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Additional Supporting Information may be found in the online version of this article.

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IJC_25295_sm_suppfigure-1.tif22060KSupplementary Figure 1. Statins inhibit the isoprenylation of Rap1, a surrogate assay for statin uptake and HMGCR inhibition. Total protein (25 μg) from lysed A2780ADR cells treated with 20 μM statins for up to 24 h was subjected to immunoblotting for Rap1. The full-length blot shown is representative of at least three independent experiments. lova, lovastatin; atorva, atorvastatin; fluva, fluvastatin; rosuva, rosuvastatin.
IJC_25295_sm_suppfigure-2.tif19812KSupplementary Figure 2. Statins do not alter doxorubicin accumulation in parental cells. Cells were treated as indicated for 3 h and intracellular doxorubicin fluorescence was detected by flow cytometry. Relative intracellular doxorubicin fluorescence was determined by normalizing all values to that of cells treated with doxorubicin alone (normalized to 1). In all panels, bars represent the mean of at least four independent experiments, with error bars indicating standard deviation. doxo, doxorubicin.
IJC_25295_sm_suppfigure-3.tif19810KSupplementary Figure 3. Lovastatin, but not all statins, modulates doxorubicin transport in additional MDR tumor cell lines. Cells were treated as indicated for 3 h and intracellular doxorubicin fluorescence was detected by flow cytometry. Relative intracellular doxorubicin fluorescence was determined by normalizing all values to that of cells treated with doxorubicin alone. A. Only lovastatin significantly increases intracellular doxorubicin accumulation in additional MDR tumor cell lines. p-values shown denote statistically significant differences from cells treated with doxorubicin alone (normalized to 1) by one-sample t-test. B. The effect of lovastatin is independent of inhibition of the MVA pathway. The p-values shown represent results from two-sample t-tests between bracketed groups. C. Lovastatin is less potent than CsA at inhibiting doxorubicin transport mediated by MDR drug transporters. The p-values shown represent results from two-sample t-tests between bracketed groups. In all panels, bars represent the mean of at least four independent experiments, with error bars indicating standard deviation. doxo, doxorubicin; lova, lovastatin; MVA, mevalonate; CsA, cyclosporin A.
IJC_25295_sm_suppfigure-4.tif12218KSupplementary Figure 4. Lovastatin synergizes with doxorubicin in an MDR cell line. Combination index analysis of MTT assay data gathered from parental A2780 cells treated with lovastatin and doxorubicin alone, and both drugs in combination, reveals no significant difference from an additive effect (CI=1) in the combination treatment. In the MDR A2780ADR cells, similar treatments reveal a synergistic interaction (CI<1) between lovastatin and doxorubicin. Bars represent the mean CI, from at least four independent experiments, at a given MTT reduction inhibitory concentration value, with error bars representing standard deviation. The p-values shown represent results testing differences from additivity (CI=1) by one-sample t-test.
IJC_25295_sm_suppinfotables.doc55KSupplementary Table 1. Sensitivity of human parental and multidrug-resistant tumor cell lines to doxorubicin by MTT assay. Supplementary Table 2. Coefficients from General Linear Modeling of Statin:Doxo interactions.

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