Effectiveness of Indomethacin as an Antitumor Agent in Colon 26-Bearing Conventional and Nude Mice, and Telomerase Activity in the Tumors.

Abstract

The antitumor effect of indomethacin on Colon 26 tumor was investigated in conventional (CDF1) and nude mice (BALB/c nu/nu), and the telomerase activity in the tumor tissues treated with indomethacin was monitored. Growth of Colon 26 tumor was significantly suppressed with indomethacin treatment compared to the controls both in conventional and nude mice. And telomerase activity in the tumor tissues noticeably declined in contrast to normal somatic tissues (testis, liver and colon), which were not affected by indomethacin treatment. We also showed that indomethacin can suppress tumor growth in association with a preferential decrease in telomerase activity in tumor tissues both in conventional and nude mice to the same extent. This study suggests a method for investigating the mechanism of tumor suppression by indomethacin, and suggests that indomethacin might be useful as a novel agent for human cancer therapy.

An Update on the Other Telomerase Inhibitors: Non-G-Quadruplex Interactive Agent, Non-Antisense, Non-Reverse Transcriptase Telomerase Inhibitors

“…The other inhibitors were 2-(2,3,4-trifluorophenyl) isothiazololin-3-one; ethyl 4-(3-oxo-3H-2-isothiazol-2-yl)benzoate; and 2-methylthio-4-(3-oxo-3H-isothiazol-2-yl)benzonitrile. The telomerase inhibitory activity of TMPI was completely reversed by the addition of the thiol reagents dithiothreitol or glutathione, suggesting that TMPI suppresses telomerase by interaction with a cysteine in its active center [227]. TMPI did not inhibit any other reverse transcriptases.…”

“…The conventional TRAP assay [13] was used in combination with a scintillation proximity assay as described by Savoysky [226] in the screening of another chemical library. This revealed four isothiazolone derivatives as telomerase inhibitors with an IC50 < 10 µM [227]. The most potent of these was 2-[3-(trifluoromethyl)phenyl] isothiazonolin-3-one (TMPI)(IC50=1 µM).…”

Recent advances in the development of telomerase inhibitors for the treatment of cancer

“…Conversely, when cells resistant to either (2) or (3) were exposed to these agents, no decline in enzyme activity was observed. Others have also noted a decrease in levels of telomerase activity upon treatment with 5-fluorouracil (4) [59], cisplatin [60,61], tamoxifen (5) [62] and indomethacin (6) [63]. However, as telomerase activity is known to be downregulated as a result of drug-induced cell killing, these results should not necessarily be interpreted as direct inhibition of the telomerase enzyme being a component of drug efficacy, as some initially advocated.…”

“…Daunorubicin, a structurally-related anthracycline, is also reported to inhibit telomerase activity in U937 cells [166] (5) induced similar decreases in MCF-7 cells [62]. Indomethacin (6) is reported to reduce telomerase expression in vivo against colon 26 tumour-bearing mice [63].…”

“…For example, PKC inhibitor C 18 -sphingosine (61) produced a small inhibitory effect against telomerase, while treatment with staurosporine (62) resulted in moderate inhibition of enzyme activity. A structurally-related bisindolylmaleimide (63) and an isoquinoline derivative (64) were both described as effecting more potent inhibition. Similarly, 9-hydroxyellipticine (65), an antitumour alkaloid with protein kinase activity, was shown to inhibit telomerase activity in human pancreatic cancer cell cultures, although this compound was found not to directly inhibit telomerase activity when evaluated in the cell-free TRAP assay [165].…”