A sulindac analogue is effective against malignant pleural effusion in mice
Introduction
Malignant pleural effusion (MPE) is a common clinical problem mostly secondary to metastatic carcinomas, with adenocarcinomas being the most common histological type [1], [2]. MPE is an ominous prognostic sign for cancer patients, since it indicates that the tumor is incurable by surgery and that life expectancy is short [3]. In addition, MPE causes progressive dyspnea that severely compromises quality of life. Control of fluid accumulation is therefore the foremost management issue in order to minimize symptoms and it is accomplished primarily by pleurodesis, i.e. obliteration of the pleural space by fibrotic tissue. Alas, available pleurodesing strategies have a suboptimal success rate, frequent side-effects, offer no survival advantage and up to half of the patients are not even suitable candidates [4], [5]. Although little is known about MPE pathogenesis, angiogenesis and pleural vascular hyper-permeability are considered crucial [6], [7], [8], [9], and may be therapeutically targeted to block pleural fluid accumulation.
Since the early 1980s the role of NSAID's in cancer prevention and treatment has been studied extensively. The anticancer actions of NSAID's include induction of apoptosis, inhibition of cell proliferation and angiogenesis, via both cyclooxygenase (COX)-dependent and COX-independent mechanisms [10], [11], [12]. Sulindac, a non selective COX inhibitor, and its metabolites have been studied in this context with emphasis in their apoptotic and anti-angiogenic properties [13], [14]. Gourzoulidou et al. [15] synthesized a sulindac analogue, 2-((1E,Z)-1-benzylidene-5-bromo-2-methyl-1H-inden-3-yl)acetic acid (C-18) that was recently reported to block growth factor-induced endothelial migration and proliferation, thus exerting a strong anti-angiogenic activity [16].
In the present study we aimed to investigate whether C-18 could block lung adenocarcinoma-induced MPE in mice. We hypothesized that C-18 would down-regulate tumor angiogenesis and pleural vascular permeability, thus reducing pleural fluid formation and pleural tumor dissemination.
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In vivo studies
C57BL/6 mice (Hellenic Pasteur Institute, Athens, Greece) were inbred at the General Hospital “Evangelismos” (Athens, Greece). Experiments were approved by the Veterinary Administration Bureau, Prefecture of Athens, Greece.
Intrapleural injections with syngeneic mouse Lewis lung adenocarcinoma (LLC) cells (ATCC, Manassas, VA) and sacrifice (14 day following LLC injection) were performed as described previously [7], [8], [9], [17]. Starting on day three after the intrapleural injection of LLC
C-18 limits pleural fluid accumulation and intrapleural tumor dissemination
C-18 significantly decreased pleural fluid volume in both treatment groups, in a dose-dependent manner. In particular, the mean ± SEM pleural fluid volume was 758 ± 63 μl for the control group, compared to 492 ± 120 μl and 279 ± 77 μl (ANOVA, p = 0.002) for the low dose and high dose group of C-18 respectively (Fig. 1). Similarly, C-18 reduced the extent of tumor spread in the pleural cavity, estimated by the measurement of pleural tumor implantations. Control group animals had 6.2 ± 1 pleural tumors,
Discussion
In the present study we examined whether a compound that derives from a non-selective COX inhibitor would suppress MPE formation. We found that C-18 limited pleural fluid formation, partially inhibited pleural tumor dissemination and reduced pleural vascular permeability without affecting tumor angiogenesis and tumor-associated pleural inflammation.
Control of pleural fluid accumulation is the prominent management issue in patients with MPE. Since present-day treatment modalities are suboptimal,
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by: the “Thorax” Foundation (Athens, Greece) and a “Kapodistrias” research grant of the University of Athens.
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