Modulation of the reversibility of actinomycin D cytotoxicity in HeLa cells by verapamil

Yung, Benjamin Yat‐Ming; Chang, Fin-Junga; Bor, Amy Meei-Shuu

doi:10.1016/0304-3835(91)90117-z

Cited by 7 publications

(4 citation statements)

References 7 publications

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“…7-Amino ACTD and its derivatives are DNA-binding antitumor agents that act in vivo by inhibiting DNA dependent RNA polymerase activities ( , ). Structural studies and footprinting results have shown that the planar chromophore portions of 7-amino ACTD intercalate into 5‘GpC3‘ sequences via the minor groove.…”

Section: Resultsmentioning

confidence: 99%

Enthalpy/Entropy Compensation: Influence of DNA Flanking Sequence on the Binding of 7-Amino Actinomycin D to Its Primary Binding Site in Short DNA Duplexes

Ren

Riccelli

et al. 2003

Biochemistry

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The effect of the context of the flanking sequence on ligand binding to DNA oligonucleotides that contain consensus binding sites was investigated for the binding of the intercalator 7-amino actinomycin D. Seven self-complementary DNA oligomers each containing a centrally located primary binding site, 5'-A-G-C-T-3', flanked on either side by the sequences (AT)(n) or (AA)(n) (with n = 2, 3, 4) and AA(AT)(2), were studied. For different flanking sequences, (AA)(n)-series or (AT)(n)-series, differential fluorescence enhancements of the ligand due to binding were observed. Thermodynamic studies indicated that the flanking sequences not only affected DNA stability and secondary structure but also modulated ligand binding to the primary binding site. The magnitude of the ligand binding affinity to the primary site was inversely related to the sequence dependent stability. The enthalpy of ligand binding was directly measured by isothermal titration calorimetry, and this made it possible to parse the binding free energy into its energetic and entropic terms. Our results reveal a pronounced enthalpy-entropy compensation for 7-amino actinomycin D binding to this family of oligonucleotides and suggest that the DNA sequences flanking the primary binding site can strongly influence ligand recognition of specific sites on target DNA molecules.

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Section: Resultsmentioning

confidence: 99%

Enthalpy/Entropy Compensation: Influence of DNA Flanking Sequence on the Binding of 7-Amino Actinomycin D to Its Primary Binding Site in Short DNA Duplexes

Ren

Riccelli

et al. 2003

Biochemistry

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“…Since none of the transcription factors tested was linked to the Src pathway, we next asked whether Src kinases require DNA transcription to transmit the scattering response. To address this question, cells were treated with actinomycin D for 30 min, leading to irreversible inhibition of RNA synthesis from chromosomal DNA (Yung et al ., 1990). Four hours after the removal of the drug, cells were injected with plasmids encoding an active form of Src (F527Src) or Ras (L61Ras).…”

Section: Resultsmentioning

confidence: 99%

Src and Ras are involved in separate pathways in epithelial cell scattering

Boyer

Roche

Denoyelle

et al. 1997

EMBO J

135

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We have demonstrated previously that Src controls the epidermal growth factor (EGF)‐induced dispersion of NBT‐II carcinoma epithelial cells. Here we show that while only Src and Yes were expressed and activated by EGF, microinjected kinase‐inactive mutants of Src (SrcK−) and Fyn (FynK−) were able to exert a dominant‐negative effect on the scattering response. Both SH2 and SH3 domains of FynK− were required for inhibition of cell scattering. Expression of dominant‐negative N17Ras also abrogated EGF‐induced dispersion, showing that Ras is another regulator of cell dispersion. Expression of SrcK− did not alter EGF‐evoked Shc tyrosine phosphorylation, Shc–Grb2 complex formation and MAPK activation, three elements of the Ras pathway. Furthermore, the expression of Jun–Fos and Slug rescued the block induced by N17Ras but not by SrcK−, showing that Src kinases and Ras operate in separate pathways. In addition, actinomycin D inhibition of RNA synthesis repressed the ability of the activated mutant L61Ras but not that of F527Src to induce epithelial cell scattering. Since tyrosine phosphorylation of cytoskeleton‐associated proteins pp125FAK and cortactin were abolished in EGF‐stimulated SrcK− cells, we concluded that, in contrast to Ras, Src kinases may control epithelial cell dispersion in the absence of gene expression and by directly regulating the organization of the cortical cytoskeleton.

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“…In the dominant mechanism, intracellular levels of cytotoxic drugs are reduced below lethal thresholds by active extrusion of the cytotoxic drug(s) from the tumor cell, operated by ATP-dependent pumps such as P-glycoprotein and multidrug resistance-associated protein (1)(2)(3)(4)(5)(6)(7). Inhibition of the extrusion is a main approach to overturn MDR (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine Inhibits Multidrug Resistance Extrusion Pumps and Enhances Responses to Chemotherapy in Syngeneic and in Human Xenograft Mouse Tumor Models

et al. 2004

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Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10-to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2-to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.

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Modulation of the reversibility of actinomycin D cytotoxicity in HeLa cells by verapamil

Cited by 7 publications

References 7 publications

Enthalpy/Entropy Compensation: Influence of DNA Flanking Sequence on the Binding of 7-Amino Actinomycin D to Its Primary Binding Site in Short DNA Duplexes

Enthalpy/Entropy Compensation: Influence of DNA Flanking Sequence on the Binding of 7-Amino Actinomycin D to Its Primary Binding Site in Short DNA Duplexes

Src and Ras are involved in separate pathways in epithelial cell scattering

Fluoxetine Inhibits Multidrug Resistance Extrusion Pumps and Enhances Responses to Chemotherapy in Syngeneic and in Human Xenograft Mouse Tumor Models

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