Anticancer effect of trehalose by modulating oxidative stress, apoptosis and autophagy

Abstract

Trehalose is a novel disaccharide sugar that contains two glucose motifs. Nowadays, the major applications of trehalose have applied in the medical field. It has been investigated whether trehalose has inhibitory or protective effects on different types of tumor and non-tumor cells. Trehalose effect depends mainly on type of the target cells. Some studies reported that trehalose could potentially be employed as a novel anticancer agent that could be used safely and effectively to treat tumors by decreasing oxidative stress, autophagy, and increasing apoptosis. Some other studies found that trehalose is a potent autophagy inducer for some other cancer cell types. In this short review, we shed a light on the potential role played by trehalose as an anticancer, antioxidant or oxidative stress inducer, apoptotic or anti-apoptotic, and autophagy inhibitor or inducer agent.

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1
Nasr Eldeen et al., 2018, AJMS 2(1):1-3, DOI:10.5455/ajms.13
Anticancer eect of trehalose by modulating oxidative stress, apoptosis and
autophagy
Arabian Journal of Medical Sciences
http://www.ajms.tk
Abstract
Article Info
Keywords:
Trehalose,
Autophagy,
Apoptosis,
Oxidative stress
Received Nov 7,
Revised Dec 2,
Published Dec 7, 2018
*Corresponding author:
sciencesamah@gmail.com
Trehalose is a novel disaccharide sugar that contains two glucose motifs. Nowadays, the major applications
of trehalose have applied in the medical eld. It has been investigated whether trehalose has inhibitory or
protective eects on dierent types of tumor and non-tumor cells. Trehalose eect depends mainly on type
of the target cells. Some studies reported that trehalose could potentially be employed as a novel anticancer
agent that could be used safely and eectively to treat tumors by decreasing oxidative stress, autophagy, and
increasing apoptosis. Some other studies found that trehalose is a potent autophagy inducer for some other
cancer cell types. In this short review, we shed a light on the potential role played by trehalose as an anticancer,
antioxidant or oxidative stress inducer, apoptotic or anti-apoptotic, and autophagy inhibitor or inducer agent.
Samah K Nasr Eldeen a*, Mohammed A. El-Magd b, Abeer Khamis a, Wafaa M. Ibrahim c, Afrah F. Salama a
a Department of Chemistry, Biochemistry Division, Faculty of Science, Tanta University, Egypt
b Department of Anatomy, Faculty Veterinary Medicine, Kafrelsheikh University, Egypt
c Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Egypt
Trehalose structure and properties
Trehalose(α-glucopyranosyl-(1→1)-α-D-glucopyranoside;
C12H22O11; molecular weight 342.31 g/mol) is a disaccharide
found in many microorganisms and plants. It has 45% sweetness
more than sucrose sugar so it is commonly used in the food industry
as a sweetener. There are many isomers of trehalose such as α,β (neo-
trehalose) and β, β (isotrehalose) which have been rst synthesized
in 1994. The α form is the isomer commonly dened as trehalose (α,
α -trehalose, α -D-glucopyranosyl α-D-glucopyranoside, mushroom
sugar, mycose).
Trehalose is very stable disaccharide sugar due to its unique
physicochemical properties, including high degree of optical rota-
tion, thermal stability (unique primary melting point at 97οC, crystal-
lization at 130 οC, and melting of its anhydrous form at 203 ο C) and
wide PH range (Elbein et al., 2003).
Trehalose extraction and production
Trehalose has been rst extracted from yeast in 1994 but this
method was too expensive and produced very low concentration. An-
other method for trehalose extraction was performed in 1995 using
two bacterial enzymes, malto-oligosyltrehalose synthase (or MTSase)
and malto-oligosyltrehalosetrehalohydorolase (or MTHase), isolated
from genus Arthrobacter sp. Q36 in the soil (Maruta et al., 1995).
MTSase catalyzes the transfer of one glucose molecule at the
reducing end of oligosaccharide from α-1, 4 bonds to α-1, 1bond,
to produce oligosyltrehalose, which contains trehalose residue at the
end of the saccharide chain. Subsequently, MTHase broke oligos-
yltrehalose for trehalose liberation. These enzymes can act on α-1,
4 glucose bond repeatedly and can produce up to 80 % trehalose.
There is another method for trehalose production from starch by the
eect of α-amylase followed by isoamylase, which can produce am-
ylose. The latter can then be converted eciently into trehalose by
MTHase and MTSase.
Applications of trehalose
Trehalose has unique functions that are dierent from sucrose,
lactose, and maltose, including the protective action against stress-
ors such as nutrient deprivation, oxidative stress, and cold (Jain and
Roy, 2009). It could also prevent inammation induced by endoge-
nous and exogenous toxins (Minutoli et al., 2008). Trehalose report-
edly inhibits protein denaturation of bacterial plasma membranes
(Leslie et al., 1995) and human cells (Guo et al., 2000).
In addition, the low cost of trehalose permits a widespread ap-
plication in the medical eld such as preservation of mammalian
embryos for a long time, preservation of cells under freeze-dried
conditions, cryopreservation of platelets, and treatment of Hunting-
ton’s disease and dry eye syndrome (Matsuo et al., 2002; Mori et
al., 2010; Nakamura et al., 2008; Takeuchi et al., 2011; Tanaka et
al., 2004).
It can increase the viability of preserved bovine embryos in liq-
uid nitrogen (Saha et al., 1996). It can also increase the viability of
mammalian cells producing insulin during freezing and so it can aid
in treatment of diabetes disease (Beattie et al., 1997). Trehalose has
a therapeutic and protective eect in various neurodegenerative dis-
eases, such as Alzheimer ’s disease, frontotemporal dementia, pro-
gressive supranuclear palsy and corticobasal degeneration (Kruger
et al., 2012). A recent study emphasized that trehalose also has a
therapeutic eect on cardiac remodeling after myocardial infarction
(Sciarretta et al., 2018).
Trehalose eect on oxidative stress, apoptosis and auto-
phagy
Trehalose suppresses the oxidative stress by reducing the harm-
ful free radicals in yeast cells by the binding with the membrane
and so it can suppress the oxidation of the unsaturated fatty acids
in the cell membranes (Herdeiro et al., 2006; Oku et al., 2003). On
the other hand, mycolic acid-containing glycolipids, such as cord
factor (CF) (trehalose 6, 6-dimycolate [TDM]), trehalose trimycola,

