Most
cancer cells have an immortal growth capacity as a consequence of
telomerase reactivation. Inhibition of this
enzyme leads to increased telomere dysfunction, which limits the proliferative capacity of
tumor cells; thus,
telomerase inhibition represents a potentially safe and universal target for
cancer treatment. We evaluated the potential of two thio-
phosphoramidate oligonucleotide inhibitors of
telomerase,
GRN163 and GRN163L, as
drug candidates for the treatment of human
hepatoma.
GRN163 and GRN163L were tested in preclinical studies using systemic administration to treat flank xenografts of different human
hepatoma cell lines (Hep3B and Huh7) in nude mice. The studies showed that both
GRN163 and GRN163L inhibited
telomerase activity and
tumor cell growth in a dose-dependent manner in vitro and in vivo. The potency and efficacy of the
lipid-conjugated antagonist, GRN163L, was superior to the nonlipidated parent compound,
GRN163. Impaired
tumor growth in vivo was associated with critical telomere shortening, induction of telomere dysfunction, reduced rate of cell proliferation, and increased apoptosis in the treatment groups. In vitro, GRN163L administration led to higher prevalence of chromosomal telomere-free ends and DNA damage foci in both
hepatoma cell lines. In addition, in vitro chemosensitivity assay showed that pretreatment with GRN163L increased
doxorubicin sensitivity of Hep3B. In conclusion, our data support the development of GRN163L, a novel lipidated conjugate of the
telomerase inhibitor
GRN163, for systemic treatment of human
hepatoma. In addition to limiting the proliferative capacity of
hepatoma, GRN163L might also increase the sensitivity of this
tumor type to conventional
chemotherapy.