Curcumin: A naturally occurring autophagy modulator

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DOI: 10.1002/jcp.27404

R E V I E W A R T I C L E

Curcumin: A naturally occurring autophagy modulator

Abolfazl Shakeri

¹

| Arrigo F. G. Cicero

²

| Yunes Panahi

³

| Mohammad Mohajeri

⁴

|

Amirhossein Sahebkar

^5,6,7

1Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

3Chemical Injuries Research Center, System Biology and Poisoning Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

4Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

5Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

6Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

7School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Correspondence

Amirhossein Sahebkar, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, P.O.

Box: 91779‐48564, Mashhad, Iran.

Email: [email protected];

[email protected]

Abstract

Autophagy is a self

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degradative process that plays a pivotal role in several medical conditions associated with infection, cancer, neurodegeneration, aging, and metabolic disorders. Its interplay with cancer development and treatment resistance is complicated and paramount for drug design since an autophagic response can lead to tumor suppression by enhancing cellular integrity and tumorigenesis by improving tumor cell survival. In addition, autophagy denotes the cellular ability of adapting to stress though it may end up in apoptosis activation when cells are exposed to a very powerful stress. Induction of autophagy is a therapeutic option in cancer and many anticancer drugs have been developed to this aim. Curcumin as a hydrophobic polyphenol compound extracted from the known spice turmeric has different pharmacological effects in both in vitro and in vivo models. Many reports exist reporting that curcumin is capable of triggering autophagy in several cancer cells. In this review, we will focus on how curcumin can target autophagy in different cellular settings that may extend our understanding of new pharmacological agents to overcome relevant diseases.

K E Y W O R D S

autophagy, cell death, curcumin, molecular mechanisms

1 | I N T R O D U C T I O N

There are three main forms of cellular death with morphologically and biochemically distinct characteristics, namely necrosis (type III), apoptosis (type I), and autophagy (type II). Necrosis refers to a passive cell death arising from adenosine triphosphate depletion and rapid loss of cellular integrity that culminates in spillage of intracellular contents, which further triggers inflammation and impairment to surrounding cells (Y. Lee & Gustafsson, 2009). As for apoptosis or“self‐killing,”it is considered a form of programmed cell death and a major constituent of various processes, such as balance of cellular regeneration and elimination, function of the immune system, and so forth (Elmore, 2007). Upon induction of apoptosis, morphologically characteristic changes occur, including cell shrink- age, DNA damage, chromatin condensation, membrane blebbing, as

well as fragmentation and development of apoptotic bodies in nucleus (Jayakiran, 2015). When it comes to autophagy or “self‐ eating,”a complex of cellular processes is involved in the degradation of cellular constituents and organelles and takes place in response to stressful conditions, including starvation, hypoxia, chemoradiother- apy, aging, and environmental toxins (Ojha, Bhattacharyya, & Singh, 2015; J. Zhang, 2013). Indeed, autophagy commences with encapsu- lation of cytoplasm and organelles into double‐membraned vesicles and fusion of lysosomes, which are subsequently followed by autophagolysosomal degradation (Basile et al., 2013). This genetically programmed and evolutionarily conserved event is found in all eukaryotic cells ranging from yeasts to mammals (Jia, Li, Qin, & Liang, 2009). Autophagy has been shown responsible for several physiolo- gical processes (e.g., development and protein quality control) as well as for a host of diseases (e.g., cancer, neurodegenerative diseases,

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and aging; Basile et al., 2013; Jia et al., 2009). Moreover, three different types of autophagy have been described, such as macro- autophagy, microautophagy, and chaperone‐mediated autophagy (Rubinsztein, Mariño, & Kroemer, 2011). The first is a homeostatic process which comes about in all eukaryotic cells and sequesters cytoplasmic components within autophagosomes, ending up in fusion with lysosomes and then degradation (Bassham et al., 2006; A. M. K.

Choi, Ryter, & Levine, 2013). In microautophagy, cytoplasmic components undergo disruption through direct invaginations of the lysosomal membrane. Microautophagy is more likely to take place via the delivery of proteins into late endosomes, a process contingent on the chaperone Hsc70 (Vijayan & Verstreken, 2017). The last is the only type of autophagy in mammalian cells that selectively regulates the delivery of cytosolic proteins into lysosomes for degradation using a targeting motif and is largely implicated in protein quality control (Dice, 2007; G. Wang & Mao, 2014). Our current knowledge concerning the involvement of autophagy in human medical conditions is far of get to know how it devotes to pathogenesis, biomolecules that lack specificity for autophagy, and few pharmacological agent with sufficient clinical efficacy (A. M. K. Choi et al., 2013). Overall, the autophagic process normally enhances cell viability, however, its overactivation leads to nonapoptotic programmed cell death and impairs essential proteins and organelles (Zhou, Zhang, Zhang, Sun, & Chen, 2014). In the case of diseases, its contribution appears to involve many complications. In cancerous events, for example, it plays a role as both tumor suppressor, and enhancer through eliminating damaged proteins–organelles and preserving cellular homeostasis during nutrient deprivation and hypoxic condition, respectively (Ojha et al., 2015). The implications of autophagy in cancer are more likely cancer‐type specific, and contingent on the genetic composition of the cancer cells together with the constitution of the external stresses used (Bialik & Kimchi, 2008). In light of such breakthroughs regarding the involvement of autophagy, some clinically relevant agents have been developed to modulate it in many diseases, particularly in cancer, including tamoxifen, Kringle 5, imatinib, arsenic trioxide, ritonavir, rapamycin, chloroquine, omeprazole, and BMS1‐4 (Høyer‐Hansen & Jäättelä, 2008). Finding natural compounds whereby various medical conditions that target autophagy are overcome constitutes the leading part of the present therapeutic strategies (J. Zhang, 2013).

Rapamycin, isolated from Streptomyces hygroscopicus, is the most known natural autophagy inducer in a series of autophagy‐related issues (Vezina, Kudelski, & Sehgal, 1975). Several naturally occurring products have also been identified with antitumor effects related to the induction of autophagy in cancer cells, namely resveratrol, triterpenoid saponins from soybean, vitamin D analog EB1089, and so on (Kondo & Kondo, 2006). In this regard, some have pinpointed natural autophagy regulators of plant origin, especially curcumin, a hydrophobic polyphenol with considerable potential to affect many cellular functions (Ding et al., 2015; X. Zhang, Chen, Ouyang, Cheng,

& Liu, 2012). A huge number of studies have dealt with biological activities of curcumin, more important protective against cancer (Jia et al., 2009; Oyama et al., 1998; Pal et al., 2005, 2001; R. A. Sharma,

Gescher, & Steward, 2005; Sugimoto et al., 2002). The inhibiting effects of curcumin on cancer cell growth are found to arise from autophagy (Aoki et al., 2007; Jia et al., 2009; Kim et al., 2012; Y. J.

Lee, Kim, Suh, & Lee, 2011; X. Liu, Shao, & Sun, 2013; O’Sullivan‐ Coyne, O’sullivan, O’Donovan, Piwocka, & McKenna, 2009;

Yamauchi, Izumi, Asakura, Hayashi, & Nomori, 2012). Nevertheless, numerous anticancer compounds could exert inhibitory and stimulating influences on the autophagy process that may complicate drug design; put it differently, autophagy induction may come up with cytoprotective or apoptosis‐stimulant outcomes. The latter of which (stimulant autophagy) should be enhanced, whereas the inhibition of protective autophagy is another possible strategy for application in chemotherapy (Ding et al., 2015; Singletary & Milner, 2008). Other medical conditions, namely neuropathies (e.g., Huntington’s disease, Alzheimer’s disease [AD], and Parkinson’s disease [PD]) and ischemic heart disease can benefit from autophagy via removing toxic assets and improving cell survival (Glick, Barth, & Macleod, 2010). Hitherto, the contribution of natural products to apoptosis has been well documented, while conversely, their interaction with autophagy is still in need for further research. This review aimed at resuming the underlying mechanisms behind the interaction between curcumin and the process of autophagy.

