Elsevier

Advances in Biological Regulation

Volume 67, January 2018, Pages 190-211
Advances in Biological Regulation

Effects of berberine, curcumin, resveratrol alone and in combination with chemotherapeutic drugs and signal transduction inhibitors on cancer cells—Power of nutraceuticals

https://doi.org/10.1016/j.jbior.2017.09.012Get rights and content

Abstract

Over the past fifty years, society has become aware of the importance of a healthy diet in terms of human fitness and longevity. More recently, the concept of the beneficial effects of certain components of our diet and other compounds, that are consumed often by different cultures in various parts of the world, has become apparent. These “healthy” components of our diet are often referred to as nutraceuticals and they can prevent/suppress: aging, bacterial, fungal and viral infections, diabetes, inflammation, metabolic disorders and cardiovascular diseases and have other health-enhancing effects. Moreover, they are now often being investigated because of their anti-cancer properties/potentials. Understanding the effects of various natural products on cancer cells may enhance their usage as anti-proliferative agents which may be beneficial for many health problems. In this manuscript, we discuss and demonstrate how certain nutraceuticals may enhance other anti-cancer drugs to suppress proliferation of cancer cells.

Introduction

Berberine (BBR), curcumin (CUR) and resveratrol (RES) are examples of three commonly consumed nutraceuticals which have been investigated for prevention/treatment of various diseases and ailments for centuries (McCubrey et al., 2017a, McCubrey et al., 2017b). These and other nutraceuticals are contained in different components of our diet, such as; fruits, berries, grapes, spices obtained from plants such as turmeric, oils from plants and fish and in addition leaves from various plants and trees. In general, they are not toxic at doses that we consume normally. Moreover, they have been associated with long life and the prevention of common health problems such as: cardiovascular, bacterial, fungal and viral infections, diabetes, inflammation and even obesity. There are many other nutraceuticals. Other commonly consumed nutraceuticals are olive oil and fish oil. More recently they have been investigated for their anti-cancer and anti-aging effects, two processes which are often intimately related (Cusimano et al., 2017).

Nutraceuticals can affect neurological processes. It turns out that signaling pathways are dysregulated in neurological diseases such as: Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and others (Tomita, 2017, Bradshaw et al., 2015, Shamseddine et al., 2015, Tu-Sekine et al., 2015, Aditi et al., 2016, Rohacs, 2016, Giudici et al., 2016, Yang et al., 2016, Kang et al., 2016, Hayashi et al., 2016 Scarlata et al., 2016, Ghim et al., 2016, Raben and Barber, 2017). The PI3K/PTEN/Akt/mTORC1/GSK-3 signaling pathway is often regulated by nutraceuticals and it plays critical roles in: diabetes, cardiovascular diseases, inflammation, neurology, obesity, as well as cancer (Lupieri et al., 2015, Guidetti et al., 2015, Beretta et al., 2015, Mikoshiba, 2015, Huang and Natarajan, 2015, McCubrey et al., 2017c, McCubrey et al., 2017d,; Carman and Han, 2017, Hermida et al., 2017, Gowda et al., 2017a, Gowda et al., 2017b, Nishida et al., 2017, Ricciardi et al., 2017, Ruvolo, 2017, Ruzzene et al., 2017, Hatch et al., 2017, Yamauchi et al., 2017, Shears et al., 2017, Ramazzotti et al., 2017, Schrock et al., 2017, McCubrey et al., 2017c, Coant et al., 2017, Ebenezer et al., 2017, Mérida et al., 2017, Gowda et al., 2017a, Gowda et al., 2017b, Campa and Hirsch, 2017, Ryuno et al., 2017). One of the first and most effective drugs to treat certain neurological diseases is lithium which is often administered to manic depressive patients. A target of lithium is GSK-3 which is a key component of the PI3K/PTEN/AKT/mTORC1/GSK-3, WNT-beta-catenin pathways and others (McCubrey et al., 2017a, McCubrey et al., 2017b).

