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Pharmacodynamics of Telomerase Inhibition and Telomere Shortening by Noncytotoxic Suramin

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Abstract

We reported that suramin is an effective chemosensitizer at noncytotoxic concentrations (<50 μM); this effect was observed in multiple types of human xenograft tumors in vitro and in vivo. Clinical evaluation of noncytotoxic suramin is ongoing. Because (a) suramin inhibits reverse transcriptase, (b) telomerase is a reverse transcriptase, and (c) inhibition of telomerase enhances tumor chemosensitivity, we studied the pharmacodynamics of noncytotoxic suramin on telomerase activity and telomere length in cultured cells and tumors grown in animals. In three human cancer cells that depend on telomerase for telomere maintenance (pharynx FaDu, prostate PC3, breast MCF7), suramin inhibited telomerase activity in cell extracts and intact cells at concentrations that exhibited no cytotoxicity (IC50 of telomerase was between 1 and 3 μM vs. >60 μM for cytotoxicity), and continuous treatment at 10–25 μM for 6 weeks resulted in gradual telomere shortening (maximum of 30%) and cell senescence (measured by β-galactosidase activity and elevation of mRNA levels of two senescence markers p16 and p21). In contrast, noncytotoxic suramin did not shorten the telomere in telomerase-independent human osteosarcoma Saos-2 cells. In mice bearing FaDu tumors, treatment with noncytotoxic suramin for 6 weeks resulted in telomere erosion in >95% of the tumor cells with an average telomere shortening of >40%. These results indicate noncytotoxic suramin inhibits telomerase, shortens telomere and induces cell senescence, and suggest telomerase inhibition as a potential mechanism of its chemosensitization.

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Abbreviations

CxT50 :

Concentration-time product (total drug exposure) for 50% effect

DC50 :

Drug concentration causing 50% cell death

FBS:

Fetal bovine serum

FISH:

Fluorescence in situ hybridization

IC50 :

50% inhibitory drug concentration

hTERT:

Reverse transcriptase component of human telomerase

hTR:

RNA component of human telomerase

MEM:

Minimum essential medium

PBS:

Phosphate-buffered saline

TALA:

Solution hybridization-based telomere amount and length assay

TRAP:

Telomeric repeat amplification protocol

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Acknowledgments

This study was supported in part by a research grant RO1CA77091 from the National Cancer Institute, NIH, DHHS.

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Authors and Affiliations

  1. College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio, 43210, USA

    Yuebo Gan, Jie Lu, Bertrand Z. Yeung, M. Guillaume Wientjes & Jessie L.-S. Au

  2. Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma, 73117, USA

    Bertrand Z. Yeung & Jessie L.-S. Au

  3. Optimum Therapeutics LLC, 9363 Towne Centre Drive, San Diego, California, 92121, USA

    Christopher T. Cottage, M. Guillaume Wientjes & Jessie L.-S. Au

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  1. Yuebo Gan
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  2. Jie Lu
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  3. Bertrand Z. Yeung
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  5. M. Guillaume Wientjes
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  6. Jessie L.-S. Au
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Correspondence to Jessie L.-S. Au.

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Gan, Y., Lu, J., Yeung, B.Z. et al. Pharmacodynamics of Telomerase Inhibition and Telomere Shortening by Noncytotoxic Suramin. AAPS J 17, 268–276 (2015). https://doi.org/10.1208/s12248-014-9703-7

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  • DOI: https://doi.org/10.1208/s12248-014-9703-7

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