2 | C U R C U M I N A S A M U L T I F U N C T I O N A L P H Y T O C H E M I C A L

Curcumin (diferuloylmethane; 1,7‐bis(4‐hydroxy‐3‐methoxyphenyl)‐1, 6‐heptadiene‐3,5‐dione) constitutes the vital fraction ofCurcuma longa (Goel, Kunnumakkara, & Aggarwal, 2008). Traditionally, it has wide applications as a dietary spice and coloring agent (Shishodia, Sethi, &

Aggarwal, 2005). Furthermore, it has been reported to possess numerous implications for medical purposes, namely inflammation, neoplasm, anorexia, dyslipidemia, and so on (Cicero et al., 2017; L. Guo et al., 2015; Iranshahi et al., 2010; Jiang et al., 2015; Mirzaei et al., 2016;

Panahi, Alishiri, Parvin, & Sahebkar, 2016; Panahi, Ghanei, Bashiri, Hajihashemi, & Sahebkar, 2014; Panahi et al., 2015; Panahi, Kianpour, et al., 2016; Panahi, Saadat, Beiraghdar, & Sahebkar, 2014; Rahmani et al., 2016; Sahebkar, 2014, 2015; Shishodia et al., 2005). Numerous biological properties have been reported for curcumin, including radical scavenging, antitumor, anti‐inflammatory, analgesic, and cytoprotective activities (Chattopadhyay, Biswas, Bandyopadhyay, & Banerjee, 2004;

Mohajeri, Behnam, Cicero, & Sahebkar, 2018; Noorafshan & Ashkani‐ Esfahani, 2013; Panahi, Ghanei, Hajhashemi, & Sahebkar, 2016;

Sahebkar & Henrotin, 2016; Sahebkar, Cicero, Simental‐Mendía, Aggarwal, & Gupta, 2016). Structurally, it is a symmetric molecule with two similar aromatic rings where o‐methoxy phenolic groups are located and linked to an α,β‐unsaturated β‐diketone moiety (Priyadarsini, 2014). Moreover, curcumin acts as an electron donor in many redox reactions due to the presence of conjugated double bonds in its chemical structure and thereby stabilizing the structure (Priyadarsini, 2014). Considering its propensity for accumulation in hydrophobic regions (e.g., plasma membrane), curcumin has the ability

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to function as an antioxidant agent skin to vitamin E, and counteract the formation of reactive oxygen species (ROS; O. P. Sharma, 1976).

Besides, there have been many reports that curcumin can be beneficial for lipoprotein metabolism, manifest in the reduction of low‐density lipoprotein cholesterol and triglycerides, and augmentation of high‐ density lipoprotein cholesterol. Indeed, curcumin has the ability to reverse conditions that evade normal lipid profile (Ganjali et al., 2017).

More recently, curcumin showed the potential to be applied in various materials and devices with a focus on its contribution to hemostasis as well as anticoagulation. The combination of curcumin with different drug delivery formulations can culminate not only in better efficacy and compatibility but also in anticoagulant and antiplatelet functions;

that is, the presence of curcumin in such devices diminishes the biocompatibility issues associated with repetitive injections (Keiha- nian, Saeidinia, Bagheri, Johnston, & Sahebkar, 2018). Curcumin has been documented as a useful agent for many pathological aspects of diabetes, namely insulin resistance and hyperglycemia. These positive effects occur by decreasing the differentiation of preadipocytes to adipocytes, enhancing adipocyte energy metabolism, promoting apoptosis, and inhibiting angiogenesis in an adipose tissue. In addition, the protective activities of curcumin against diabetes may be ascribed to its capability of downregulating leptin, resistin, and visfatin, and at the same time upregulating adiponectin as the most important adipokines (Hajavi et al., 2017). More to the point, the administration of curcumin appears beneficial for the treatment of systemic lupus erythematosus, an inflammatory and chronic autoimmune‐mediated disease recognized by the accumulation of autoantibodies and immune complexes in distinct organs, elevation of autoreactive and inflammatory T cells, along with inappropriate rise of plasma proinflammatory cytokines. Actually, curcumin can afford to recover an imbalance present among T‐helper cell subsets, regulatory T cells, and dendritic cells observed in these patients (Momtazi‐Borojeni et al., 2018).

Noteworthy, curcumin may retard the development of amyloid plaques in AD and thus ameliorating this condition. Of note, the supportive role of curcumin against inflammatory bowel disease is more likely to arise from its free‐radical scavenging and antioxidant actions that impact a number of signaling pathways, particularly the kinases (Noorafshan & Ashkani‐Esfahani, 2013; Prasad, Gupta, Tyagi,

& Aggarwal, 2014). The biosafety of curcumin, even at high concentrations, has been corroborated by several in vitro and in vivo studies (Aggarwal & Harikumar, 2009; Bhavani Shankar, Shantha, Ramesh, Murthy, & Murthy, 1980; Lao et al., 2006; Zhang, Tang, Xu, &

Li, 2013). A curcumin dose of 12,000 mg has been documented to be the maximum tolerated dose without no marked undesirable effects in healthy volunteers (Lao et al., 2006).

3 | R O L E O F C U R C U M I N I N A U T O P H A G Y 3.1 | Curcumin’s promotion of autophagy

Autophagy, known as type II cell death, plays a crucial regulatory role in cancer therapy. Natural products as safe and effective compounds that target to autophagy have garnered a great deal of attention.

The interplay between natural agents and this process has been addressed in myriads of studies (Cattani, Goldoni, Pastoris, Sinibaldi,

& Orsi, 1997; Fulda, 2008; Lima et al., 2017; Stoller, Braekman, Daloze, & Vandevyver, 1988; Umezawa, Aoyagi, Tanaka, & Takeuchi, 1993). Furthermore, numerous studies have demonstrated the induction or inhibition of autophagy by curcumin in various in vitro or in vivo models by employing distinct molecular mechanisms.

Molecular mechanisms of curcumin‐induced autophagy are diverse.

Many signaling pathways are activated in different tumor cells, namely the knockdown of the phosphoinositide 3‐kinase–AKT‐ mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, induction of adenosine monophosphate (AMP)‐activated protein kinase (AMPK) pathway and extracellular signal‐regulated kinases 1 and 2 (ERK1/2) pathway, formation of ROS, as well as development of endoplasmic reticulum (ER) stress (J. Zhang et al., 2016). Of them, mTOR seems to be the leading negative regulator of autophagy in cancerous cells. It exists in the form of multiprotein complexes;

mTOR complex 1 (mTORC1) plays the role of a positive regulator of protein synthesis and yet a negative regulator of autophagy (H. R.

Lee et al., 2016). Simultaneously, it is itself under control of a number of kinase signaling cascades, primarily AMPK/ERK/TSC2/mTOR (inhibits mTORC1 and activates autophagy) and JAK/PI3K/Akt/

mTOR (maintains mTORC1 activity and inhibits autophagy; Zenkov et al., 2016).

3.2 | Solid tumors

It was suggested that the modulation of autophagy may provide benefits for the patients with glioblastoma because many antiglioma approaches, such as oncolytic virotherapy, chemotherapy, and ionizing radiation produces autophagy induction (Ulasov, Lenz, &

Lesniak, 2018). It was shown that curcumin inhibited the growth of U87‐MG and U373‐MG human malignant glioma cells by inducing G2/M cell cycle arrest and autophagy via the suppression of the Akt/

mTOR/p70S6K pathway and stimulation of the ERK1/2 pathway (Aoki et al., 2007). In another study, curcumin triggered the differentiation of glioblastoma cells from glioma‐initiating cells in vivo and in vitro subsequent to the induction of autophagy through the inhibition of PI3K/Akt/mTOR signaling pathway (Zhuang et al., 2012). In human A375 and C8161 melanoma cells, curcumin inhibits their proliferation and cause autophagy by deactivating the PI3K/

Akt/mTOR/P70S6K pathway (Zhao et al., 2016). In gastric SGC‐7901 and BGC‐823 cancer cell lines, curcumin inhibits cell proliferation, induced apoptosis and autophagy by activated the P53 signaling pathway by upregulating P53 and P21 and inhibited PI3K‐signaling pathway through downregulating PI3K/Akt/mTOR pathway (Fu et al., 2018). Moreover, exposure to curcumin led to cellular apoptosis and stimulant autophagy in another human gastric cancer cell line B MKN‐28, which also associated with the inhibition of the PI3K/Akt/

mTOR signaling pathway (Li et al., 2017). On the other hand, ROS is identified as signaling molecules in several pathways regulating both cell survival and death (Azad, Chen, & Gibson, 2009). Another study indicated that curcumin in combination with tamoxifen (an estrogen

