Telomerase as a new target for the treatment of hormone-refractory prostate cancer

Abstract

Prostate cancer is the leading cause of cancer-related deaths in men. Androgen ablation is the mainstay of treatment for advanced prostate cancer. This therapy is very effective in androgen-dependent cancer; however, these cancers eventually become androgen independent, rendering anti-androgen therapy ineffective. The exploration of novel modalities of treatment is therefore essential to improve the prognosis of this neoplasia.Telomeres are specialized heterochromatin structures that act as protective caps at the ends of chromosomes. Telomere maintenance in the majority of tumor cells is achieved by telomerase, a reverse transcriptase enzyme that catalyzes the synthesis of further telomeric DNA. Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue. Moreover, the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of telomerase, is regulated by androgens as well as by different oncogenes including Her-2, Ras, c-Myc and Bcl-2, which seem to play an important role in prostate cancer progression. Thus, telomerase may represent a very good candidate for targeted therapy in prostate tumors. To inhibit telomere maintenance by telomerase, approaches that directly target either telomerase and telomeres or the telomerase regulatory mechanisms have been used. Moreover, strategies targeting telomerase-positive cells as a means to directly kill the tumor cells have been tested. This review summarizes the most promising results achieved by anti-telomerase strategy in different solid tumors. Most of the telomeraseassociated therapies described here have proved very promising for the treatment of prostate cancer. On the basis of the good results obtained and considering the multigenic defects of human tumors, including prostate cancer, the combination of anti-telomerase strategies with conventional drugs and/or molecules capable of interfering with oncogenic pathways could efficiently improve the response of this neoplasia.

Evaluation Of Effects Of Quercetin (3,3',4',5,7-pentohidroxyflavon) On Apoptosis And Telomerase Enzyme Activity In Mcf-7 And Nih-3t3 Cell Lines To Compared With Tamoxifen

“…Our results in MCF-7 cells were not consistent with several reports which showed that quercetin, H-89 or herbimycin A did not significantly inhibit telomerase enzyme activity (30). Kudo et al showed that, although 100 µM quercetin could not influence the HSP90 expression, which is essential for telomerase enzyme acitivity, quercetin might affect the interaction between HSP90 and actin filaments without influencing HSP90 expression itself.…”

Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model

“…17 A previous study showed that OBP-401 in combination with docetaxel efficiently enhanced the antitumor efficacy in an in vivo human lung tumor model. 12 Because telomerase activity is reportedly higher in aggressive prostate cancer than in non-aggressive forms, 18 we speculate that progressive prostate cancer, such as androgen-independent prostate cancer, preferentially responds to OBP-301 treatment. These findings thus suggest that the concomitant use of docetaxel may therefore augment the effect of OBP-301 against prostate cancer.…”

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

“…In this sense, our results suggest that PZsc may have a stronger ability to promote PCa progression. Several groups have reported that sex hormones can regulate hTERT expression, [54][55][56] but the mechanism is unknown. We also found that E2 increased hTERT mRNA expression.…”