Perifosine as a potential novel anti-telomerase therapy

Abstract

Most tumors circumvent telomere-length imposed replicative limits through expression of telomerase, the reverse transcriptase that maintains telomere length. Substantial evidence that AKT activity is required for telomerase activity exists, indicating that AKT inhibitors may also function as telomerase inhibitors. This possibility has not been investigated in a clinical context despite many clinical trials evaluating AKT inhibitors. We tested if Perifosine, an AKT inhibitor in clinical trials, inhibits telomerase activity and telomere maintenance in tissue culture and orthotopic xenograft models as well as in purified CLL samples from a phase II Perifosine clinical trial. We demonstrate that Perifosine inhibits telomerase activity and induces telomere shortening in a wide variety of cell lines in vitro, though there is substantial heterogeneity in long-term responses to Perifosine between cell lines. Perifosine did reduce primary breast cancer orthotopic xenograft tumor size, but did not impact metastatic burden in a statistically significant manner. However, Perifosine reduced telomerase activity in four of six CLL patients evaluated. Two of the patients were treated for four to six months and shortening of the shortest telomeres occurred in both patients' cells. These results indicate that it may be possible to repurpose Perifosine or other AKT pathway inhibitors as a novel approach to targeting telomerase.

Role of Telomeres and Telomerase in Aging and Cancer

“…There are also many methods to measure telomere length including TRF (terminal restriction fragment) analysis (6), in situ Q-FISH (85–86), Flow FISH (87), Q-PCR (88), chromosome specific single telomere length analysis (STELA) (89), and Universal STELA (90–91). In addition, there is now whole genome sequencing (TelSeq) to estimate average or mean telomere length that is quantitative but somewhat still expensive compared to other methods (92).…”

“…Single chromosome STELA is perhaps less useful in cancer since there is a great variation and losses in chromosome numbers. Universal STELA (90–91) has recently emerged to measure the shortest telomeres on all chromosomes, but neither single cell nor universal STELA are high throughput methods, so large scale studies would be more difficult. Issues to consider when conducting telomere testing for disease susceptibility and aging are provided in Table 2.…”

Biophysics in cancer: The relevance of drug-membrane interaction studies

“…The knowledge acquired with this kind of studies may play a significant role in the design of new drugs and delivery systems, and the identification of new membrane targets that may be the base of a membrane-lipid therapy. In fact, there are already a number of anticancer drugs that exert their therapeutic effects by modulating the environment of tumor membranes [6,7].…”

Telomere length and reactive oxygen species levels are positively associated with a high risk of mortality and recurrence in hepatocellular carcinoma

“…Recently, perifosine, a protein kinase B (AKT) inhibitor, was shown to decrease telomerase activity and telomere lengths in the lung cancer cell lines, cervical cancer cell lines, and chronic lymphocytic leukemia blood samples . This study suggested that AKT pathway inhibitors such as perifosine could function as potential telomerase inhibitors .…”