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receptor blocker in breast cancer treatment) can synergistically increase autophagy and apoptosis in chemoresistant human melanoma cells more than each drug alone through depolarization of mitochondria membranes and enhancement of ROS production. This study reported no marked toxic effects on noncancerous cells (Chatterjee & Pandey, 2011). Besides, curcumin suppresses the proliferation and survival of oral squamous cell carcinoma as a result of autophagy manifest in high levels of autophagic vacuoles formation, light chain 3 (LC3)‐I to LC3‐II conversion, and ROS generation (Kim et al., 2012). Recently, several lines of evidence have dealt with substrates of AMPK and their involvement in different cell behaviors, namely growth, metabolism, autophagy, and polarity processes (Mihaylova & Shaw, 2011). It was unraveled that curcumin activated the AMPK signaling pathway, thereby triggering autophagy in the A549 human lung adenocarcinoma cell line to selectively inhibit their growth without any cytotoxic influences on IMR‐90 normal lung fibroblast cells (Xiao et al., 2013). More important, mitogen‐activated protein kinase (MAPK) family has been demonstrated to be involved in the process of autophagy by curcumin, as well. ERK1/2 are members of MAPK family, which regulate a wide range of cellular functions, including cell proliferation, transforma- tion, differentiation, cell survival, and death (L. Zhu et al., 2011). In an in vitro study by Y. J. Lee et al. (2011) on HCT116 human colon cancer cell, curcumin‐associated autophagy and cell death arose from the production of ROS, and accordingly activation of ERK1/2 and p38 MAPK, but not c‐Jun N‐terminal kinase (JNK). Then, the autophagic effect of curcumin on HCT116 cells resulted in cellular senescence accompanied with observations of autophagosomes and LC3‐II expression (Mosieniak et al., 2012). Moreover, Beclin‐1 located on Golgi apparatus is an autophagy‐related gene and also a key marker of autophagy. Indeed, Beclin‐1 has the responsibility to stimulate the development of autophagosome and modulates the localization of various autophagy proteins on autophagosome precursor membrane encoded by the BECN1 gene (C. Wang, Zhang, Teng, Zhang, & Li, 2014). The role of Beclin‐1 in autophagy is contingent on the presence of B‐cell lymphoma/leukemia‐2 (Bcl‐2), an antiapoptotic protein with inhibitory influences on autophagy through binding and isolating Beclin‐1 under nutrient‐rich conditions (He & Klionsky, 2009). More to the point, the Bcl‐2 signaling cascade has been found in connection with PI3K/Akt, leading molecules in the survival mechanism (Akkoç et al., 2015). Administration of curcumin was associated with the apoptotic and autophagic death of the chronic myeloid leukemia cell line K562 cells, reduced expression of Bcl‐2, and yet enhanced levels of Beclin‐1 (Jia et al., 2009). Furthermore, autophagy and apoptosis occurred in MCF‐7 breast cancer cells via an increase in the Beclin‐1 expression (Akkoç et al., 2015).

Noteworthy, curcumin was shown to act as a trigger of apoptosis and autophagy in castration‐resistant prostate cancer cells (i.e., DU145 and PC3 cell lines) by means of its iron‐chelating features;

put it differently, curcumin was able to cause an increase in the expression levels of transferrin receptor 1 and iron regulatory protein 1 characteristic of iron deprivation, and then increased

apoptosis as well as protective autophagy (Yang et al., 2017). The favorable contribution of stimulative autophagy is not limited only to cancerous conditions.

3.3 | Neurologic involvement

Autophagy has also implications in neuronal damage in many neurodegenerative and neuropsychiatric disease. Numerous studies have shown that the induction of autophagy in early stages may have a protective effect in neurodegenerative models (Pellacani & Costa, 2018). The aggregation, deposition, and dysfunction of α‐synuclein (α‐Syn) are the neuropathological hallmarks of neurodegenerative disorders such as PD (Marques & Outeiro, 2012). It was reported that overexpression of miR‐7 could results to the degradation of α‐Syn and its aggregates by promoting autophagy which indicates that miR‐7 is a target for therapeutic intervention for PD (D. C. Choi, Yoo, Kabaria, & Junn, 2018). The presence of extracellular amyloid plaques containing β‐amyloid (Aβ) and formation of intracellular neuroﬁbrillary tangles composed of the hyperphosphorylated tau protein are the hallmarks of AD (Shakeri & Sahebkar, 2016).

Curcumin impedes the formation and accumulation of Aβ via the induction of autophagy through downregulating the PI3K/Akt/mTOR signaling pathway (C. Wang et al., 2014). Inhibition of miR‐128 by curcumin pretreatment in monocytes from AD patients improves Aβ (1‐42) degradation (Howell et al., 2013; Tiribuzi et al., 2014). Another study put stress on the contribution of curcumin to neuroprotection from hippocampal neuronal cell death with origin of status epilepticus by provoking the production of Beclin‐1 and LC3 (autophagy proteins), as well as the inhibition of mixed lineage kinase domain‐like protein and receptor interaction protein kinase 1 (necroptosis proteins; H. R. Lee et al., 2016). Youssef, Peiris, Kelley, and Grant (2013) in an attempt to examine the role of vitamin D and curcumin in treating gonorrhea, suggested that there may be a synergic interplay between these two compounds, culminating in the improvement of gonorrhea through the synthesis of cathelicidin followed by an autophagic response. Additionally, curcumin was reported to have the capability of rescuing paraquat‐induced neurotoxicity and oxidative stress in human neuroblastoma cells (i.e., SH‐SY5Y cell line), which was, in turn, attributed to the increased expression of antiapoptotic and antioxidant genes, and the development of autophagy activity (Jaroonwitchawan, Chaicharoenaudom- rung, Namkaew, & Noisa, 2017).

3.4 | Vascular injury

In oxidative stress‐related cardiovascular diseases, curcumin can afford to protect human umbilical vein endothelial cells from hydrogen peroxide (H2O2)‐induced viability loss by means of activating autophagy through the suppression of the PI3K/Akt/

mTOR signaling pathway, separation of BECN1 and Bcl‐2 from each other, elevation of free BECN1 in the cytoplasm, prevention of forehead box O1 (FoxO1; a mediator of autophagy) nuclear

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T A B L E 1 In vitro studies supporting regulation of the curcumin and autophagy

References Cell type used Interaction CUR and autophagy Major findings

Y. Zhang et al. (2017) MG‐63 cell line CUR‐induces apoptosis and autophagy in osteosarcoma cells

JNK has role in CUR‐induced autophagy and cur

↑phosphorylation of JNK in MG‐63 cells; JNK inhibitor SP600125 is able to reverse CUR‐ induced autophagy

Yang et al. (2017) BGC‐823, SGC‐ 7901, KN‐28 cell lines

PI3K/Akt/mTOR signaling pathway activation was suppressed with CUR and autophagy inhibitor (3‐MA) promoted apoptotic cell death induced by CUR

Autophagy inhibitor treatment provide a novel and effective strategy for↑anticancer effect of curcumin against gastric cancer

Masuelli et al. (2017) Human MM‐B1, H‐ Meso‐1, MM‐F1 cells line; mouse (#40a) MM cells

CUR induces an increase in LC3‐II/ LC3‐I and autophagosome formation in ACC‐MESO‐1 cell line also trigger autophagy but autophagicﬂux was blocked as revealed by the increase of p62/SQSMT1

CUR activation and impairment of autophagy and activation of apoptosis observed in MM cell lines and due to activation of ERK1/2 and p38 signaling the last items responsible for the JNK inhibition

J. Liu et al. (2017) PC3, DU145, LNCaP, and RWPE‐ 1 cell lines

CUR restitutes miR‐143/miR‐145 cluster expression serving as demethylation reagent and miR‐143 can sensitize cancer cells to radiation by suppressing autophagy by downregulating ATG2B

CUR intenerate prostate cancer cells to radiation by epigenetic activation of miR‐143 and miR‐143 intercede autophagy inhibition

Li, Zhou, et al. (2017) BGC‐823, sGC‐7901 an MKN‐28 cell lines

CUR inhibits the Akt/mTOR signaling in gastric cancer cells, that contribute to induce both apoptosis and autophagy in human gastric cancer cells

CUR induces apoptotic cell death and protective autophagy in human gastric cancer cells in vitro

Jaroonwitchawan et al. (2017)

SH‐SY5Y cell lines CUR treatment triggers↑in LC3‐I/II expression in SH‐SY5Y cells and indicating the induction of autophagy pathway

CUR induces LC3‐I/II upregulation and activated autophagy in SH‐SY5Y cells

Zhao et al. (2016) In vitro: C8161 cell lines

CUR induces autophagy by↓ phosphorylation of AKT, mTOR, and P70S6K

CUR↓activation of AKT, mTOR, and P70S6K proteins and suppressor of cell viability and invasion, simultaneously an inducer of autophagy in A375 and C8161 cells Paulino et al. (2016) A375 cell line Anti‐inflammatory effect of DM1 is mediated

by inhibition of iNOS and COX‐2 expression, also involved with autophagy modulation

DM1 modulates iNOS and COX‐2 gene expression in cultured RAW 264.7 cells and induces autophagy on A375 cell line

Niu et al. (2016) A375 cell line CUR combined with red united blue light irradiation‐induces autophagy and plays a vital role in G2/M cell cycle arrest

CUR combined with red united blue light irradiation generates photochemopreventive eﬀects by enhancing apoptosis and triggering autophagy

Gu et al. (2016) THP‐1 cell line LC3‐II and p62 markers levels altered in THP‐1 cells to treat and decrease in the degradation of oxLDL and intracellular accumulation of lipids;↓LC3‐II expression and↑p62 levels in THP‐1 cells

Nicotinate‐curcumin rescued the impaired autophagy flux via↑level of LC3‐II

Xu et al. (2015) NSCLC A549 and 95D cell line

BDMC impel autophagy in NSCLC cells 95D and A549 along with BDMC induced apoptosis

Blockage of autophagy can attenuate the toxicity of BDMC so autophagy is involved in the antitumor of BDMC in NSCLC via including the downregulation of hedgehog‐Gli1 Xu et al. (2015) 95D cell line BDMC suppresses invasion and migration of

highly metastatic 95D cell line through downregulation vimentin and upregulation E‐cadherin expression

Obstruction of autophagy via Beclin1‐ targetedinterfering RNA attenuated inhibition of BDMCon 95D‐cell migration and invasion

Chen et al. (2015) HUVEC Antioxidant and antiproliferative property of CUR accelerated reendothelialization and suppressed Ih so, EC autophagy important in↑of neointimal lesions and rapid cell proliferation lead to extensive nutrient depletion

CUR expose beneficial effects via↑proliferation and migration of ECs by enhancing its autophagy level

(Continues)

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localization, and promotion of cytoplasmic acetylated FoxO1. As another influential mechanism, Rab7, a small GTPase coming from the Ras‐like GTPase superfamily, was found to participate in this autophagic response to protect vascular endothelial cells from oxidative stress damage. Indeed, curcumin caused an upregulation of Beclin‐1 and diminution of the interaction between Beclin‐1 and Bcl‐2 by elevating Rab7 expression, providing a protection against oxidative stress (Han et al., 2012).

