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First published on June 6, 2005; DOI: 10.1124/mol.105.011494

0026-895X/05/6803-779-786$20.00
Mol Pharmacol 68:779-786, 2005

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Pharmacological Telomerase Inhibition Can Sensitize Drug-Resistant and Drug-Sensitive Cells to Chemotherapeutic Treatment

Ryan J. Ward, and Chantal Autexier

Faculty of Medicine, Department of Anatomy and Cell Biology (C.A.) and Division of Experimental Medicine (R.J.W., C.A.), McGill University, Montréal, Québec, Canada; and Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Canada (R.J.W., C.A.)

Effective strategies to reverse or prevent chemotherapeutic resistance are required before cancer therapies can be curative. Telomerase is the ribonucleoprotein responsible for de novo synthesis and maintenance of telomeres, and its activity is predominantly observed in cancer cells. The telomerase enzyme has been successfully inhibited or inactivated to sensitize cells to cellular stresses; however, no studies have determined yet the effect of combining a pharmacological inhibitor of telomerase catalysis and traditional chemotherapeutics for the treatment of drug-sensitive or drug-resistant cancers. Here, we describe the effect of 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small-molecule inhibitor of telomerase catalytic activity, on drug-resistant leukemia and breast cancer cells and their parental counterparts when treated in combination with chemotherapeutics. We observed that BIBR1532-treated cells show progressive telomere shortening, decreased proliferative capacity, and sensitization to chemotherapeutic treatment. These effects are telomere length-dependent, because cells insensitive to BIBR1532 or cells released from telomerase inhibition did not demonstrate changes in growth ability or drug sensitivity. Our novel observations suggest that pharmacological telomerase inhibition in combination therapy may be a valid strategy for the treatment of both drug-sensitive and drug-resistant cancers.

Received January 27, 2005; accepted June 6, 2005

Address correspondence to: Dr. Chantal Autexier, Bloomfield Centre for Research in Aging, Sir Mortimer B. Davis Jewish General Hospital, 3755 Rue Cote Sainte-Catherine, Montréal, Québec, Canada, H3T 1E2. E-mail: chantal.autexier{at}mcgill.ca




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 Molecular Cancer TherapeuticsHome page
M. A. Cerone, J. A. Londono-Vallejo, and C. Autexier
Telomerase inhibition enhances the response to anticancer drug treatment in human breast cancer cells.
Mol. Cancer Ther., July 1, 2006; 5(7): 1669 - 1675.
[Abstract] [Full Text] [PDF]


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