Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma

Masood A. Shammas, Robert J. Shmookler Reis, Masaharu Akiyama, Hemanta Koley, Dharminder Chauhan, Teru Hideshima, Raj K. Goyal, Laurence Hurley, Kenneth C. Anderson, Nikhil C. Munshi

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Abstract

Objective: The aim of this study was to test the efficacy of telomerase inhibitor (TMPyP4 [tetra( N-methyl-4-pyridyl)-porphyrin chloride]; a G-quadruplex-intercalating porphyrin) as a potential therapeutic agent for multiple myeloma. Materials and Methods: We studied telomere length, telomerase activity, and effect of telomerase inhibition in multiple myeloma cells. Several myeloma cell lines were analyzed for telomerase activity, telomere length, and gene expression. Three myeloma cell lines (U266, ARH77, and ARD) were treated with TMPyP4 for 3-4 weeks. Viable cell number was assessed by trypan blue exclusion, and nature of cell death was determined by annexin labeling and/or DNA fragmentation. In situ oligo ligation technique was used to identify specific DNase I-type DNA cleavage. Results: We report high telomerase activity and shortened telomeres in myeloma cells compared to normal B cells. We have also observed inhibition of telomerase activity, reduction in telomere length, and decline of myeloma cell growth, as measured by trypan blue dye exclusion, following exposure to TMPyP4. Exposure to porphyrin reduced telomerase activity of U266, ARH77, and ARD myeloma cells by 98%, 92%, and 99%, respectively. Exposure to porphyrin had no effect on viability for the first 14 days, followed by death of 75-90% of cells over the next 2 weeks. The nature of cell death was apoptotic, as determined by annexin and DNA nick labeling. Majority of cells showed DNA fragmentation specific to caspase-3-activated DNase I. Conclusions: These results demonstrate antiproliferative activity of G-quadruplex- intercalating agents, and suggest telomerase as an important therapeutic target for myeloma therapy.

Original languageEnglish (US)
Pages (from-to)825-833
Number of pages9
JournalMolecular Cancer Therapeutics
Volume2
Issue number9
StatePublished - Sep 2003

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G-Quadruplexes
Telomerase
Multiple Myeloma
Porphyrins
Growth
Telomere
Annexins
Trypan Blue
Deoxyribonuclease I
DNA Fragmentation
Cell Death
Intercalating Agents
Telomere Shortening
Single-Stranded DNA Breaks
Cell Line
DNA Cleavage
Caspase 3
Ligation
Chlorides
B-Lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Shammas, M. A., Shmookler Reis, R. J., Akiyama, M., Koley, H., Chauhan, D., Hideshima, T., ... Munshi, N. C. (2003). Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma. Molecular Cancer Therapeutics, 2(9), 825-833.

Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma. / Shammas, Masood A.; Shmookler Reis, Robert J.; Akiyama, Masaharu; Koley, Hemanta; Chauhan, Dharminder; Hideshima, Teru; Goyal, Raj K.; Hurley, Laurence; Anderson, Kenneth C.; Munshi, Nikhil C.

In: Molecular Cancer Therapeutics, Vol. 2, No. 9, 09.2003, p. 825-833.

Research output: Contribution to journalArticle

Shammas, MA, Shmookler Reis, RJ, Akiyama, M, Koley, H, Chauhan, D, Hideshima, T, Goyal, RK, Hurley, L, Anderson, KC & Munshi, NC 2003, 'Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma', Molecular Cancer Therapeutics, vol. 2, no. 9, pp. 825-833.
Shammas MA, Shmookler Reis RJ, Akiyama M, Koley H, Chauhan D, Hideshima T et al. Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma. Molecular Cancer Therapeutics. 2003 Sep;2(9):825-833.
Shammas, Masood A. ; Shmookler Reis, Robert J. ; Akiyama, Masaharu ; Koley, Hemanta ; Chauhan, Dharminder ; Hideshima, Teru ; Goyal, Raj K. ; Hurley, Laurence ; Anderson, Kenneth C. ; Munshi, Nikhil C. / Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma. In: Molecular Cancer Therapeutics. 2003 ; Vol. 2, No. 9. pp. 825-833.
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abstract = "Objective: The aim of this study was to test the efficacy of telomerase inhibitor (TMPyP4 [tetra( N-methyl-4-pyridyl)-porphyrin chloride]; a G-quadruplex-intercalating porphyrin) as a potential therapeutic agent for multiple myeloma. Materials and Methods: We studied telomere length, telomerase activity, and effect of telomerase inhibition in multiple myeloma cells. Several myeloma cell lines were analyzed for telomerase activity, telomere length, and gene expression. Three myeloma cell lines (U266, ARH77, and ARD) were treated with TMPyP4 for 3-4 weeks. Viable cell number was assessed by trypan blue exclusion, and nature of cell death was determined by annexin labeling and/or DNA fragmentation. In situ oligo ligation technique was used to identify specific DNase I-type DNA cleavage. Results: We report high telomerase activity and shortened telomeres in myeloma cells compared to normal B cells. We have also observed inhibition of telomerase activity, reduction in telomere length, and decline of myeloma cell growth, as measured by trypan blue dye exclusion, following exposure to TMPyP4. Exposure to porphyrin reduced telomerase activity of U266, ARH77, and ARD myeloma cells by 98{\%}, 92{\%}, and 99{\%}, respectively. Exposure to porphyrin had no effect on viability for the first 14 days, followed by death of 75-90{\%} of cells over the next 2 weeks. The nature of cell death was apoptotic, as determined by annexin and DNA nick labeling. Majority of cells showed DNA fragmentation specific to caspase-3-activated DNase I. Conclusions: These results demonstrate antiproliferative activity of G-quadruplex- intercalating agents, and suggest telomerase as an important therapeutic target for myeloma therapy.",
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AU - Chauhan, Dharminder

AU - Hideshima, Teru

AU - Goyal, Raj K.

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AU - Anderson, Kenneth C.

AU - Munshi, Nikhil C.

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