In an inflammatory disease such as osteoarthritis, curcumin exerted suppressive effects on apoptosis and inflammatory signaling by activating the ERK1/2‐induced autophagy in chondrocytes (Li, Feng, et al., 2017). It has also been found that curcumin decreased H2O2‐induced oxidative stress through modulating the Akt/mTOR pathway in endothelial cells, characterized by inhibition of apoptosis and promotion of autophagy (S. Guo et al., 2016). On the contrary, some evidence put light on the implications of protective autophagy in treating different medical conditions. Curcumin was found to impede damage caused by autophagy in prostate cancer cells exposed to radiation. The underlying mechanism regards the activation of miR‐143, a miRNA (microRNA) that downregulates the autophagy‐related 2B gene expression (J. Liu, Li, Wang, & Luo, 2017).

Anticancer effect of curcumin and its analogues, through modulating the expression of miRNAs in different cancer cells has already reviewed (Momtazi et al., 2016). Curcumin suppressed the progression of laryngeal squamous cell carcinoma by upregulation of miR‐145 and inhibition of the PI3K/Akt/mTOR pathway (X. Zhu &

Zhu, 2018). Reversing autophagy via the mechanism of miR‐143 and

subsequent knockdown of this gene was also addressed in various contexts, such as osteosarcoma (J. Zhou, et al., 2015), non‐small‐cell lung cancer (Wei et al., 2015), and lymphocytic leukemia (Kovaleva et al., 2012). Using a model of maleate‐intoxicated male Wistar rats, it was shown that curcumin applied nephroprotection against oxidative stress by diminishing mitochondrialﬁssion and autophagy, as evident in the high expressions of phosphothreonine 389 from p70 ribosomal protein S6 kinase, Beclin‐1, microtubule‐associated protein 1A/1B–LC3‐II, autophagy‐related gene 5 and 12 complex, p62, and lysosomal‐associated membrane protein 2 (Molina‐Jijón et al., 2016).

Addition of curcumin to human embryonic kidney 293T cells exposed to HA14‐1, a promoter of oxidative stress and apoptosis in cancer cells, counteracted ROS and toxic response by downregulation of antiapoptotic proteins and autophagy (Ranjan, Sharma, Surolia, &

Pathak, 2014). A more recent study highlighted the protective impact of curcumin against hypoxia/reoxygenation injury in the H9c2 myocytes by retarding apoptosis and autophagy in such a way that the expression of Bcl‐2 was on the rise, while a decline was observed in the levels of Bcl‐2 associated X protein (Bax), Beclin‐1, silent information regulation 1 (SIRT1; a nicotine adenine dinucleotide‐ dependent deacetylase regulating autophagy), and Bcl‐2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3; a potent trigger of autophagy; Huang et al., 2015). Despite a great breadth of curcumin biological properties, a major obstacle to the clinical implication of curcumin is related to its reduced bioavailability, and low absorption owing to rapid metabolism and rapid systemic elimination (Ibrahim et al., 2010).

T A B L E 1 (Continued)

References Cell type used Interaction CUR and autophagy Major findings

Zhou, Ye, et al. (2014) SMMC‐7721, BEL‐ 7402, HL‐7702, HCT116, A549 cells lines

EF25‐(GSH)2 compel autophagy by means of a biphasic mechanism

EF25‐(GSH) has potential as a low toxicity chemotherapeutic agent for HCC and antitumor and EF25‐(GSH)2 involved in autophagic, apoptotic mechanisms and combination of EF25‐(GSH)2 with chloroquine provide a safer and effective treatment of HCC Zhou, Xu, Sun, Chen,

et al. (2014)

A549 cell line ↑LC3‐II expression in IHCH‐treated A549 cells

LC3‐II protein expression↑in IHCH‐treated cells in a dose‑dependent manner and suggests IHCH induced autophagy in the A549 cells Li et al. (2014) 293T cell line CUR↓monomeric TTR via promoting

autophagy and without toxic effects

CUR↓monomeric TTR by recovering autophagy also defect of autophagy show pathogenesis of TTR‐FAP with Y114C mutation

Xiao et al. (2013) A549 and IMR‐90 cell line

CUR impels autophagy by activating AMPK and autophagy is inhibiting effect of cur lung adenocarcinoma cells

CUR‐induced autophagy in A549 cells, that inhibit via 3‐MA, an autophagy inhibitor

Li and Han (2013) HUVEC cell line CUR↑BECN1 expression, inhibits (PtdIns3K)‐AKT and reverses FOXO1 nuclear localization along with causing an↑ level of cytoplasmic acetylation of FOXO1 and interaction of acetylated FOXO1 and ATG7

CUR has a potential for use as an autophagic‐ related antioxidant for prevention and treatment of oxidative stress

Note. AMPK: AMP‐activated protein kinase; BDMC: bisdemethoxycurcumin; COX‐2: cyclooxygenase‐2; CUR: curcumin; EC: endothelial cell; ERK1/2:

extracellular signal‐regulated kinase 2; FOXO1: forehead box O1; iNOS: inducible nitric oxide synthase; JNK: c‐Jun N‐terminal kinase; HCC:

hepatocellular carcinoma; HUVEC: human umbilical vein endothelial cell; miR: microRNA; NSCLC: non‐small‐cell lung cancer; oxLDL: oxidized low‐density lipoprotein; TTR‐FAP: transthyretin familial amyloid polyneuropathy.

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4 | C U R C U M I N D E R I V A T I V E S A N D A U T O P H A G Y

Curcumin derivatization is an effective approach to overcome such limitations. A recent study reported that curcumin‐based zinc compound triggered mutant p53H175 protein degradation via autophagy as indicated by reactivation of wild‐type p53 transactiva- tion, an increase of LC3‐II expression, and a decrease of p62 levels (Garufi et al., 2014). Another study used bisdemethoxycurcumin (BDMC), one of the chief derivatives of curcumin found in turmeric and exhibited its potential to cause autophagy in non‐small‐cell lung cancer cells and highly metastatic lung cancer 95D cells through downregulation of the Hedgehog–Gli1 pathway (Xu et al., 2015). A synthetic analog of curcumin, 4‐[3,5‐bis(2‐chlorobenzylidene‐4‐oxo‐ piperidine‐1‐yl)‐4‐oxo‐2‐butenoic acid], was developed by Lagisetty, Vilekar, Sahoo, Anant, and Awasthi (2010) and observed to induce autophagy in lung adenocarcinoma cell line H441, which are apoptosis‐resistant cancerous cells. What is more, bis‐dehydroxycur- cumin, another curcumin derivative, was presented with a potent function to induce selective cytotoxicity, ER stress‐induced autophagy, and consequently apoptosis in human colon cancer cells (Basile et al., 2013). The anticancer activity of another curcumin derivative 2E,6E‐ 2‐(1H‐indol‐3‐yl)methylene)‐6‐(4‐hy‐droxy‐3‐methoxybenzylidene)‐cy- clohexanone (IHCH) was reported by Zhou, Xu, Sun, and Chen (2014) in an in vitro model of A549 lung cancer cells that was accompanied with direct evidence from western blot analysis (e.g., conversion of LC3‑I to LC3‑II and aggregation of LC3 in the cytoplasmic compart- ment) in support of the occurrence of autophagy. Some studies have been performed on tetrahydrocurcumin (THC), as the major metabo- lite of curcumin. It was found that THC can afford to cause autophagic cell death more than curcumin via the inhibition of the PI3K/Akt and MAPK‐signaling pathways in human HL‐60 promyelocytic leukemia

cells (Wu et al., 2011). Furthermore, neuroprotective effects of THC against apoptotic neuronal death with the origin of traumatic brain injury came about through amelioration of autophagy and PI3K/Akt pathways (Gao et al., 2016).