BBRs are contained in many plants and fruits including: Berberis aetnensis C. Presl., Berberis aristata, Berberis vulgaris, Coptis chinensis, Coptis japonica, Coptis rhizome, Hydrastis canadensis, Phellondendron amurense and Tinosora cordifolia. BBR is an isoquinoline quaternary alkaloid (a 5,6-dihydrodibenzo [a,g]quinolizinium derivative). The health promoting effects of BBR has been known for centuries. BBR is often used in traditional Chinese and Indian medicine and is frequently consumed.

BBR, like CUR and RES, are sometimes considered dietary supplement. However, certain fruits containing BBR can be purchased over the counter at many different types of stores. BBR is also consumed for alleviation of various conditions/diseases such as: abdominal pain, coronary artery disease, diabetes, diarrhea, fatty liver disease, gastroenteritis, hyperlipidemia, hypertension, metabolic syndrome, neurodegeneration, obesity, polycystic ovary syndrome (McCubrey et al., 2017a, McCubrey et al., 2017b, McCubrey et al., 2017c, McCubrey and Cocco, 2017) BBR is being examined in at least 35 clinical trials.

A new aspect of BBR may be in the treatment of certain cancers. BBR is believed to have anti-diabetic, anti-inflammatory and anti-microbial (both anti-bacterial and anti-fungal) properties. BBRs can influence the expression of various genes that are involved in: apoptosis, autophagy, metastasis and proliferation such as: BCL2, BCLXL, PARP1, Beclin-1, TP53, p21Cip1, MMP9 (Cordell et al., 2001, Tillhon et al., 2012). In addition, BBRs may induce double strand DNA breaks and cell cycle arrest (Wang et al., 2012). These properties of BBR may be related to its potential anti-cancer effects.

BBRs may interact with DNA and RNA via the nitrogen atom at the 7-positon in the alkaloid BBR skeleton. This interaction between BBR and nucleic acids may inhibit telomerases and topoisomerases (Qin et al., 2007, Kim et al., 1998, Gatto et al., 1996, Bhowmik et al., 2012). In addition, BBRs may influence gene transcription by interacting with the TATA-binding protein and the TATA-box present in certain promoter regions (e.g., BCL2) (Xiao et al., 2012, Wang et al., 2011).

Some of the potential anti-diabetic and anti-cancer effects of BBRs are their ability to localize to the mitochondria and inhibit the electron transport chain and activate 5′ AMP-activated protein kinase (AMPK) and suppress mTOR activity (Wang et al., 2010a, Liu et al., 2011). The PI3K/PTEN/Akt/mTORC1 and Raf/MEK/ERK pathways are inhibited when AMPK is activated.

BBR can also inhibit senescence by altering gero-conversion from the process of cell cycle arrest to the induction of senescence by targeting mTOR/S6 and the generation of ROS (Zhao et al., 2013, Halicka et al., 2012).

The nutraceutical CUR is frequently obtained as an extract from the plant Curcuma longa (Turmeric). However, there are other compounds present in the extract which are referred to as curcuminoids. The turmeric extract consists of 60–70% CUR, 20–27% demethooxycurcumin and 10–15% bisdemethoxycurcumin (Nelson et al., 2017). These curcuminoid comprise 1–6% of the total weight of the turmeric tuber.

CUR is believed to have many health promoting properties including: anti-aging, anti-cancer, anti-hypertensive, anti-inflammatory and anti-neurological activities. The market for CUR is thought to be close to $100 million by 2022 (http://www.grandviewresearch.com/industry-analysis/turmeric-extract-curcumin-market). The effects of CUR are being examined in at least 129 clinical trials for various diseases.

CUR may exert some of its effects by altering drug transporter activity in cancer cells. CUR could enhance the anti-tumor properties of the DNA cross linking agent mitomycin C by inhibiting the expression of ATP-binding cassette transporter G2 (ABCG2, a.k.a breast cancer resistance protein, BCRP) expression. CUR treatment also increased the sensitivity of MCF-7 and MDA-MB-231 breast cancer cells to multiple chemotherapeutic drugs including: cisplatin, doxorubicin and paclitaxel and inhibited the sphere forming capacity of the cells when both CUR and a chemotherapeutic drug were added together. These events were shown to be dependent upon the suppression of ABCG2 by CUR treatment (Zhou et al., 2015a).

