Curcumin has an anti-tumor role in gastric cancer cells via inhibiting invasion and proliferation and inducing apoptotic cell death

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ABSTRACT​

Curcumin is a phenolic pigment, naturally present in Curcuma longaspecies. It is a yellow active ingredient and shows a pivotal role in the modulation of biological processes resulting in the prevention of cancer particularly due to its radical scavenging activities. In gastrointestinal cancer cells, curcumin has been shown to induce cell death through apoptosis and to cause cell cycle arrest, down-regulating glycolytic enzyme expressions alongside inhibition of the matrix metalloproteinase-2 (MMP-2) promoter activity and SDF-1α-induced cell invasion. It also activates the expression of cleaved caspase-3, reduces cell viability, regulates the ratio of Bcl-2/Bax, decreases the number of cells in the proliferative G0/G1 phase and increases the number of cells in the S phase. Additionally, curcumin prevents DNA from replication during the S phase. This review discusses the chemo-preventive role of curcumin and its mechanisms against human gastrointestinal cancers to understand its activity and potential utilization as a therapeutic moiety.

 

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1. Introduction​

A deadly disease like cancer causes a great deal of death on a global scale (Mohan et al., Citation2020). Cancer is brought on by genetic mutations (Patra et al., Citation2020). These mutations cause dysregulations in the molecular signaling pathways that aid in the genesis and progression of cancer (Tewari et al., Citation2019). Numerous malignant behaviors distinguish cancer cells from healthy cells, including prolonged growth signals, resistance to apoptosis, resistance to anti-growth factors, migration and metastasis into nearby and distant cells and tissues, increased angiogenesis, enhanced proliferative capacity, and genome instability (Banik et al., Citation2019).

Cancer incidence rates continue to rise, endangering the general public’s health. According to epidemiological research, cancer poses a serious hazard to a large number of people worldwide (J. X. Hu et al., Citation2021). For instance, it is projected that there would be 23 million cancer patients by 2035, which is a significant increase from the 14 million cases reported in 2012 (Ferlay et al., Citation2015). The basic causes of cancer formation and their regulation through pharmacological and genetic therapies must therefore be thoroughly researched. It is now pretty evident that anomalies in signaling networks play a major role in the development of cancer thanks to studies conducted in recent decades and cellular approaches employed for genomics screening (Ashrafizadeh et al., Citation2020).

Globally, gastrointestinal (GI) cancers are prevailing at alarming rates and 65% of the deaths from reported cases are being recorded in the Asian region followed by Europe and North America (Arnold et al., Citation2020). To cure malignancy, various approaches are adopted amongst which the treatment from natural compounds is preferred due to their safer nature and fewer or no side effects. The phrase “gastrointestinal (GI) cancers” refers to malignancies that can develop in any part of the gastrointestinal tract, including the oesophagus, pancreas, liver, small intestine, colorectum, and stomach (Thomson et al., Citation2003). With an additional 5.0 million new cases diagnosed in the same year, they are predicted to be responsible for 3.5 million deaths globally in 2020. After lung and breast cancers, colorectal cancer is the most prevalent type of GI cancer. By comparison, gastric, liver, esophageal, and pancreatic cancers are ranked as the fifth, sixth, eighth, and twelfth most frequently diagnosed cancers, respectively (Sung et al., Citation2021).

 

