The AAPS Journal

, Volume 17, Issue 1, pp 268–276 | Cite as

Pharmacodynamics of Telomerase Inhibition and Telomere Shortening by Noncytotoxic Suramin

  • Yuebo Gan
  • Jie Lu
  • Bertrand Z. Yeung
  • Christopher T. Cottage
  • M. Guillaume Wientjes
  • Jessie L.-S. Au
Research Article

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.

Key words

noncytotoxic suramin pharmacodynamics senescence telomerase telomere 

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

Notes

Acknowledgments

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

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Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Yuebo Gan
    • 1
  • Jie Lu
    • 1
  • Bertrand Z. Yeung
    • 1
    • 2
  • Christopher T. Cottage
    • 3
  • M. Guillaume Wientjes
    • 1
    • 3
  • Jessie L.-S. Au
    • 1
    • 2
    • 3
  1. 1.College of PharmacyThe Ohio State UniversityColumbusUSA
  2. 2.Department of Pharmaceutical SciencesUniversity of OklahomaOklahoma CityUSA
  3. 3.Optimum Therapeutics LLCSan DiegoUSA

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