CUR has been shown to have effects on microRNA (miR) expression. CUR treatment of cutaneous T-cell lymphoma (CTCL) inhibited JAK-3 activity and induced miR-22 expression and suppressed the expression of many genes including: cyclin dependent kinase 2 (CDK2), histone deacetylase 6 (HDAC6), MYC associated factor X (MAX), MYC binding protein (MYCBP), nuclear receptor coactivator 1 (NCOA1), and PTEN. (Sibbesen et al., 2015).

An additional miR that is regulated by CUR is miR-34. CUR and miR-34 will regulate the expression of histone modifying enzymes. Histone modifying enzymes can affect the accessibility of promoter regions to transcription factors (Tao et al., 2013).

CUR can also suppress the PI3K/PTEN/AKT/mTORC1 pathway. CUR can induce the expression of miR-192-5b expression in A549 lung cancer cells. This resulted in decreased PI3K/PTEN/Akt/mTORC1 activity and increased apoptosis (Ye et al., 2015, Jin et al., 2015).

RES is often present in the skins of red grapes. RES is also contained in Polygonum cuspidatum, which is considered an invasive weed as it is related to bamboo. Historically, RES has been associated more with red wine, however, RES is also consumed as a non-alcoholic dietary supplement as a pill. It was estimated in 2012 that the global market for RES was $50 million (http://www.nutraingredients.com/Markets-and-Trends/US-dominates-global-resveratrol-market). This may be an actual underestimate today as RES is often sold in pill or liquid forms as a dietary supplement (non-alcohol based).

RES has many different effects. Perhaps one of the most studied effects of RES is the activation of sirtuins. Sirtuins are a family of proteins involved in regulation of gene expression. Many sirtuins function as histone deacetylates. The induction of sirtuins by RES has been postulated to be responsible for the beneficial effects of the Mediterranean diet (Russo et al., 2014). RES can also modulate NF-kappaB activity and inhibit cytochrome P450 isoenzyme (CYP A1) drug metabolism and cyclooxygenase activity. In addition, RES may influence TP53, FAS/FAS-ligand (FAS-L = CD95, tumor necrosis factor receptor superfamily member 6 [TNFRSF6]) induced apoptosis and mammalian target of rapamycin/mechanistic target of rapamycin (mTOR) activity. RES may also have effects on immune-regulatory cells by inducing the apoptosis of activated T cells and suppress tumor necrosis factor-alpha (TNF-alpha), interleukin 17 (IL-17) and additional pro-inflammatory cytokines (Diaz-Gerevini et al., 2016, Han et al., 2015a).

At least 110 clinical trials are or have been performed with RES. These trials examine the effects of RES on many different diseases ranging from aging, cardiovascular disorders, cancer, neurodegenerative, obesity and others. RES can activate AMPK. This important kinase is involved in insulin signaling and glucose uptake. Although it was initially studied in metabolism and metabolic diseases such as diabetes, it is now known to play essential roles in cancer as metabolism is very important in cancer development. Treatment of Neuro-2a (N2A) muscle cells with RES led to AMPK, AKT and GSK-3beta phosphorylation. The AMPK inhibitor compound C inhibited RES-mediated AMPK activation as well as AKT and GSK-3beta phosphorylation, glucose uptake and insulin signaling (Patel et al., 2011). Part of the anti-diabetic effects of the drug metformin are the induction of AMPK.

RES can have neuroprotective effects (Varamini et al., 2014, Lin et al., 2014 Abdel-Aleem et al., 2016). Often these effects are mediated at least in part by the PI3K/PTEN/AKT/mTORC/GSK-3 pathway. Treatment with RES can protect against cerebral ischemia. This was shown to be due to its anti-oxidant and oxygen free radicals scavenging abilities (Simão et al., 2012).

