Induction of apoptosis in human cancer cell lines by the novel anthracenyl-amino acid topoisomerase I inhibitor NU/ICRF 505

Abstract

Summary Anthracenyl-amino acid conjugates represent a novel chemical class of topoisomerase (topo) inhibitor. NU/ICRF 505 is a lead compound that stabilises topo I cleavable complexes and is actively cytotoxic at low MM concentrations. In this study, endonucleolytic DNA cleavage was used as a marker of apoptosis to investigate mechanisms of cell death produced by this compound. NU/ICRF 505 (5 yM) induced a substantial increase in the level of DNA fragmentation in HL60 cells (up to 30% of total extracted DNA) but only after a 48 and 72 h drug exposure (compared with 6 h after treatment with camptothecin), as determined qualitatively by conventional gel electrophoresis and quantitatively by spectrofluorimetry. This effect was substantially reversed by co-treatment with zinc (1 mM). Subsequent studies with the human lung (NX002), ovarian (A2780) and colon (HT29) cancer cell lines yielded evidence of formation of higher molecular weight DNA fragments in NX002 and A2780 cells in response to NU/ICRF 505 (5 uM). Co-treatment with zinc (1 mM) caused a small decrease in DNA fragmentation. These data suggest that the induction of apoptosis may play an important role in the mechanism of cytotoxicity of NU/ICRF 505 in HL60 cells and that other pathways of cell death may also be operative in NX002 and A2780 in conjunction with apoptosis.

Synthesis and evaluation of selected 1,3,4-oxadiazole derivatives for in vitro cytotoxicity and in vivo anti-tumor activity

“…The DNA ladder assay conducted on Hep-2 cell lines showed that two active compounds viz., AMK OX-11 and AMK OX-12, produced fragmentation of DNA (apoptotic phenomenon) by ladder formation. Ladder formation is the marker of apoptotic phenomenon (Meikle et al 1996). The chemical nature of oxadiazoles would have to be suspected as causing DNA-damage leading to apoptosis induction in cancer cell lines.…”

Design, synthesis and anticancer properties of novel oxa/azaspiro[4,5]trienones as potent apoptosis inducers through mitochondrial disruption

“…1] [4]. In continuation to our previous work, herein we report the detailed biological profiling of oxaspiro [4,5] trienones; II and azaspiro [4,5]trienones; III along with their structure activity relationship (SAR) studies. The literature survey shows that structurally related antitumor compounds bearing enone moiety may facilitate ROS production which in turn can induce apoptosis [ Fig.…”

“…A series of twenty seven oxa/azaspiro [4,5]trienone derivatives were synthesized and their anticancer properties have been explored. GI 50 values of all these compounds were evaluated against four types of human cancer cell lines, i.e.…”

“…With the exceeding cases of cancer patients every year and lesser success in anticancer drug development, new scaffolds need to be identified as potential leads [3]. In our efforts to study the pharmaceutical potential of new scaffolds, we have identified novel oxaspiro [4,5]trienones; II possessing anti-proliferative properties [4]. These spiro [4,5]trienones were designed as constrained tamoxifen; I mimic to develop new selective estrogen receptor modulators (SERMs), however in vitro screening of these compounds revealed that they are not selective towards ER positive breast cancer cell line (MCF-7) and were found to be equally potent against ER negative breast cancer cell line (MDA-MB-231) [ Fig.…”

Aminoacyl-analogues of mitoxantrone as novel DNA-damaging cytotoxic agents

“…[15][16][17][18][19] They were also shown to act by inhibiting topoisomerases I and II and appeared as promising new drugs. However, all of the previous compounds were lacking the hydroxyl groups in the aromatic planar system, characteristic of Mx and known to improve drug activity to a substantial extent.…”