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Turmeric (Curcuma longa) belongs to the ginger family Zingiberaceae. It has many functional and nutraceutical properties and rich source of curcumin. It is a type of herb and is used as a spice to naturally add color and taste to different food items. It has promising beneficial health-promoting perspectives due to the presence of the bioactive compound curcumin having an orange-yellow color and is lipophilic in nature (Kocaadam & Şanlier, Citation2017). It has been reported that tumors can be reduced at different stages of the cell cycle using curcumin. It blocks various enzymes that participate in the growth and development of tumors and may resist tumor treatment. Furthermore, curcumin also modulates cellular progressions, i.e., protein kinase C activity, EGF (epidermal growth factor) receptor intrinsic kinase activity, nuclear factor kappa (NF-kB) activity, nitric oxide synthesize activity, and suppresses lipid peroxidation (Imran et al., Citation2018). Curcumin, a plant-derived polyphenol, has been identified as a therapeutically effective food that exhibits pleiotropic pharmacological effects on a variety of malignancies (Lim, Citation2022). Di-hydrocurcumin, tetra-hydrocurcumin, hexa-hydrocurcumin and octa-hydrocurcumin are most common metabolites of curcumin in a cellular culture. Among these, tetra-hydrocurcumin and hexa-hydrocurcumin are most abundant. Although several studies, both in vitro and in vivo, have explored the metabolic pathways of curcumin’s secondary metabolites, direct relation of these metabolites in amelioration of cancer prevention or treatments has not been made. The most documented functions of these metabolites are anti-oxidative and anti-inflammatory, which could lead to the speculation that they play an anti-cancer role (Aggarwal et al., Citation2014; Pandey et al., Citation2020).

Curcumin has an anti-tumor role in gastric cancer cells via inhibiting invasion and proliferation and inducing apoptotic cell death in experimental subjects (Kwiecien et al., Citation2019). Curcumin has been chosen by the National Cancer Institute as a third-generation cancer chemo preventive drug (Abd El‐Hack et al., Citation2021). In different in vivo and in vitro studies, curcumin has exhibited anticancer effects involving mechanisms such as reduction in the formation of liver tumors, suppression of metastasis of primordial germ cell (PGC), CXCR4 expression, and inhibition of stromal cell-derived factor-1/CXCR4 signaling (Gu et al., Citation2019). Furthermore, curcumin suppresses the p-Akt protein expression, increments in PTEN expression, and reduction in miR-21 levels. It also shows suppression of STAT3 phosphorylation, blocked STAT3-mediated signaling, induction of growth arrest, and apoptosis (Qiang et al., Citation2019). Curcumin has the effects of reducing the dosage, resistance and side effects of chemotherapy drugs, besides a pivotal role in the modulation of biological processes resulting in the prevention of cancer particularly due to its radical scavenging activities and other mechanisms (Zhou et al., Citation2011, Citation2017). The anti-neoplastic effects of curcumin are attained by the suppression of molecular pathways involving proliferation and inflammation and supporting the development of colorectal cancer. In a mouse model of colorectal cancer fed with a diet supplemented with curcumin, there is a reduction in the incidence of cancer, colonic inflammation, and the formation of adenoma/adenocarcinomas (Guo et al., Citation2018). Curcumin has been shown to have positive effects that can reduce tumor volume and chemoresistance in preclinical studies which examine the interaction between curcumin and colorectal cancer chemotherapeutics, such as 5-fluorouracil or oxaliplatin (Hosseini et al., Citation2017). Several studies done by using curcumin in conjunction with various anticancer compounds, as in piperine, selenium, prednisolone and ursolic acid, have shown significant suppression, reduction/inhibition of IL-6, IL-1β, IL-19, TNF-α and COX-2 (Al-Dossari et al., Citation2020; X. Q. Hu et al., Citation2016; Neyrinck et al., Citation2013; Tremmel et al., Citation2019; Yan et al., Citation2019). While flavocoxid in combination with curcumin reduced the transcription factors NF-κB and STAT3 mRNA expression (D’Ascola et al., Citation2019). In similar in vivo studies, boswellic acid and irbesartan in combination with curcumin showed reduction in TNF-α and IL-6 cytokines (Khaled & Mahfouz, Citation2010; Khayyal et al., Citation2018). Reduction in EGFR signaling and glycogen synthase kinase-3 was also observed when paclitaxel was used in conjunction with curcumin (M. Zhou et al., Citation2015). Meanwhile, increased apoptosis and downregulation of XIAP was reported when curcumin was used with resveratrol (Du et al., Citation2013). Since curcumin’s competency to inhibit different cancers is of great importance, the main objective of this review is to summarize specifically its roles in the prevention of gastrointestinal cancers (Figure 1).

