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Differential antiproliferative mechanisms of novel derivative of benzimidazo[1,2-alpha]quinoline in colon cancer cells depending on their p53 status

Sedic, M.; Poznic, M.; Gehrig, P.; Scott, M.; Schlapbach, R.; Hranjec, M.; Karminski-Zamola, G.; Pavelic, K.; Kraljevic Pavelic, S.

Molecular Cancer Therapeutics 7(7): 2121-2132

2008


ISSN/ISBN: 1535-7163
PMID: 18645022
DOI: 10.1158/1535-7163.mct-07-2261
Accession: 052607738

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In the present article, we describe a mechanistic study of a novel derivative of N-amidino-substituted benzimidazo[1,2-alpha]quinoline in two human colorectal cancer cell lines differing in p53 gene status. We used a proteomic approach based on two-dimensional gel electrophoresis coupled with mass spectrometry to complement the results obtained by common molecular biology methods for analyzing cell proliferation, cell cycle, and apoptosis. Tested quinoline derivative inhibited colon cancer cell growth, whereby p53 gene status seemed to be critical for its differential response patterns. DNA damage and oxidative stress are likely to be the common triggers of molecular events underlying its antiproliferative effects. In HCT 116 (wild-type p53), this compound induced a p53-dependent response resulting in accumulation of the G(1)- and S-phase cells and induction of apoptosis via both caspase-3-dependent and caspase-independent pathways. Quinoline derivative triggered transient, p53-independent G(2)-M arrest in mutant p53 cells (SW620) and succeeding mitotic transition, whereby these cells underwent cell death probably due to aberrant mitosis (mitotic catastrophe). Proteomic approach used in this study proved to be a valuable tool for investigating cancer cell response to newly synthesized compound, as it specifically unraveled some molecular changes that would not have been otherwise detected (e.g., up-regulation of the p53-dependent chemotherapeutic response marker maspin in HCT 116 and impairment in ribosome biogenesis in SW620). Finally, antiproliferative effects of tested quinoline derivative on SW620 cells strongly support its possible role as an antimetastatic agent and encourage further in vivo studies on the chemotherapeutic potential of this compound against colorectal carcinoma.

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