Modulation of Ras/ERK and Phosphoinositide Signaling by Long-Chain n-3 PUFA in Breast Cancer and Their Potential Complementary Role in Combination with Targeted Drugs

Abstract

A potential complementary role of the dietary long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFA) in combination with innovative mono-targeted therapies has recently been proposed. These compounds are thought to act pleiotropically to prevent the development and progression of a variety of cancers, including breast cancer. We hereinafter critically analyze the reports investigating the ability of LCn-3 PUFA to modulate the Ras/ERK and the phosphoinositide survival signaling pathways often aberrantly activated in breast cancer and representing the main targets of innovative therapies. The in vitro or in vivo animal and human interventional studies published up to January 2017 investigating the effects of LCn-3 PUFA on these pathways in normal and cancerous breast cells or tissues were identified through a systematic search of literature in the PubMed database. We found that, in most cases, both the in vitro and in vivo studies demonstrated the ability of LCn-3 PUFA to inhibit the activation of these pro-survival pathways. Altogether, the analyzed results strongly suggest a potential role of LCn-3 PUFA as complementary agents in combination with mono-targeted therapies. Moreover, the results indicate the need for further in vitro and human interventional studies designed to unequivocally prove the potential adjuvant role of these fatty acids.

<p>Nanomedicine-based formulations containing &omega;-3 polyunsaturated fatty acids: potential application in cardiovascular and neoplastic diseases</p>

“…51 Roy et al 50 observed a clear cytotoxic effect (measured by the MTT assay) when they administered 50-100 µM DHA in the form of free fatty acid for 4 days to MDA-MB-231 cultured in vitro, whereas lower concentrations showed no effect. This finding was in line with the results of several papers [52][53][54][55][56] analyzed by us in a recent review, 57 showing that treatments of the triplenegative MDA-MB-231 or MDA-MB-453 breast cancer cells with EPA or/and DHA in the 30-100 µM range for 1-5 days were necessary to inhibit cell growth and proliferation, and to enhance apoptosis or breast cancer cell sensitivity to docetaxel (DTX). Unexpectedly, however, Roy et al 50 found that, when lower concentrations of DHA (1-10 µM) were enclosed in NCs, they induced the proliferation of MDA-MB-231 cancer cells.…”

“…In our opinion, this topic deserves particular attention, particularly by the researchers who have been studying for decades the beneficial effects of ω-3 PUFAs in the prevention of CVD and cancer. 1,39,57,62,96,98,117 Even though this issue cannot be tackled exhaustively in just one paragraph, it is essential to outline some considerations.…”

“…This hypothesis is particularly interesting, since p-Akt represents a biomarker associated with poor prognosis in breast cancer, and used to evaluate the activity of the tyrosine kinase receptor signaling, often deregulated in breast cancer carcinogenesis. 57,61 A possible future ω-3 PUFA-containing nano-based approach for breast cancer may be suggested on the basis of the above analyzed remarkable results, obtained by both Alaarg et al 58 Since ω-3 PUFAs are known to potentially act as an adjuvant therapy to strengthen the activity of conventional chemotherapeutics or targeted drugs in the therapy of breast cancer, 57,62 it would be remarkable to develop nanoliposomal structures that are able to deliver simultaneously both ω-3 PUFAs and drugs with previously acknowledged activity in breast cancer. This liposomal combined approach could also be experimented in the clinical setting, since some liposomes are known to be safe and have already been clinically approved.…”

Chemoprevention of Breast Cancer With Vitamins and Micronutrients: A Concise Review

“…The protective effect of polyunsaturated fatty acids against breast carcinogenesis was supported by multiple animal experiments and in vitro studies (88)(89)(90)(91). Current evidence from experimental studies has shown that ratio of n-3/n-6 PUFAs can reduce the amount of proinflammatory lipid derivatives, growth factor receptor signalling, the NF-ĸB mediated cytokine production, and can modulate the signal transduction mediated by the mammalian target of rapamycin (mTOR) and the growth of breast cancer cells, by competing for cyclooxygenase and lipoxygenase metabolic pathway (92).…”

“…key signalling pathways involved Curcumin Chang et al, 2012 Induction of cell cycle arrest Carvalho Ferreira et al, 2015 Induction of apoptosis Ravindran et al, 2009 Disruption of signalling within the tumour microenvironment Modulation of cancer immunity and cancer related micro RNAs Mukherjee et al, 2014 (21-24) Inhibition of clonal expansion of breast cancer stem cells Inhibition of proliferation Inhibition of angiogenesis Key signalling pathways: NFkB, PI3K/Akt/mTOR MAPK and JAK/STAT Piperine Zheng et al, 2016 Induction of apoptosis Do et al, 2013 Inhibition of breast cancer cells migration Lai et al, 2012 Inhibition of proliferation Abdelhamed et al, 2014 (30-32, 36) Key signalling pathways: (EGF)-mediated expression of both MMP-9 and MMP-13 Sulforaphane Atwell et al, 2015 Induction of cell cycle arrest Jackson et al, 2004 Induction of apoptosis Pledgie-Tracy et al, 2007 Induction of oligonucleosomal DNA fragmentation Azarenko et al, 2008 Disruption of signalling within the tumour microenvironment Ramirez et al, 2009 Inhibition of proliferation Meeran et al, 2010 (39-44) Indole-3-carbinol Katz et al, 2018 Induction of apoptosis Bosetti et al, 2002 Modulation of oestrogen metabolism Rahman et al, 2003 Aggarwal et al, 2005 (45-48) Quercetin Chahar et al, 2011 Induction of TRAIL-mediated apoptosis Gibellini et al, 2011 Restoration of tumour suppressor Rauf et al, 2018 Modulation of epigenetic alterations Carlos-Reyes et al, 2019 (55-58) Down-regulation of oncogene expression Up-regulation of tumour-suppressor genes expression Epigallocatechin Yiannakopoulou, 2014 Induction of apoptosis gallate (EGCG) Sur et al, 2017 Inhibition of matrix metalloproteinases (MMPs) Rafieian-Kopaei et al, 2017Inhibition of vascular endothelial growth factor (VEGF)Beltz et al, 2006 Induction of reactive oxygen species (ROS)Xu et al, 1992 Inhibition of the formation of DNA adductsNarisawa et al, 1993 Inhibition of clonal expansion of breast cancer stem cellsKaur et al, 2007 Modulation of epigenetic alterationsLin et al, 2003 Downregulation of oncogene expressionGianfredi et al, 2017 Upregulation of tumour-suppressor genes expressionChikara et al, 2018 Inhibition of angiogenesisThangapazham et al, 2007 Key signalling pathways: HER-2/neu, insulin-like growth factor-1,Min et al, 2012 (70-81) (IGF-1)-mediated signalling, nuclear factor-ĸB (NF-ĸB), activator protein 1 (AP-1), MAPKs, cyclo-oxygenase-2 (COX2), nitric oxide synthesis, EGF-mediated signal transduction. Omega-3Karmali et al, 1984 Reduction in proinflammatory lipid derivatives polyunsaturatedRose et al, 1991 Key signalling pathways: Growth factor receptor (EGFR), fatty acids (PUFAs)Chajès et al, 1995 the NF-ĸB mediated cytokine production, the mammalian target ofSerini et al, 2017 rapamycin (mTOR), cyclooxygenase (COX) andFabian et al, 2015 (88-92) lipoxygenase (LOX) metabolic pathway.…”