Conversely, THC was shown to possess antiautophagic effects on hyperhomocysteinemia mice undergoing the ischemia–reperfusion injury where homocysteinylation of cytochromecdiminished through inhibiting the activation of oxidative stress and matrix metallopro- teinase‐9 (Tyagi et al., 2012). Another study developed a soluble curcumin analog, 3,5‐bis(2‐hydroxybenzylidene)tetrahydro‐4H‐pyr- an‐4‐one glutathione conjugate that modulate autophagy in a concentration‐dependent manner; that is, low concentrations (<5μmol/L) increased autophagy, whereas an arrested autophagy process occurred at high concentrations (>10μmol/L) in hepatocellular carcinoma (Zhou, Ye et al., 2014).

5 | I N F L U E N C E O F C U R C U M I N O N A U T O P H A G Y ‐ A P O P T O S I S C R O S S T A L K

There have some research studies addressing the effect of curcumin or its derivatives on the crosstalk between autophagy and apoptosis. For instance, it has shown that overexpression of Beclin‐1 in A549 cells promotes apoptosis (Gao et al., 2016). In addition, Qu et al. (2013) utilized monocarbonyl analog of curcumin (B19), whose autophagic effects were corroborated based on the presence of classic autophagic vacuoles with double membranes in the cytoplasm of HO8910 cells, aggregation of LC3‐II in autophagosomal membranes, and elevation of LC3‐II to LC3‐I ratio. Of note, inhibition of B19‐induced autophagy paved the way for ER stress‐induced apoptosis. Similar findings were reported using hydroxyl acetylated curcumin (Zheng et al., 2016).

T A B L E 2 In vivo studies supporting regulation of the curcumin and autophagy

References Model Impact of CUR on autophagy Major findings

Tsai et al. (2017) Sprague– Dawley rats

THC is more effective than CUR and↓hepatic collagen accumulation along with activation of HSCs via downregulation of TGF‐β1 signaling and autophagy

THC treatment↓costaining of aSMA and LC3‐I in liver and THC may abolish activation of HSCs via the downregulation of autophagy

X. Li et al. (2017) Sprague– Dawley rats

CUR↑expression of phosphorylated (ERK1/2) and autophagy marker light chain 3 (LC3)‐II, and Beclin‐ 1 in chondrocytes

CUR suppresses apoptosis and inflammatory signaling by serving as ERK1/2‐induced autophagy in chondrocytes

Molina‐Jijón et al. (2016)

Wistar rats CUR↓oxidative damage and activates autophagy in endothelial cells by Akt/mTOR pathway

Neuroprotective effect of CUR in maleate‐induced renal damage is connected with↓mitochondrial fission and autophagy

C. Wang et al. (2014)

Double‐ transgenic mice

CUR↓expression of PI3Kand mTOR at protein levels, CUR also induces of autophagy via downregulating PI3K/Akt/mTOR signaling pathway

CUR↑expression of Beclin↑formation of autophagosomes and↓aggregation of intracellular and extracellular Aβ

Gao et al. (2016) Sprague– Dawley rats

Tetrahydrocurcumin treats neurons from TBI‐ induced apoptosis by modulation of autophagy and the PI3K/AKT pathways

Autophagy inhibitor 3‐methyladenine and the PI3K kinase inhibitor LY294002 partially turn the neuroprotection of Tetrahydrocurcumin after TBI Note. Aβ:β‐amyloid;αSMA:α-smooth muscle actin; CUR: ERK1/2: extracellular signal‐regulated kinase 2; HSC: hematopoietic stem cell; TBI: traumatic brain injury; TGF: transforming growth factor.

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Combination of curcumin with red united blue light irradiation not only promoted apoptosis, but also induced autophagy in human melanoma A375 cell line via enhancing oxidative stress‐mediated cell death observable in cellular morphology, and developing autophagosomes manifest in LC3‐II upregulation and SQSTM1 downregulation. More important, autophagy inhibition increased apoptosis and converted reversible arrested cells to senescence (Niu, Tian, Mei, & Guo, 2016). Such a controversy also exists in other studies. Yamauchi et al. (2012) employing ACC‐MESO‐1 as a human‐derived mesothelioma cell line, observed that curcumin decreased cell viability and gave rise to autophagy through the increased LC3B‐II expression and autophagosome formation, but not apoptosis. On the other hand, Masuelli et al. (2017) recently observed that curcumin activated apoptosis in a range of human (MM‐B1, H‐Meso‐1, and MM‐F1) and mouse (#40a) malignant mesothelioma cell lines, while elevating Bax/Bcl‐2 ratio, p53 expression, caspase 9 activation, ERK1/2 and p38 phosphorylation, c‐Jun expression and phosphorylation, poly(ADP‐ribose) polymerase 1 cleavage, and yet declining nuclear factor‐κB nuclear translocation, p54 JNK, and Akt phosphorylation. Interestingly, curcumin also evoked and subsequently abolished autophagy as presented by changes in p62 expression in this setting. Zhang et al emphasized an apoptotic influence of curcumin on human osteosarcoma MG‐63 cells, which was ascribed to the activation of caspase 3 pathway and reduction of Bcl‐2 expression. Besides this, curcumin‐induced autophagy in MG‐63 cells occurred through the enhancement of the JNK signaling pathway. Moreover, the inhibition of apoptosis led to an increase in curcumin‐induced autophagy and vice versa (Y. Zhang et al., 2017). Differently, Xu et al. (2015) indicated that suppression of autophagy caused by BDMC prevented from not only growth inhibition, but also apoptosis induction.

6 | C O N C L U S I O N S A N D F U T U R E P E R S P E C T I V E

Since the inhibition of apoptosis in cancer cells has been found to cause multidrug resistance to chemotherapy, autophagic cell death could be an alternative for developing new functional agents. On the other hand, it has been suggested that autophagy is one of the most important mechanisms to promote cancer cell survival and relapse of the disease. To this aim, autophagy modulators coming from natural products have garnered much attention due to their effectiveness and safety in humans. Extant evidence from in vitro (Table 1) and in vivo (Table 2) studies has shown that curcumin‐ induced autophagy is mediated by a number of signaling pathways, including PI3K/Akt/mTOR, AMPK, MAPK/ERK1/2, Bcl‐2 signaling cascade, and Rab GTPase network (Figure 1). Additionally, some studies have related this potential of curcumin to its iron‐chelating features. Overall, the stimulating effect of curcumin and its derivatives on autophagy depends on the stress‐producing stimulus and cellular setting. However, curcumin has also been shown to mitigate cancer through inhibiting rather than activating autophagy, an effect that could be mediated by the stimulation of miR‐143, protection of renal function through reduction of ROS, and alleviation of hypoxia/reoxygenation injury through regulation of some proteins’ activity. It would be interesting to investigate whether curcumin‐induced autophagy can selectively target the cancerous cells with predetermined dose and duration, and if modulation of autophagy by curcumin can be verified in clinical trials.

C O N F L I C T S O F I N T E R E S T

The authors declare that there are no conflicts of interest.

F I G U R E 1 Interaction of curcumin with components with the pathways and mediators involved in autophagy regulation [Color figure can be viewed at wileyonlinelibrary.com]

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O R C I D

Arrigo F. G. Cicero http://orcid.org/0000-0002-4367-3884 Amirhossein Sahebkar http://orcid.org/0000-0002-8656-1444

R E F E R E N C E S

Aggarwal, B. B., & Harikumar, K. B. (2009). Potential therapeutic effects of curcumin, the anti‐inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases.The International Journal of Biochemistry & Cell Biology,41(1), 40–59. https://doi.org/10.1016/j.biocel.2008.06.010

Akkoç, Y., Berrak, Ö., Arısan, E. D., Obakan, P., Çoker‐Gürkan, A., &

Palavan‐Ünsal, N. (2015). Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl‐2 through activation of autophagy in MCF‐7 cells.Biomedicine & Pharmacother- apy,71, 161–171. https://doi.org/10.1016/j.biopha.2015.02.029 Aoki, H., Takada, Y., Kondo, S., Sawaya, R., Aggarwal, B. B., & Kondo, Y.

(2007). Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: Role of Akt and extracellular signal‐regulated kinase signaling pathways.

Molecular Pharmacology, 72(1), 29–39. https://doi.org/10.1124/mol.

