Cancer Letters

Cancer Letters

Volume 396, 28 June 2017, Pages 76-84
Cancer Letters

Original Article
An anti-prostate cancer benzofuran-conjugated iridium(III) complex as a dual inhibitor of STAT3 and NF-κB

https://doi.org/10.1016/j.canlet.2017.03.016Get rights and content

Highlights

  • Four benzofuran-conjugated metal complexes were synthesized and screened.

  • Complex 1 was identified as the STAT3 and NF-κB dual inhibitor.

  • Complex 1 engages and stabilizes STAT3 and NF-κB in cell lysates.

  • Complex 1 shows the antiproliferative activity in the prostate cell line.

Abstract

Four benzofuran-conjugated iridium(III) or rhodium (III)-based metal complexes are synthesized to screen as an inhibitor of STAT3 activity in prostate cancer cells. All complexes show the high stability and solubility in the biological system. In this study, an iridium(III) complex engages STAT3 and NF-κB to inhibit their translocation and transcriptional activities. Moreover, complex 1 shows more potential antiproliferative activity against DU145 cells and suppresses tumor growth in a prostate cancer xenograft mouse without observable adverse effects. Complex 1 may provide the basis for developing new therapeutic strategy in vivo and in vitro for the treatment of advanced prostate cancer.

Introduction

Prostate cancer is a disease that shows prolonged latency, with high morbidity and mortality [1], [2]. It is the second-most common malignancy in men, with about 1 million new cases each year, with a fatality rate of around one-third, accounting for 10% of all new cancer diagnoses in men globally [3]. Radiation therapy, which uses high energy waves to kill cancer cells, is widely used for treating prostate cancer [4]. However, side effects include sore skin, nausea, vomiting, hair loss and problems with eating and drinking [5].

NF-κB and STAT3 are ubiquitously expressed transcription factors and control numerous physiological processes including development, differentiation, immunity, metabolism and cancer [6], [7]. NF-κB and STAT3 have different activation pathways, being induced by TNF-α and IL-6, respectively [8], [9], though there may be some overlap in downstream targets [10]. Cyclin D1 is activated by NF-κB signaling and is required for progression through the G1 phase of the cell cycle [11], [12]. Meanwhile, survivin is a STAT3-dependent downstream protein and that is stably detected in most cancers [13], [14]. The regulator factor c-Myc and the anti-apoptotic protein Bcl-2 are activated by both NF-κB and STAT3 [15], [16].

Our research group has previously identified a number of different natural product-like compounds or metal complexes as inhibitors of STAT3 and NF-κB [17], [18], [19], [20]. Benzofuran and its derivatives have received attention due to their presence in natural products and biologically-active molecules [21], [22], [23]. Benzofuran molecules have been developed as inhibitors of PI3 kinase [24], mTOR [25], mPTPB [26] and β-amyloid aggregation [27].

In this study, we sought to conjugate benzofuran motif with Group 9 organometallic compounds, which have garnered increased interest in therapeutic and bioanalytical applications due to their flexible reactivity, water solubility, stability, and relative synthetic ease [28], [29]. As Group 9 metal complexes have been previously reported as NF-κB inhibitors [17], [18], [30], we hypothesized that the combination of the benzofuran scaffold with a Group 9 metal complex into a single molecular entity could potentially generate a dual inhibitor of STAT3 and NF-κB for the treatment of prostate cancer. The advantage of such a multimodal agent is that the two oncogenic mediators STAT3 and NF-κB can be simultaneously targeted with a single molecule, eliminating the risk of undesirable drug–drug interactions, and also possibly increasing efficacy especially in cases where the tumors have become resistant to a single form of attack.

Section snippets

Materials

Reagents were purchased from Sigma–Aldrich (St. Louis, MO, USA) and used as received unless specified. Deuterated solvents for NMR purposes were obtained from Cambridge Isotope Labs, iridium(III) chloride hydrate (IrCl3·xH2O) and rhodium(III) chloride hydrate (RhCl3·xH2O) were purchased from Precious Metals Online (Australia).

General experiment

High resolution mass spectrometry was carried out at the Mass Spectroscopy Unit in Hong Kong Baptist University, Hong Kong (China). 1H and 13C NMR were recorded on a

Results and discussion

Complexes 14 are Group 9 organometallic compounds that bear the same Hdpa NˆN ligand (where Hdpa = di(pyridine-2-yl)amine) derivatized to a ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate moiety via a pentyl chain (Fig. 1A). Complexes 1 and 2 bear 2,4-F-ppy (where 2,4-F-ppy = 2-(2,4-difluorophenyl)pyridine) CˆN ligands, while complexes 3 and 4 bear ppy (where = 2-phenylpyridine) CˆN ligands. Complexes 1 and 3 have iridium(III) centers while complexes 2 and 4 have rhodium(III) complexes. All

Conclusions

In summary, we have reported a novel benzofuran-conjugated iridium(III) complex 1 as a direct STAT3 and NF-κB dual inhibitor. Complex 1 inhibited both IL-6-induced STAT3 activity and TNF-α-induced NF-κB activity in DU145 cells. Moreover, complex 1 inhibited both STAT3 and NF-κB translocation from the cytoplasm to nucleus. The ability of 1 to block the DNA-binding activity of STAT3 was confirmed in an ELISA. Complex 1 could engaged STAT3 and NF-κB directly and affact the downstream proteins.

Acknowledgements

This work is supported by Hong Kong Baptist University (FRG2/15-16/002), the Health and Medical Research Fund (HMRF/14130522), the Research Grants Council (HKBU/12301115, HKBU/204612 and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12-Oligoswitch), the Natural Science Foundation of China (21575121), Guangdong Province Natural Science Foundation (2015A030313816), the Hong Kong Baptist University Century Club Sponsorship Scheme 2016,

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    These authors contributed equally to this work.

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