Figure 1. Scheme of therapeutic potentials of curcumin against gastrointestinal cancers.

 

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Your biggest problem is not cancer but your large pussy with std, cure that first.

 

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Cut off your cb and chemo your hole.

 

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1.1. Chemical structure and source of curcumin​

Curcumin is a plant derived phenolic compound naturally present in turmeric. It is also present in mango ginger. It has health endorsing potential due to its antioxidant and anti-inflammatory properties as well as exhibits antiviral, antibacterial, and anticancer activities.

Curcumin belongs to the group of curcuminoids, yellow pigment polyphenol. It has been used historically in ayurvedic medicines. It is a combination of a seven-carbon linker and three functional groups: an α, β-unsaturated, β-diketone moiety, and O-methoxy-phenolic group. The O-methoxy-phenolic group is linked by two α, β-unsaturated carbonyl groups shown in Figure 1 (Kita et al., Citation2008). In acidic/neutral aqueous solutions and cell membranes, the keto form is predominant. On the other hand, in an alkaline medium, the enol form of the heptadienone chain predominates. Due to the presence of a highly active, central carbon atom, the keto form of curcumin functions as a very potent H-atom donor in the pH range of 3–7. Because of the delocalization of the unpaired electrons on the nearby oxygens, the C-H bonds of this carbon are particularly weak. The heptadienone moiety of curcumin’s keto-enol-enolate balance controls its physicochemical and antioxidant characteristics (Stanić, Citation2017).

 

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Your biggest problem is not cancer but your large pussy with std, cure that first.

 

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2. Anticancer perspectives​

Curcumin shows multispectral anticancer effects and recent studies have explored its mechanism of action to design and develop anticancer therapies. Anticancer role of curcumin against gastrointestinal cancers has been summarized in Table 1. The effect of curcumin treatments on various gastrointestinal cancers is discussed below.

Table 1. Anticancer role and mechanisms of curcumin against gastrointestinal cancers.​

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2.5. Stomach or gastric cancer​

The induction of DMH (dimethylhydrazine) is associated with cancer-causing agent in experimental subjects via enhancing p53 protein expressions along with phosphorylation of p53, significantly increasing the glucose (14C) and 3 H-thymidine uptake, lactate dehydrogenase and alkaline phosphatase activities, and declining the p53 acetylation at residue 382. On the other side, curcumin treatment for the DMH-treated rats normalized these changes to normal levels (Silva et al., Citation2018). Curcumin treated with HGC-27 markedly lowered cell viability, inhibited invasion & migration, negatively regulated the metalloproteinase 2 expression, and induced apoptosisin a dose-dependent way (Dhivya et al., Citation2017; Haghi et al., Citation2017; X. Zhou et al., Citation2016). Likewise, curcumin (25 μm) suppresses cell growth, causes apoptosis, up-regulates the caspase-3, lowers gastrin secretion, enhances gastric pH, lowers gastric secretion, and inhibits gastric cancer progression in gastric cancer cells of mice. Likewise, a different group of researchers reported diverse anticancer mechanisms in MKN-28 and BGC-823 (human gastric cancer cell lines) attributed to curcumin in a dose and time-dependent way. The curcumin potentially suppressed the cell viability, active-caspase-3, caused cell apoptosis, increased the Bax protein, reduced the bcl-2 protein, −9, as well as also enhanced the autophagy-related proteins (Beclin1, Atg5, Atg7 and Atg12), and suppressed the PI3K/Akt/mTOR activation. Moreover, treatment with curcumin also caused the formation of vesicular organelles which are acidic in nature in cytoplasm, alteration of LC3-I into LC3-II (Tung et al., Citation2018; D. Yang et al., Citation2017). Mechanisms