106.033167

Azad, M. B., Chen, Y., & Gibson, S. B. (2009). Regulation of autophagy by reactive oxygen species (ROS): Implications for cancer progression and treatment.Antioxidants & Redox Signaling,11(4), 777–790. https://

doi.org/10.1089/ARS.2008.2270

Basile, V., Belluti, S., Ferrari, E., Gozzoli, C., Ganassi, S., Quaglino, D., … Imbriano, C. (2013). Bis‐dehydroxy‐curcumin triggers mitochondrial‐ associated cell death in human colon cancer cells through ER‐stress induced autophagy.PLOS One,8(1), e53664. https://doi.org/10.1371/

journal.pone.0053664

Bassham, D. C., Laporte, M., Marty, F., Moriyasu, Y., Ohsumi, Y., Olsen, L. J., &

Yoshimoto, K. (2006). Autophagy in development and stress responses of plants.Autophagy,2(1), 2–11.

Bhavani Shankar, T. N., Shantha, N. V., Ramesh, H. P., Murthy, I. A. S., &

Murthy, V. S. (1980). Toxicity studies on turmeric (Curcuma longa):

Acute toxicity studies in rats, guineapigs and monkeys.Indian Journal of Experimental Biology,18(1), 73–75.

Bialik, S., & Kimchi, A. (2008). Autophagy and tumor suppression: Recent advances in understanding the link between autophagic cell death pathways and tumor development.Advances in Experimental Medicine and Biology,615, 177–200.

Cattani, L., Goldoni, P., Pastoris, M. C., Sinibaldi, L., & Orsi, N. (1997).

Bafilomycin A1 and intracellular multiplication ofLegionella pneumo- phila.Antimicrobial Agents and Chemotherapy,41(1), 212–214.

Chatterjee, S. J., & Pandey, S. (2011). Chemoresistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy.Cancer Biology & Therapy,11(2), 216–228.

Chattopadhyay, I., Biswas, K., Bandyopadhyay, U., & Banerjee, R. K.

(2004). Turmeric and curcumin: Biological actions and medicinal applications.Current Science,87, 44–53.

Chen, D., Tao, X., Wang, Y., Tian, F., Wei, Y., Chen, G.,…Chen, G. (2015).

Curcumin accelerates reendothelialization and ameliorates intimal hyperplasia in balloon-injured rat carotid artery via the upregulation of endothelial cell autophagy. International journal of molecular medicine,36(6), 1563–1571.

Choi, A. M. K., Ryter, S. W., & Levine, B. (2013). Autophagy in human health and disease.New England Journal of Medicine,368(7), 651–662.

https://doi.org/10.1056/NEJMra1205406

Choi, D. C., Yoo, M., Kabaria, S., & Junn, E. (2018). MicroRNA‐7 facilitates the degradation of α‐ synuclein and its aggregates by promoting autophagy. Neuroscience Letters, 678, 118–123. https://doi.org/10.

1016/j.neulet.2018.05.009

Cicero, A. F. G., Colletti, A., Bajraktari, G., Descamps, O., Djuric, D. M., Ezhov, M., … Banach, M. (2017). Lipid lowering nutraceuticals in clinical practice: Position paper from an International Lipid Expert Panel.Archives of Medical Science,13(5), 965–1005. https://doi.org/10.

5114/aoms.2017.69326

Dice, J. F. (2007). Chaperone‐mediated autophagy. Autophagy, 3(4), 295–299.

Ding, Q., Bao, J., Zhao, W., Hu, Y., Lu, J., & Chen, X. (2015). Natural autophagy regulators in cancer therapy: A review.Phytochemistry Reviews,14(1), 137–154.

Elmore, S. (2007). Apoptosis: A review of programmed cell death.

Toxicologic Pathology,35(4), 495–516.

Fu, H., Wang, C., Yang, D., Wei, Z., Xu, J., Hu, Z.,…Cai, Q. (2018). Curcumin regulates proliferation, autophagy, and apoptosis in gastric cancer cells by affecting PI3K and P53 signaling.Journal of Cellular Physiology, 233(6), 4634–4642. https://doi.org/10.1002/jcp.26190

Fulda, S. (2008). Betulinic acid for cancer treatment and prevention.

International Journal of Molecular Sciences, 9(6), 1096–1107. https://

doi.org/10.3390/ijms9061096

Ganjali, S., Blesso, C. N., Banach, M., Pirro, M., Majeed, M., & Sahebkar, A.

(2017). Effects of curcumin on HDL functionality. Pharmacological Research,119, 208–218. https://doi.org/10.1016/j.phrs.2017.02.008 Gao, Y., Li, J., Wu, L., Zhou, C., Wang, Q., Li, X., … Wang, H. (2016).

Tetrahydrocurcumin provides neuroprotection in rats after traumatic brain injury: Autophagy and the PI3K/AKT pathways as a potential mechanism.Journal of Surgical Research, 206(1), 67–76. https://doi.

org/10.1016/j.jss.2016.07.014

Garufi, A., Pucci, D., D’Orazi, V., Cirone, M., Bossi, G., Avantaggiati, M. L., &

D’Orazi, G. (2014). Degradation of mutant p53H175 protein by Zn (II) through autophagy.Cell Death & Disease,5(5), e1271. https://doi.org/

10.1038/cddis.2014.217

Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: Cellular and molecular mechanisms.The Journal of Pathology,221(1), 3–12. https://

doi.org/10.1002/path.2697

Goel, A., Kunnumakkara, A. B., & Aggarwal, B. B. (2008). Curcumin as

“Curecumin”: From kitchen to clinic.Biochemical Pharmacology,75(4), 787–809. https://doi.org/10.1016/j.bcp.2007.08.016

Gu, H.-F., Li, H.-Z., Tang, Y.-L., Tang, X.-Q., Zheng, X.-L., Liao, D.-F. (2016).

Nicotinate-curcumin impedes foam cell formation from THP-1 cells through restoring autophagy flux.PloS one,11(4), e0154820.

Guo, L., Shen, Y., Zhao, X., Guo, L., Yu, Z., Wang, D., …Liu, J. (2015).

Curcumin combined with oxaliplatin effectively suppress colorectal carcinoma in vivo through inducing apoptosis.Phytotherapy Research, 29(3), 357–365. https://doi.org/10.1002/ptr.5257

Guo, S., Long, M., Li, X., Zhu, S., Zhang, M., & Yang, Z. (2016). Curcumin activates autophagy and attenuates oxidative damage in EA.hy926 cells via the Akt/mTOR pathway.Molecular Medicine Reports, 13(3), 2187–2193. https://doi.org/10.3892/mmr.2016.4796

Hajavi, J., Momtazi, A. A., Johnston, T. P., Banach, M., Majeed, M., &

Sahebkar, A. (2017). Curcumin: A naturally occurring modulator of adipokines in diabetes. Journal of Cellular Biochemistry, 118(12), 4170–4182. https://doi.org/10.1002/jcb.26121

Han, J., Pan, X. Y., Xu, Y., Xiao, Y., An, Y., Tie, L.,…Li, X. J. (2012). Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage.Autophagy,8(5), 812–825. https://doi.org/10.

4161/auto.19471

He, C., & Klionsky, D. J. (2009). Regulation mechanisms and signaling pathways of autophagy.Annual Review of Genetics,43, 67–93. https://

doi.org/10.1146/annurev‐genet‐102808‐114910

Howell, J. C., Chun, E., Farrell, A. N., Hur, E. Y., Caroti, C. M., Iuvone, P. M.,

& Haque, R. (2013). Global microRNA expression profiling: Curcumin (diferuloylmethane) alters oxidative stress‐responsive microRNAs in human ARPE‐19 cells.Molecular Vision,19, 544–560.

Huang, Z., Ye, B., Dai, Z., Wu, X., Lu, Z., Shan, P., & Huang, W. (2015). Curcumin inhibits autophagy and apoptosis in hypoxia/reoxygenation‐induced

(10)

myocytes.Molecular Medicine Reports,11(6), 4678–4684. https://doi.org/

10.3892/mmr.2015.3322

Høyer‐Hansen, M., & Jäättelä, M. (2008). Autophagy: An emerging target for cancer therapy.Autophagy,4(5), 574–580.

Ibrahim, A., El‐Meligy, A., Fetaih, H., Dessouki, A., Stoica, G., & Barhoumi, R. (2010). Effect of curcumin and Meriva on the lung metastasis of murine mammary gland adenocarcinoma.In Vivo,24(4), 401–408.

Iranshahi, M., Sahebkar, A., Hosseini, S. T., Takasaki, M., Konoshima, T., &

Tokuda, H. (2010). Cancer chemopreventive activity of diversin from Ferula diversivittata in vitro and in vivo. Phytomedicine, 17(3‐4), 269–273. https://doi.org/10.1016/j.phymed.2009.05.020

Jaroonwitchawan, T., Chaicharoenaudomrung, N., Namkaew, J., & Noisa, P.

(2017). Curcumin attenuates paraquat‐induced cell death in human neuroblastoma cells through modulating oxidative stress and autophagy.

Neuroscience Letters,636, 40–47. https://doi.org/10.1016/j.neulet.2016.

10.050

Jayakiran, M. (2015). Apoptosis‐biochemistry: A mini review.Journal of Clinical and Experimental Pathology,5, 1–4.

