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Platinum-acridinylthiourea conjugates show cell line-specific cytotoxic enhancement in H460 lung carcinoma cells compared to cisplatin

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Abstract

Recently, we reported a new class of DNA-targeted hybrid platinum-acridine agents. The parent intercalator, ACRAMTU, a 9-aminoacridine derivative, intercalates into the minor groove of DNA, causing the corresponding prototypical conjugate, PT-ACRAMTU (type I/n=2), to form DNA adducts dissimilar to traditional platinum drugs. Both these agents show cytotoxic activity in leukemic and ovarian cancer cells. Following the use of clonogenic survival assays, we report on the cytotoxic effects of ACRAMTU, PT-ACRAMTU, and three PT-ACRAMTU derivatives, on additional cell lines including colon (RKO), lung (H460), and cisplatin-sensitive (A2780) and cisplatin-resistant (A2780/CP) ovarian cells. While a dose-dependent effect was observed with both ACRAMTU and PT-ACRAMTU, an enhanced cytotoxic effect was seen with PT-ACRAMTU in all cell lines. PT-ACRAMTU appeared to have a similar IC50 value to cisplatin except in H460 lung cancer cells in which PT-ACRAMTU had a twofold lower IC50 value. PT-ACRAMTU appeared to act in a time-dependent manner. In H460 cells the IC50 value of PT-ACRAMTU was 235-fold higher following a 1-h incubation than following a 24-h incubation (0.27 μM), while following an 8-h incubation the IC50 value was 0.41 μM. Three derivatives of PT-ACRAMTU were also tested. A tetraalkylated derivative, type II/n=2, generated the highest IC50 values in all cell lines, while the trialkylated derivative, type III/n=2, generated IC50 values similar to its isomer, PT-ACRAMTU. PT-ACRAMTU with an added CH2 group in the thiourea linker (type I/n=3) showed IC50 values similar to the type I/n=2 prototype in H460 lung cells. An apoptotic response to PT-ACRAMTU appeared to be generated in H460 cells as evidenced by DNA laddering. These results suggest that type I/n=2 and type I/n=3 may be promising agents for the treatment of lung cancer and should be pursued in animal models.

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Abbreviations

ACRAMTU:

1-[2-(acridin-9-ylaminoethyl]-1,3-dimethylthiourea

PT-ACRAMTU:

[PtCl(en)(ACRAMTU)](NO3)2

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Acknowledgement

This study was supported in-part by a grant from the National Institutes of Health (R01 CA101880) and the Cross Campus Collaborative Research Fund of Wake Forest University.

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Authors and Affiliations

  1. Department of Radiation Oncology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA

    Suzanne M. Hess, Amanda M. Mounce & Russel C. Sequeira

  2. Department of Neurosurgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Suzanne M. Hess

  3. The Brain Tumor Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Suzanne M. Hess

  4. Comprehensive Cancer Center of Wake Forest University, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    Suzanne M. Hess & Ulrich Bierbach

  5. Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27109, USA

    Todd M. Augustus, Margaret C. Ackley & Ulrich Bierbach

Authors
  1. Suzanne M. Hess
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  2. Amanda M. Mounce
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  3. Russel C. Sequeira
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  4. Todd M. Augustus
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  5. Margaret C. Ackley
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  6. Ulrich Bierbach
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Correspondence to Ulrich Bierbach.

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Hess, S.M., Mounce, A.M., Sequeira, R.C. et al. Platinum-acridinylthiourea conjugates show cell line-specific cytotoxic enhancement in H460 lung carcinoma cells compared to cisplatin. Cancer Chemother Pharmacol 56, 337–343 (2005). https://doi.org/10.1007/s00280-004-0987-7

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  • DOI: https://doi.org/10.1007/s00280-004-0987-7

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