RES can also stimulate AMPK protein levels and ERK1,2 and AKT activation in myoblast cells. This can affect differentiation and muscle hypertrophy. Thus, REV has been postulated to be potentially useful in treatment of chronic functional and morphological muscle impairment (Montesano et al., 2013). AKT can mediate some of its effects on skeletal myotubes hypertrophy by suppressing GSK-3 (Rommel et al., 2001). GSK-3 is a key component of the PI3K/PTEN/AKT/mTORC1 and WNT/beta-catenin pathways.

RES treatment can reduce cardiac mitochondrial swelling and infarct size at reperfusion and lead to cardio-protection. Phosphorylation of GSK-3beta, which often results in its inactivation, is enhanced upon RES treatment. The mitochondrial permeability transition pore (mPTP) may be target by RES. This may lead to the translocation of GSK-3 from cytosol to mitochondrial. This permits GSK-3beta to interact with cyclophilin D to regulate mPTP (Xi et al., 2009).

GSK-3 inhibition has been shown to stimulate the interactions between muscle fructose-1,6-bisphosphatase (FBP2) and cardiac mitochondria. This protects mitochondria against swelling. In addition, the interaction of proteins involved in formation of mPTP is suppressed. This could be part of the mechanism responsible for RES-induced suppression of cardiac mitochondria swelling (Gizak et al., 2012).

Treatment of human umbilical vein endothelial cells (HUVEC) with five micromolar activates the Raf/MEK/ERK and PI3K/PTEN/AKT/mTORC1 pathways. This results in RES-mediated phosphorylation of GSK-3beta. The expression of VEGF and angiogenesis were induced at this RES concentration. However, RES at concentrations such as twenty micromolar, negative effects were observed. At the lower RES concentrations, the increase in VEGF expression was on the accumulation of beta-catenin in the nucleus possibly due to inhibition of GSK-3 activity (Wang et al., 2010b).

Section snippets

Signaling pathways affected by nutraceuticals—Common link with cancer

Nutraceuticals often exert their effects through signaling pathways such as Ras/Raf/MEK/ERK, PI3K/PTEN/AKT/mTORC1/GSK-3, JNK, JAK/STAT and TP53. These pathways are central in many biological processes (Cervello et al., 2017, McCubrey et al., 2017a, McCubrey et al., 2017b). These pathways play essential roles proliferation as well as diabetes, inflammation, and neurological disorders such as Parkinson's Disease and AD and are often aberrantly regulated in cancer. The roles of these pathways in

Combining nutraceuticals with signal transduction inhibitors

The effects of combining nutraceuticals such as CUR with PI3K inhibitors have been examined in many cancer models. Co-addition of CUR with the PI3K inhibitor LY294002 increased apoptosis in MCF-7 breast cancer cells. (Kizhakkayil et al., 2010). Likewise, the effects of combining BBR with the dual EGFR/HER2 inhibitor lapatinib. BBR inhibited the lapatinib-resistance of HER2+ breast cancer. The co-treatment resulted in elevated ROS levels. Lapatinib treatment was determined to induce the

Effects of BBR on pancreatic and breast cancer cells

The effects of either BBR or a combination of BBR and different nutraceutical, chemotherapeutic drugs or signal transduction pathway inhibitors were examined in pancreatic and breast cancer cell lines. This scientific approach has clinical relevance as a common goal in cancer therapy is to lower the doses of either chemotherapeutic drugs or signal transduction inhibitors by inclusion of an agent such as a nutraceutical which is normally provided or consumed at low, non-toxic doses. The

Effects of combining BBR with chemotherapeutic drugs on pancreatic cancer cells

The effects of BBR and four different chemotherapeutic drugs on MIA-PaCa-2 cells were examined (Fig. 5). When MIA-PaCa-2 cells were cultured with different doses of doxorubicin, an IC50 of approximately 300 nM was observed (Panel A). When these same cells were cultured with doxorubicin and the suboptimal concentration of BBR, the concentration of doxorubicin required to reach the IC50 was approximately 40 nM, a reduction of 7.5-fold.