Jia, Y. L., Li, J., Qin, Z. H., & Liang, Z. Q. (2009). Autophagic and apoptotic mechanisms of curcumin‐induced death in K562 cells.Journal of Asian Natural Products Research,11(11), 918–928. https://doi.org/10.1080/

10286020903264077

Jiang, A., Wang, X., Shan, X., Li, Y., Wang, P., Jiang, P., & Feng, Q. (2015).

Curcumin reactivates silenced tumor suppressor gene RARβ by reducing DNA methylation. Phytotherapy Research, 29(8), 1237–1245. https://doi.org/10.1002/ptr.5373

Keihanian, F., Saeidinia, A., Bagheri, R. K., Johnston, T. P., & Sahebkar, A.

(2018). Curcumin, hemostasis, thrombosis and coagulation.Journal of Cellular Physiology, 233(6), 4497–4511. https://doi.org/10.1002/jcp.

26249

Kim, J. Y., Cho, T. J., Woo, B. H., Choi, K. U., Lee, C. H., Ryu, M. H., & Park, H. R.

(2012). Curcumin‐induced autophagy contributes to the decreased survival of oral cancer cells.Archives of Oral Biology,57(8), 1018–1025.

https://doi.org/10.1016/j.archoralbio.2012.04.005

Kondo, Y., & Kondo, S. (2006). Autophagy and cancer therapy.Autophagy, 2(2), 85–90.

Kovaleva, V., Mora, R., Park, Y. J., Plass, C., Chiramel, A. I., Bartenschlager, R.,

… Seiffert, M. (2012). MiRNA‐130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells.Cancer Research,72(7), 1763–1772. https://doi.org/10.1158/0008‐ 5472.CAN‐11‐3671

Lagisetty, P., Vilekar, P., Sahoo, K., Anant, S., & Awasthi, V. (2010).

CLEFMA—An anti‐proliferative curcuminoid from structure–activity relationship studies on 3,5‐bis(benzylidene)‐4‐piperidones.Bioorganic

& Medicinal Chemistry,18(16), 6109–6120. https://doi.org/10.1016/j.

bmc.2010.06.055

Lao, C. D., Ruffin, M. T., Normolle, D., Heath, D. D., Murray, S. I., Bailey, J. M.,

…Brenner, D. E. (2006). Dose escalation of a curcuminoid formulation.

BMC Complementary and Alternative Medicine,6(1), 10. https://doi.org/10.

1186/1472‐6882‐6‐10

Lee, H. R., Kim, D. H., Kim, M. G., Lee, J. S., Hwang, J. H., & Lee, H. T.

(2016). The regulation of autophagy in porcine blastocysts: Regulation of PARylation‐mediated autophagy via mammalian target of rapamycin complex 1 (mTORC1) signaling. Biochemical and Biophysical Research Communications,473(4), 899–906. https://doi.org/10.1016/

j.bbrc.2016.03.148

Lee, Y., & Gustafsson, Å. B. (2009). Role of apoptosis in cardiovascular disease.Apoptosis,14(4), 536–548. https://doi.org/10.1007/s10495‐ 008‐0302‐x

Lee, Y. J., Kim, N. Y., Suh, Y. A., & Lee, C. (2011). Involvement of ROS in curcumin‐induced autophagic cell death. The Korean Journal of Physiology & Pharmacology, 15(1), 1–7. https://doi.org/10.4196/kjpp.

2011.15.1.1

Li, H., Zhang, Y., Cao, L., Xiong, R., Zhang, B., Wu, L.,…Chen, S.-D. (2014).

Curcumin could reduce the monomer of TTR with Tyr114Cys

mutation via autophagy in cell model of familial amyloid polyneuropathy.Drug design, development and therapy,8, 2121.

Li, W., Zhou, Y., Yang, J., Li, H., Zhang, H., & Zheng, P. (2017). Curcumin induces apoptotic cell death and protective autophagy in human gastric cancer cells.Oncology Reports,37(6), 3459–3466. https://doi.

org/10.3892/or.2017.5637

Li, X., Feng, K., Li, J., Yu, D., Fan, Q., Tang, T.,…Wang, X. (2017). Curcumin inhibits apoptosis of chondrocytes through activation ERK1/2 signaling pathways induced autophagy. Nu, 9(4), 414. https://doi.

org/10.3390/nu9040414

Li, X-J., Han, J. (2013). Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage.The FASEB Journal,27(Suppl. 1), lb613–lb6133.

Lima, T. I., Araujo, H. N., Menezes, E. S., Sponton, C. H., Araújo, M. B., Bomfim, L. H. M.,…Silveira, L. R. (2017). Role of microRNAs on the regulation of mitochondrial biogenesis and insulin signaling in skeletal muscle.Journal of Cellular Physiology,232(5), 958–966. https://doi.org/

10.1002/jcp.25645

Liu, J., Li, M., Wang, Y., & Luo, J. (2017). Curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR‐143 and miR‐143 mediated autophagy inhibition.Journal of Drug Targeting, 25(7), 645–652. https://doi.org/10.1080/1061186X.2017.1315686.

Liu, X., Shao, K., & Sun, T. (2013). SIRT1 regulates the human alveolar epithelial A549 cell apoptosis induced by Pseudomonas aeruginosa lipopolysaccharide.Cellular Physiology and Biochemistry,31(1), 92–101.

https://doi.org/10.1159/000343352

Marques, O., & Outeiro, T. F. (2012). α‐Synuclein: From secretion to dysfunction and death.Cell Death & Disease,3, e350. https://doi.org/

10.1038/cddis.2012.94

Masuelli, L., Benvenuto, M., Di Stefano, E., Mattera, R., Fantini, M., De Feudis, G., … Bei, R. (2017). Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line.Oncotarget,8(21), 34405–34422. https://doi.

org/10.18632/oncotarget.14907

Mihaylova, M. M., & Shaw, R. J. (2011). The AMP signaling pathway coordinates cell growth, autophagy, & metabolism.Nature Cell Biology, 13(9), 1016–1023. https://doi.org/10.1038/ncb2329

Mirzaei, H., Naseri, G., Rezaee, R., Mohammadi, M., Banikazemi, Z., Mirzaei, H. R.,…Sahebkar, A. (2016). Curcumin: A new candidate for melanoma therapy? International Journal of Cancer, 139(8), 1683– 1695. https://doi.org/10.1002/ijc.30224

Mohajeri, M., Behnam, B., Cicero, A. F. G., & Sahebkar, A. (2018).

Protective effects of curcumin against aflatoxicosis: A comprehensive review.Journal of Cellular Physiology,233(4), 3552–3577. https://doi.

org/10.1002/jcp.26212.

Molina‐Jijón, E., Aparicio‐Trejo, O. E., Rodríguez‐Muñoz, R., León‐Contreras, J. C., Del carmen cárdenas‐Aguayo, M., Medina‐ Campos, O. N.,…Pedraza‐Chaverri, J. (2016). The nephroprotection exerted by curcumin in maleate‐induced renal damage is associated with decreased mitochondrial fission and autophagy.BioFactors,42(6), 686–702. https://doi.org/10.1002/biof.1313

Momtazi, A. A., Shahabipour, F., Khatibi, S., Johnston, T. P., Pirro, M., &

Sahebkar, A. (2016). Curcumin as a microRNA regulator in cancer: A review. Reviews of Physiology, Biochemistry and Pharmacology, 171, 1–38. https://doi.org/10.1007/112_2016_3

Momtazi‐Borojeni, A. A., Haftcheshmeh, S. M., Esmaeili, S. A., Johnston, T. P., Abdollahi, E., & Sahebkar, A. (2018). Curcumin: A natural modulator of immune cells in systemic lupus erythematosus.Autoimmunity Reviews, 17(2), 125–135. https://doi.org/10.1016/j.autrev.2017.11.016 Mosieniak, G., Adamowicz, M., Alster, O., Jaskowiak, H., Szczepankiewicz,

A. A., Wilczynski, G. M., … Sikora, E. (2012). Curcumin induces permanent growth arrest of human colon cancer cells: Link between senescence and autophagy.Mechanisms of Ageing and Development, 133(6), 444–455. https://doi.org/10.1016/j.mad.2012.05.004.

(11)

Niu, T., Tian, Y., Mei, Z., & Guo, G. (2016). Inhibition of autophagy enhances curcumin united light irradiation‐induced oxidative stress and tumor growth suppression in human melanoma cells.Scientific Reports,6, 31383. https://doi.org/10.1038/srep31383

Noorafshan, A., & Ashkani‐Esfahani, S. (2013). A review of therapeutic effects of curcumin.Current Pharmaceutical Design,19(11), 2032–2046.

