Pornima Phatak, Fangping Dai, Melody Butler, M.P. Nandakumar, Peter L. Gutierrez, Martin J. Edelman, Hans Hendriks and Angelika M. Burger
Abstract
Purpose: KML001 (sodium metaarsenite) is an orally bioavailable arsenic compound that has entered phase I/II clinical trials
in prostate cancer. In this study, we elucidated the mode of action of KML001 and investigated its effects on telomerase
and telomeres.
Experimental Design: We compared telomere length to KML001 cytotoxicactivity in a panel of human solid tumor cell lines.
Duration of exposure and concentrations of KML001 that affect telomerase and telomeres were evaluated in relation
to established mechanisms of arseniteaction such as reactive oxygen species–related DNA damage induction. Binding
of KML001 to telomeres was assessed by matrix-assisted laser desorption/ionization mass spectrometry.
Results: We established a significant inverse correlation (r2 = 0.9) between telomere length and cytotoxicity. KML001
exhibited activity in tumor cells with short telomeres at concentrations that can be achieved in serum of patients.
We found that telomerase is not directly inhibited by KML001. Instead, KML001 specifically binds to telomeric sequences
at a ratio of one molecule per three TTAGGG repeats leading to translocation of the telomerase catalytic subunit into
the cytoplasm. In prostate cancer cells with short telomeres, KML001 caused telomere-associated DNA damage signaling
as shown by γ-H2AX induction and chromatin immunoprecipitation assays as well as a rapid telomere erosion shown by
metaphase fluorescence in situ hybridization. These effects were not seen in a lung cancer cell line with long telomeres.
Importantly, arsenification of telomeres preceded DNA lesions caused by reactive oxygen species production.
Conclusions: Sodium metaarsenite is a telomere targeting agent and should be explored for the treatment of tumors with
short telomeres.
