Telomerase inhibition and cell growth arrest after telomestatin treatment in multiple myeloma.
OBJECTIVE
The aim of this study was to test the efficacy of telomestatin, an intramolecular G-quadruplex intercalating drug with specificity for telomeric sequences, as a potential therapeutic agent for multiple myeloma.


METHODS
We treated ARD, ARP, and MM1S myeloma cells with various concentrations of telomestatin for 7 days and evaluated for telomerase activity. Myeloma cells were treated with the minimal effective telomestatin concentration for 3-5 weeks. Every 7(th) day the fraction of live cells was determined by trypan blue exclusion, aliquots of cells were removed for various molecular assays, and the remaining cells were replated at the same cell number and at the same concentration of telomestatin. Telomere length, apoptosis, and gene expression changes were monitored as described in detail in "Materials and Methods."


RESULTS
Telomestatin treatment led to inhibition of telomerase activity, reduction in telomere length, and apoptotic cell death in ARD, MM1S, and ARP myeloma cells. Gene expression profile after 1 and 7 days of telomestatin treatment revealed >/==" BORDER="0">2-fold change in only 6 (0.027%) and 51 (0.23%) of 33,000 genes surveyed, respectively. No changes were seen in expression of genes involved in cell cycle, apoptosis, DNA repair, or recombination.


CONCLUSIONS
These results demonstrate that telomestatin exerts its antiproliferative and proapoptotic effects in myeloma cells via inhibition of telomerase and subsequent reduction in telomere length. We conclude that telomerase is an important potential therapeutic target for multiple myeloma therapy, and G-quadruplex interacting agents with specificity for binding to telomeric sequences can be important agents for additional evaluation.
Shammas
Masood A
MA
Boston VA Health Care System, Boston, Massachusetts, USA.
Shmookler Reis
Robert J
RJ
Li
Cheng
C
Koley
Hemanta
H
Hurley
Laurence H
LH
Anderson
Kenneth C
KC
Munshi
Nikhil C
NC
D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010080:Oxazoles / Q000494:pharmacology*; D011995:Recombination, Genetic; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D013997:Time Factors
D010080:Oxazoles; C431888:telomestatin; D019098:Telomerase