 

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Another study on time and dose levels of curcumin has following anticancer mechanisms in BGC-823, SGC-7901, and MKN-28 (human gastric cancer cell lines) such as (i) reducing of cell viability, (ii) initiation of apoptosis, (iii) induction of autophagy, and (iv) inhibition of activation signaling pathway of PI3K/Akt/mTOR. In an in vivo study conducted by Wang and their colleagues, they explored that curcumin in gastric cancer of nude mice models markedly exhibited inhibition on cell growth and proliferation, regulation of cellular redox homeostasis, and disruption of mitochondrial homeostasis. In addition, it also lowered oxygen consumption by mitochondria and glycolysis (aerobic) via decreasing DNA polymerase γ (POLG) and mtDNA content (Xu et al., Citation2018). The decrease in cell production and initiation of apoptosis in BGC-823 and SGC-7901 (human gastric cancer cell lines) were also reported in vitro study after treatment with 5–40 μmol/L of curcumin (Silva et al., Citation2018). Multiple anticancer approaches are involved after combining the effect of curcumin with 5-FU (5-fluorouracil) and oxaliplatinhas in BGC-823 (gastric cancer cell line). Both compounds increased the level caspase 3, 8, and 9 and Bax, down-regulated the expression of Bcl-2 protein and mRNA and induced apoptosis (Dhivya et al., Citation2017; X. Zhou et al., Citation2016). A study conducted by a group of researchers on the supplementation of curcumin (IC50 40.3 μM) exhibited anticancer potential in a dose-dependent manner in gastric cancer cell line through increasing the cell death rate, downregulating survivin expression, and pSTAT3 levels (Haghi et al., Citation2017). Likewise, another study explicated that curcumin in combination with quercetin markedly inhibited proliferation of cells along with cytochrome c release, reduction in the membrane potential of mitochondria, ERK and AKT reduction in phosphorylation (J. Y. Zhang et al., Citation2015).

 

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In a scientific investigation, gastric cancer was induced in mice by tobacco deactivated the ERK1/2 (extracellular protein kinases 1 and 2), activator AP-1 (protein 1), ERK5 MAPK pathways, the JNK (Jun N-terminal kinase), p38, caused an enhancement in protein and mRNA levels of the epithelial markers (ZO-1 and E-cadherin) and N-cadherin reduction in protein and mRNA levels. Conversely, curcumin treatment significantly reverted these changes in gastric cell lines cancer. Furthermore, curcumin also abrogated JNK MAPK pathways, activation of ERK1/2 caused by TS, changes in EMT (Z. Liang et al., Citation2015). Another research conducted by Liang et al. evaluated the different doses of curcumin (80 to 160 mg/kg/day) on gastric cancer cell line (SGC-7901) and found loweredProx-1 (Prospero homeobox 1), VEGFR- (3 vascular endothelial growth factor receptor 3), and LVD (podoplanin levels, lymphatic vessel density) (Da et al., Citation2015). Dose-dependent induction of MMP damage and enhancement in the rate of cell apoptosis were reported after curcumin treatment in SGC-7901 (gastric cancer cell line). Likewise, curcumin with diazoxide impaired the MMP damage (Cao et al., Citation2015). In another study by Ji and their colleagues, they reported that curcumin has inhibitory effect on β-catenin and STAT3 pathway in mouse model of gastric cancer (Ji et al., Citation2014).

Kruppel-like factor 4 (KLF4) is a transcription factor that promotes development and progression in different types of carcinomas. Curcumin inhibits apoptosis in human BGC-823 gastric carcinoma cells by inhibiting cell invasion (Z. Liang et al., Citation2015). Curcumin has strong anticancer potential in BGC-823 (human gastric cancer cells) through various processes such as activation of ASK1, suppression of reactive oxygen species, induction and up-regulation of ASK1-MKK4-JNK signaling and their protein expressions (Wu et al., Citation2019)