vivo antitumour models. As the relationship between duration of drug exposure and cytotoxicity can give valuable information on mechanisms of toxicity (Roed et al., 1986), the patterns of sensitivity to ACLA, ADR, DAU and MITO after shor...

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“…While they do not refer particularly to a nuclear pump, in studies by Tapiero, Boule et al 22 with a variety of anticancer anthracyclines drug resistance is partly explained by outward transport: prevention of such transport by verapamil enhances drug action. These studies point to a cellular pump with no elaboration of the structures involved, but the direct observation of sequential localizations obtained with fluorescent xenobiotics and inferences, from what is known of nucleo-cytoplasmic channels, raises the possibility of a nuclear pump.…”

Section: Discussionmentioning

confidence: 95%

Spatiotemporal Mapping Of Fluorescence Paramaters In Single Living Cells The Cell's Detoxification Apparatus

et al. 1988

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Our studies with quinacrine and benzo(a)pyrene suggest the formation of a multiorganelle detoxification complex (MODC) involving the endoplasmic reticulum, the Golgi apparatus, the lysosomes and the nuclear membrane.We have indications that not only is there a trapping of xenobiotics in the cytoplasmic components of the MODC, but there may also be a "nuclear pump" powered by postulated nuclear bioenergetic pathways involved in the ejection of these chemicals from the nucleus. We are using the microspectrofluorometric approach to study the extranuclear /nuclear energy metabolism related to these processes, and we have extended this method to investigate, in situ, within different components of the MODC, the blue /red spectral shifts associated with metabolites of fluorescent xenobiotics.Recording of fluorescence emission spectra, at different excitation wavelengths in L cells, allows the application of multivariate statistical methods to analyze complex (multicomponent spectra). Eluciadation of mechanisms, involved in the organization and activity of the MODC, can result in better targeting of gene modifiers and DNA -intercalating cancer chemotherapeutics towards their expected sites of action.

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Manipulation of Drug Accumulation: Mechanisms to Overcome Resistance

Cited by 3 publications

References 24 publications

Pharmacogenomic Characterization of Cytotoxic Compounds from Salvia officinalis in Cancer Cells

Pharmacogenomic Characterization of Cytotoxic Compounds from Salvia officinalis in Cancer Cells

In vitro evaluation of the potential of aclarubicin in the treatment of small cell carcinoma of the lung (SCCL)

Spatiotemporal Mapping Of Fluorescence Paramaters In Single Living Cells The Cell's Detoxification Apparatus

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