Upon exposure of MIA-PaCa-2 cells to different doses of

Effects of suboptimal concentrations of RES and chemotherapeutic drugs on pancreatic cancer cells

This set experiments was performed on a different time than the experiments presented in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, that is a reason why the titration curves and IC50s presented may be slightly different. As a control, the effect of RES by itself, on MIA-PaCa-2 cells was examined and an IC50 of approximately 35 μM was detected (Fig. 6, Panel A). When the MIA-PaCa-2 cells were treated with chemotherapeutic drug doxorubicin, an IC50 of approximately 200 nM was observed (Panel B).

Effects of suboptimal concentrations of RES and signal transduction inhibitors and natural products on pancreatic cancer cells

When the MIA-PaCa-2 cells were treated with the proteasomal inhibitor MG132, an IC50 of approximately 10 nM was observed (Fig. 7, Panel B). Upon culture of the MIA-PaCa-2 cells with MG132 and a suboptimal concentration of 12.5 μM RES, the level of growth detected decreased and the IC50 declined from 10 nM to 4 nM, approximately 2.5-fold.

When the MIA-PaCa-2 cells were treated with the dual PI3K/mTOR inhibitor NVP-BE235, an IC50 of approximately 18 nM was observed (Fig. 7, Panel C). Upon culture

Effects of suboptimal concentrations of CUR and chemotherapeutic drugs on pancreatic cancer cells

As a control, the effects of CUR, by itself, on MIA-PaCa-2 cells were examined and an IC50 of approximately 10 μM was detected (Fig. 8, Panel A). When the MIA-PaCa-2 cells were treated with the chemotherapeutic drug doxorubicin, an IC50 of approximately 100 nM was observed (Fig. 8, Panel B). Upon culture of the MIA-PaCa-2 cells with doxorubicin and a suboptimal concentration of 5 μM CUR, the amount of growth decreased and the IC50 decreased from 100 to 8 nM (12.5-fold).

When the MIA-PaCa-2 cells

Effects of suboptimal concentrations of CUR and signal transduction inhibitors, pharmacological drugs and natural products on pancreatic cancer cells

When the MIA-PaCa-2 cells were treated with the proteasomal inhibitor MG132, an IC50 of approximately 5 nM was observed (Fig. 9, Panel D). Upon culture of the MIA-PaCa-2 cells with MG132 and a suboptimal concentration of 5 μM CUR, the amount of growth decreased substantially and the IC50 declined significantly from 5 to 0.08 nM (62.5-fold).

When the MIA-PaCa-2 cells were treated with the ER antagonist 4-hydroxytamoxifen (4HT), an IC50 of approximately 28 nM was observed (Fig. 9, Panel E). Upon

Conclusions

Natural products/nutraceuticals such as BER, CUR and RES will modulate the activities of the PI3K/PTEN/AKT/mTORC1/GSK-3, RAS/RAF/MEK/ERK and other signaling pathways which can often have suppressive effects on various diverse biochemical processes. We have demonstrated in this manuscript the effects of nutraceuticals on certain pancreatic and breast cancer cells. We have observed that the toxicity of the nutraceuticals or chemotherapeutic drugs can be frequently enhanced by co-addition of a

Conflicts of interest

The authors declare that they have no conflicts of interest with publication of this manuscript.

Acknowledgements

JAM, SLA and KL were supported in part by a grant from East Carolina University Grants (#111104 and #111110-668715-0000). MC was supported in part by grants to the CNR and from the Italian Ministry of Economy and Finance for the Project FaReBio di Qualita and the Associazione Italiana per la Ricerca sul Cancro (#18394), LC and SR were supported in part by grants from: Intesa San Paolo Foundation. AMM was supported in part by grants from: MIUR FIRB 2011 (RBAP11ZJFA_001). ML and SC were supported

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