Anticancer Activities of Pterostilbene-Isothiocyanate Conjugate in Breast Cancer Cells: Involvement of PPARγ

Abstract

Trans-3,5-dimethoxy-4′-hydroxystilbene (PTER), a natural dimethylated analog of resveratrol, preferentially induces certain cancer cells to undergo apoptosis and could thus have a role in cancer chemoprevention. Peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, is a ligand-dependent transcription factor whose activation results in growth arrest and/or apoptosis in a variety of cancer cells. Here we investigated the potential of PTER-isothiocyanate (ITC) conjugate, a novel class of hybrid compound (PTER-ITC) synthesized by appending an ITC moiety to the PTER backbone, to induce apoptotic cell death in hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cell lines and to elucidate PPARγ involvement in PTER-ITC action. Our results showed that when pre-treated with PPARγ antagonists or PPARγ siRNA, both breast cancer cell lines suppressed PTER-ITC-induced apoptosis, as determined by annexin V/propidium iodide staining and cleaved caspase-9 expression. Furthermore, PTER-ITC significantly increased PPARγ mRNA and protein levels in a dose-dependent manner and modulated expression of PPARγ-related genes in both breast cancer cell lines. This increase in PPARγ activity was prevented by a PPARγ-specific inhibitor, in support of our hypothesis that PTER-ITC can act as a PPARγ activator. PTER-ITC-mediated upregulation of PPARγ was counteracted by co-incubation with p38 MAPK or JNK inhibitors, suggesting involvement of these pathways in PTER-ITC action. Molecular docking analysis further suggested that PTER-ITC interacted with 5 polar and 8 non-polar residues within the PPARγ ligand-binding pocket, which are reported to be critical for its activity. Collectively, our observations suggest potential applications for PTER-ITC in breast cancer prevention and treatment through modulation of the PPARγ activation pathway.

Development of a Novel Experimental In Vitro Model of Isothiocyanate-induced Apoptosis in Human Malignant Melanoma Cells

“…(20-28), we focused on apoptosis in order to elucidate which underlined pathways were involved in accounting for the observed reduction of viability levels in A375 cells. Overall, ITCs induced apoptosis by activating a number of initiator (8,9,4) and effector (3,6,7) caspases indicating the involvement of various apoptotic pathways including but not limited to, the extrinsic (caspase 8), intrinsic (caspase 9) and ER-dependent (caspase 4) pathways. To the best of our knowledge, this is the first report that (i) describes a novel experimental in vitro model based on the utilization of low ITC concentrations in a manner described herein and (ii) how it exerts an anticancer effect uniquely to melanoma cells (without affecting other non-melanoma and normal keratinocyte cells) by inducing apoptosis at concentrations substantially lower than those utilized in current bibliography.…”

A Novel Peptide from <i>Vespa ducalis</i> Induces Apoptosis in Osteosarcoma Cells by Activating the p38 MAPK and JNK Signaling Pathways

“…23) The induction of apoptosis results in the activation of a series of caspases, including caspase-3. 24) Cancer cell apoptosis escape is the main cause of the hyperproliferation of cancer cells. Hence, targeting apoptosis is one of the major strategies for blocking the development of cancer treatments.…”

The Anticancer Activity of Cetraria Islandica (L.) Ach in Breast Cancer Cells Through Crosstalk of Ampk-α1 and Erk1/2 Signalling

“…However, it has also been reported to be dysregulated by some cancer type such as breast, prostate, colon, and lung (Herrera et al, 2015). PPAR-γ is a mystery to be oncogenic or tumour suppressor activity (Nikhil et al, 2014).…”

“…Notably, breast cancer has been reported to scale up among women (Nikhil et al, 2014). There are some strategies to fight against tumors e.g.…”

“…There are some strategies to fight against tumors e.g. surgery, hormone therapy (Nikhil et al, 2014) immunotherapy (Manola et al, 2011) chemotherapy (Bakker et al, 2015) and radiotherapy (Hoskin et al, 2016) treatment methods. Although emerging treatment strategies are promising, many of the current methods are not efficient and developing novel therapeutic approaches are a high priority.…”