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Nasr Eldeen et al., 2018, AJMS 2(1):1-3, DOI:10.5455/ajms.13
and sulfatide (SL) (2,3,6,6-tetraacyl trehalose 2-sulfate), are virulent
factors characteristic of acid-fast bacteria which exert various bio-
logical eects, including adjuvant activity and granuloma formation,
by the activation of macrophages, natural killer (NK) cells and T cells
(Natsuhara et al., 1990;Tabata, et al., 1996 ). In vivo administration of
mycobacterial CF induces marked thymic atrophy via the apoptotic
process (Hernandez et al., 1993; Yuriko et al., 1997).
Autophagy is induced by trehalose in a mTOR-independent man-
ner to protect various cells from dierent harmful conditions such as
dehydration, extreme heating and cooling and oxidation (Sarkar et
al., 2007). Trehalose is considered as an autophagy inducer in mam-
malian cells (as evidenced by its ability to induce autophagic genes
Atg5 and LC3-II expression) and so it can be used as an adjuvant for
various diseases treatment (Kang et al., 2010).
Anticancer eect of trehalose
Although trehalose has signicantly preservative eects on cel-
lular viabilities as far as there is few investigations that examined the
eects of trehalose on tumor cell growth. Mycobacterial CF (as a nat-
ural product containing trehalose) has the potential to kill tumor cells
in guinea pig and mice (Watanabe et al., 1999), and trehalose surfac-
tant can also trigger in vitro death of human hepatocellular carcinoma
(Hep-G2 and HuH-7) cells (Matsumoto, et al., 2013a), human colon
carcinoma and gastric carcinoma (Matsumoto et al., 2013b).
Trehalose could potentially be employed as a novel anticancer
agent that could be used safely and eectively to topically treat ma-
lignant tumors, however the exact mode of this anticancer eect
has not been elucidated yet (Takashi et al., 2012). A previous study
showed that trehalose can cause malignant melanoma cell death via
induction of apoptosis (Kudo et al., 2012).
Trehalose can trigger autophagy in many tumor cell lines (Sarkar
et al., 2007). In contrast, a recent study by our group proved that tre-
halose can induce the antitumor potential of chemotherapeutic drug
methotrexate against mice bearing Ehrlich ascites carcinoma (EAC)
through induction of apoptosis and oxidative stress, and inhibition of
autophagy in EAC cells (El-Magd et al., 2017). These conicted nd-
ings may be due to variation in cancer types and stage as reported by
Shen et al., (2015) who found both protumorigenic and antitumori-
genic eect for autophagy, depending on the cell type, developmental
stage of cancer.
Summary
Trehalose can be used as a safe drug for treatment of many diseas-
es including cancers. However, its mode of action is quietly dierent
dependant on the tissue/cell type. In non-cancer cells, trehalose ex-
erts its eect through inhibition of apoptosis, reduction of oxidative
stress, and induction of autophagy. So in disease other than cancer,
trehalose acts as a potent anti-apoptotic, antioxidant, and autophagy
inducer agent. In contrast, in cancer cells, trehalose can act either
as in non-cancer cells or in a reverse direction (a potent apoptotic,
ROS inducer, and autophagy inhibitor agent) depending on type and
stage of tumor. Therefore, further investigation are required to denote
the actual mechanism of trehalose action when used for treatment of
dierent type of tumors. It is also worth to combine trehalose with
other chemotherapeutic agent and check whether it can increase their
anticancer potential and decrease their side eects.
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