This Article Full Text Full Text (PDF) Supplementary Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sedic, M. Articles by Pavelic, S. K. PubMed PubMed Citation Articles by Sedic, M. Articles by Pavelic, S. K.

Research Articles: Therapeutics, Targets, and Development

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

¹ Division of Molecular Medicine, Ruder Boskovic Institute; ² Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia; and ³ Functional Genomics Center Zurich, Zurich, Switzerland

Requests for reprints: Mirela Sedic, Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia. Phone: 385-1-4571-267; Fax: 385-1-4561-010. E-mail: msedic{at}irb.hr

Abstract

In the present article, we describe a mechanistic study of a novel derivative of N-amidino-substituted benzimidazo[1,2-]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 G₁- and S-phase cells and induction of apoptosis via both caspase-3-dependent and caspase-independent pathways. Quinoline derivative triggered transient, p53-independent G₂-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. [Mol Cancer Ther 2008;7(7):2121–32]

Grant support: Croatian Ministry of Science, Education and Sport grants 098-0982464-2393 and 125-0982464-1356 and Croatian JEZGRE-TEST grant 14M09800. Mass spectrometry analyses were done at and financed by the Functional Genomics Center Zurich.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁵ http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed

⁶ Unpublished data.

Received 11/14/07; revised 3/28/08; accepted 3/30/08.