O’Sullivan‐Coyne, G., O’sullivan, G. C., O’Donovan, T. R., Piwocka, K., &

McKenna, S. L. (2009). Curcumin induces apoptosis‐independent death in oesophageal cancer cells.British Journal of Cancer, 101(9), 1585–1595. https://doi.org/10.1038/sj.bjc.6605308

Ojha, R., Bhattacharyya, S., & Singh, S. K. (2015). Autophagy in cancer stem cells: A potential link between chemoresistance, recurrence, and metastasis.BioResearch,4(1), 97–108. https://doi.org/10.1089/biores.

2014.0035

Oyama, Y., Masuda, T., Nakata, M., Chikahisa, L., Yamazaki, Y., Miura, K., &

Okagawa, M. (1998). Protective actions of 5′‐n‐alkylated curcumins on living cells suffering from oxidative stress. European Journal of Pharmacology,360(1), 65–71.

Pal, S., Bhattacharyya, S., Choudhuri, T., Datta, G. K., Das, T., & Sa, G.

(2005). Amelioration of immune cell number depletion and potentia- tion of depressed detoxification system of tumor‐bearing mice by curcumin.Cancer Detection and Prevention,29(5), 470–478. https://doi.

org/10.1016/j.cdp.2005.05.003

Pal, S., Choudhuri, T., Chattopadhyay, S., Bhattacharya, A., Datta, G. K., Das, T., & Sa, G. (2001). Mechanisms of curcumin‐induced apoptosis of Ehrlich’s ascites carcinoma cells.Biochemical and Biophysical Research Communications, 288(3), 658–665. https://doi.org/10.1006/bbrc.

2001.5823

Panahi, Y., Alishiri, G. H., Parvin, S., & Sahebkar, A. (2016). Mitigation of systemic oxidative stress by curcuminoids in osteoarthritis: Results of a randomized controlled trial.Journal of Dietary Supplements,13(2), 209– 220. https://doi.org/10.3109/19390211.2015.1008611

Panahi, Y., Ghanei, M., Bashiri, S., Hajihashemi, A., & Sahebkar, A. (2014).

Short‐term curcuminoid supplementation for chronic pulmonary complications due to sulfur mustard intoxication: Positive results of a randomized double‐blind placebo‐controlled trial.Drug Research,65(11), 567–573. https://doi.org/10.1055/s‐0034‐1389986

Panahi, Y., Ghanei, M., Hajhashemi, A., & Sahebkar, A. (2016). Effects of curcuminoids‐piperine combination on systemic oxidative stress, clinical symptoms and quality of life in subjects with chronic pulmonary complications due to sulfur mustard: A randomized controlled trial. Journal of Dietary Supplements, 13(1), 93–105.

https://doi.org/10.3109/19390211.2014.952865

Panahi, Y., Hosseini, M. S., Khalili, N., Naimi, E., Majeed, M., & Sahebkar, A.

(2015). Antioxidant and anti‐inflammatory effects of curcuminoid‐ piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta‐analysis. Clinical Nutrition, 34(6), 1101–1108. https://doi.org/10.1016/j.clnu.2014.

12.019

Panahi, Y., Kianpour, P., Mohtashami, R., Jafari, R., Simental‐Mendía, L. E.,

& Sahebkar, A. (2016). Curcumin lowers serum lipids and uric acid in subjects with nonalcoholic fatty liver disease: A randomized controlled trial.Journal of Cardiovascular Pharmacology,68(3), 223–229.

https://doi.org/10.1097/FJC.0000000000000406

Panahi, Y., Saadat, A., Beiraghdar, F., & Sahebkar, A. (2014). Adjuvant therapy with bioavailability‐boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: A randomized double‐blind placebo‐controlled trial. Phy- totherapy Research, 28(10), 1461–1467. https://doi.org/10.1002/

ptr.5149

Paulino, N., Paulino, A. S., Diniz, S. N., de Mendonça, S., Gonçalves, I. D., Flores, F. F., … Suarez, J. A. Q. (2016). Evaluation of the anti- inflammatory action of curcumin analog (DM1): Effect on iNOS and COX-2 gene expression and autophagy pathways. Bioorganic &

medicinal chemistry,24(8), 1927–1935.

Pellacani, C., & Costa, L. G. (2018). Role of autophagy in environmental neurotoxicity.Environmental Pollution,235, 791–805. https://doi.org/

10.1016/j.envpol.2017.12.102

Prasad, S., Gupta, S. C., Tyagi, A. K., & Aggarwal, B. B. (2014). Curcumin, a component of golden spice: From bedside to bench and back.

Biotechnology Advances,32(6), 1053–1064. https://doi.org/10.1016/j.

biotechadv.2014.04.004

Priyadarsini, K. (2014). The chemistry of curcumin: From extraction to therapeutic agent.Molecules,19(12), 20091–20112. https://doi.org/

10.3390/molecules191220091

Qu, W., Xiao, J., Zhang, H., Chen, Q., Wang, Z., Shi, H.,…Lv, J. (2013). B19, a novel monocarbonyl analogue of curcumin, induces human ovarian cancer cell apoptosis via activation of endoplasmic reticulum stress and the autophagy signaling pathway. International Journal of Biological Sciences,9(8), 766–777. https://doi.org/10.7150/ijbs.5711

Rahmani, S., Asgary, S., Askari, G., Keshvari, M., Hatamipour, M., Feizi, A.,

& Sahebkar, A. (2016). Treatment of nonalcoholic fatty liver disease with curcumin: A randomized placebo‐controlled trial.Phytotherapy Research,30(9), 1540–1548. https://doi.org/10.1002/ptr.5659 Ranjan, K., Sharma, A., Surolia, A., & Pathak, C. (2014). Regulation of

HA14‐1 mediated oxidative stress, toxic response, and autophagy by curcumin to enhance apoptotic activity in human embryonic kidney cells.BioFactors,40(1), 157–169. https://doi.org/10.1002/biof.1098 Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011). Autophagy and aging.

Cell,146(5), 682–695. https://doi.org/10.1016/j.cell.2011.07.030 Sahebkar, A. (2014). Curcuminoids for the management of hypertrigly-

ceridaemia. Nature Reviews Cardiology, 11(2), 123–123. https://doi.

org/10.1038/nrcardio.2013.140‐c1

Sahebkar, A. (2015). Dual effect of curcumin in preventing atherosclero- sis: The potential role of pro‐oxidant–antioxidant mechanisms.Natural Product Research,29(6), 491–492. https://doi.org/10.1080/14786419.

2014.956212

Sahebkar, A., Cicero, A. F. G., Simental‐Mendía, L. E., Aggarwal, B. B., &

Gupta, S. C. (2016). Curcumin downregulates human tumor necrosis factor‐αlevels: A systematic review and meta‐analysis ofrandomized controlled trials.Pharmacological Research,107, 234–242. https://doi.

org/10.1016/j.phrs.2016.03.026

Sahebkar, A., & Henrotin, Y. (2016). Analgesic efficacy and safety of curcuminoids in clinical practice: A systematic review and meta‐ analysis of randomized controlled trials.Pain Medicine,17(6), 1192– 1202. https://doi.org/10.1093/pm/pnv024

Shakeri, A., & Sahebkar, A. (2016). Optimized curcumin formulations for the treatment of Alzheimer’s disease: A patent evaluation. Journal of Neuroscience Research,94(2), 111–113. https://doi.org/10.1002/jnr.23696 Sharma, O. P. (1976). Antioxidant activity of curcumin and related

compounds.Biochemical Pharmacology,25(15), 1811–1812.

Sharma, R. A., Gescher, A. J., & Steward, W. P. (2005). Curcumin: The story so far.European Journal of Cancer,41(13), 1955–1968. https://doi.org/

10.1016/j.ejca.2005.05.009

Shishodia, S., Sethi, G., & Aggarwal, B. B. (2005). Curcumin: Getting back to the roots.Annals of the New York Academy of Sciences, 1056(1), 206–217. https://doi.org/10.1196/annals.1352.010

Singletary, K., & Milner, J. (2008). Diet, autophagy, and cancer: A review.

Cancer Epidemiology and Prevention Biomarkers, 17(7), 1596–1610.

https://doi.org/10.1158/1055‐9965.EPI‐07‐2917

Stoller, C., Braekman, J. C., Daloze, D., & Vandevyver, G. (1988). 3‐ Methyladenine from the marine spongeTopsentia genitrix.Journal of Natural Products,51(2), 383–384.

Sugimoto, K., Hanai, H., Tozawa, K., Aoshi, T., Uchijima, M., Nagata, T., &

Koide, Y. (2002). Curcumin prevents and ameliorates trinitrobenzene sulfonic acid‐induced colitis in mice. Gastroenterology, 123(6), 1912–1922. https://doi.org/10.1053/gast.2002.37050

Tiribuzi, R., Crispoltoni, L., Porcellati, S., Di Lullo, M., Florenzano, F., Pirro, M.,

…Orlacchio, A. (2014). MiR128 up‐regulation correlates with impaired amyloidβ(1‐42) degradation in monocytes from patients with sporadic