Telomerase Inhibitors as Anticancer Therapy

Masaharu      Akiyama; Teru      Hideshima; Nikhil   C.   Munshi; Kenneth   C.   Anderson

Abstract

Telomerase inhibitors have been touted as a novel cancer specific therapy, as most tumor cells have high expression of telomerase, whereas most normal somatic cells express low or undetectable levels of telomerase. Continued proliferation of tumor cells requires activation of telomerase to maintain chromosomal stability and extend life span, because telomerase elongates telomere length and rewinds the cellular mitotic clock. Conversely, shortening of telomeres by inhibition of telomerase activity induces growth arrest (senescence) and apoptosis in tumor cells. Moreover, it has been reported that inhibition of telomerase increases the susceptibility of tumor cells to apoptosis induced by anticancer agents. Thus, telomerase inhibitors could be used as an adjuvant with conventional therapy. However, there are also several potential limitations of telomerase inhibition as a therapeutic strategy. For example, there is a lag phase between telomerase inhibition and telomere shortening, with growth arrest and cell death. In this review, we will discuss the basic biology of telomeres and telomerase as a platform for the development of treatments based upon inhibition of telomerase activity.

Keywords: Telomerase Inhibitors, Anticancer Therapy, Immunotherapy, Catalytic Inhibitors, G-quadruplex Interactive Agents, hTERT Constructs, Hammerhead Ribozymes, Antisense Oligonucleotides