Simultaneous targeting of telomeres and telomerase as a cancer therapeutic approach.
Telomeres, which are important for maintaining chromosome integrity and functions, shorten with each cell division. Telomerase, responsible for telomere synthesis, is expressed in approximately 90% of human tumor cells but seldom in normal somatic cells. This study evaluated the hypothesis that simultaneous shortening of telomeres and inhibition of telomerase results in synergistic and tumor-selective cytotoxicity. In telomerase-positive human pharynx FaDu tumor cells, paclitaxel caused telomere erosion (first detected at 1 h) and apoptosis. Expression of antisense to the RNA component of human telomerase (hTR) inhibited telomerase activity, shortened telomere length, reduced cell growth rate, and resulted in a significant higher sensitivity to paclitaxel. Another telomerase inhibitor, 3'-azido-3'-deoxythymidine (AZT), at a concentration that produced little or no cell detachment or apoptosis, inhibited the telomerase activity and enhanced the paclitaxel-induced cell detachment and apoptosis. AZT also enhanced the activity of paclitaxel in mice bearing well-established s.c. FaDu xenograft tumors (i.e., reduced residual tumor size, enhanced apoptotic cell fraction, and prolonged survival time), without enhancing host toxicity. In contrast, AZT did not enhance the paclitaxel activity in the telomerase-negative osteosarcoma Saos-2 cells nor in FaDu cells where telomerase was already suppressed by antisense hTR, confirming that the AZT effect in parent FaDu cells is mediated through telomerase inhibition. These results demonstrate that combined use of agents targeting both telomere and telomerase yielded synergistic activity selective for tumors that depend on telomerase for telomere maintenance.
Mo
Yiqun
Y
College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Gan
Yuebo
Y
Song
SaeHeum
S
Johnston
Jeffrey
J
Xiao
Xiaodong
X
Wientjes
M Guillaume
MG
Au
Jessie L-S
JL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010610:Pharyngeal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D016372:RNA, Antisense / Q000008:administration & dosage* / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D016615:Telomere / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015215:Zidovudine / Q000008:administration & dosage / Q000494:pharmacology*
D016372:RNA, Antisense; D015215:Zidovudine; D019098:Telomerase; D017239:Paclitaxel