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Curcumin is a major constituent of turmeric and has been shown to have a plethora of health benefits, which include, among many, antimicrobial, anticancer, and reduction of cholesterol. However, it has also been reported that curcumin has less bioaccumulation and is quickly metabolized and cleared from the body. Nanoparticle formulations are known to increase curcumin biocompatibility and targeting. Additionally, the antimicrobial activity of curcumin has been extensively studied and the mechanism of action provides clues for the development of new drugs for drug-resistant microbes. Thus, this chapter will review the biomedical application of curcumin and its nanoformulations against different microbes and other diseases, including cancer.
Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Polokwane, South Africa
Zukile Mbita*
Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Polokwane, South Africa
*Address all correspondence to: zukile.mbita@ul.ac.za
1. Introduction
Curcumin is the major polyphenol component extracted from the rhizomes of Curcuma longa (C. longa) [1]. Curcuma longa (Figure 1) is a perennial herb of the Zingiberaceae family, which is commonly known as turmeric. The rhizome of C. longa is rectangular, egg-shaped, pyriform, and has a short branching pattern [1]. Across the globe, this tropical and subtropical plant is widely cultivated in Asia, mostly in India and China [2]. This plant is also cultivated in other regions, including Brazil [3], Nepal [4], Indonesia [5], Jamaica [6], and Pakistan [7, 8]. It was the Polish scientists who first proposed the curcumin structure in 1910 [9]. Curcumin is also known as diferuloylmethane and its IUPAC name is (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, with a chemical formula of C21H20O6 and, has a molecular weight of 368.38 [10]. Ever since the first isolation of curcumin by two Harvard college scientists, Vogel and Pelletier in 1815 [11], the interest in curcumin and its derivatives have grown steadily and many studies have discovered their biofunctional properties such as anti-inflammatory, antibacterial, anti-tumor and antioxidant activities [12, 13]. Despite being naturally derived, curcumin’s derivatives (Table 1) are produced by a chemical reaction of aryl-aldehydes with acetylacetone, as a result of this assembly method, multiple chemical analogs can be obtained, for example, compounds in which the middle carbon of the linker (C7) is substituted with an alkyl group [23, 24, 25]. A structural modification of curcumin produces compounds with multiple biological activities, such as those useful in the treatment of diabetes, cardiovascular and neurodegenerative diseases [26].
Figure 1.
A & B: Curcuma longa plant (https://www.istockphoto.com) and the structure of curcumin.
Table 1.
Structures and activities of curcumin and curcumin derivatives/analogs.
Food and Drug Administration (FDA) has confirmed curcumin to be safe [27]. Several studies have found that curcumin and its derivatives may have anti-inflammatory, antibacterial, antidiabetic, antioxidant, and anticancer benefits (Table 1). To possess an anti-inflammatory effect, curcumin blocks the activation of transcription factors, for example, nuclear factor κB (NF-kB), which regulates the expression of pro-inflammatory gene products [28, 29]. The literature on the antibacterial effects of curcumin shows that it damages the cell membranes [30], induces the expression of apoptotic inducers including reactive oxygen species (ROS) [31], and disrupt prokaryotic cell division by inhibiting FtsZ assembly [32]. To relieve diabetic complications, curcumin has been shown to reduce triglycerides levels and inflammation indicators [33]. During inflammation, cyclooxygenase (COX-2) and other pro-inflammatory indicators such NF-κB are produced in greater quantities, these inflammation indicators cause the initiation and development of cancer, thus they are reduced by curcumin [33, 34, 35]. Curcumin also prevented the development and progression of cancer by acting as a strong antioxidant agent by regulating the production of ROS, which influence the tumor microenvironment [36]. Additionally, curcumin exerts its anticancer activity by targeting NF-kB, which regulates the expression of proteins such as interleukin (IL)-1, implicated in multiple cell signaling pathways linked to cancer progression and inflammation [25, 37]. Despite its therapeutic potential, curcumin’s poor aqueous solubility and low bioavailability remain a challenge [13, 38, 39]. Below we will compare literature on the antibacterial and anticancer activities of curcumin, incorporating nanoformulation as an area that can be explored to fix the therapeutic challenges associated with curcumin.
The majority of bacteria are not harmful to humans, and some strains even assist in the digestion of food or compete against opportunistic pathogens, but infection by bacteria is one of the most common ailments among humans [40]. Many diseases are connected to bacterial infections, such as inflammatory bowel diseases [41], obesity [42], diabetes [43], liver diseases [44], heart diseases [45], cancers [46], HIV-AIDS [47], and autism [48]. Infections caused by bacteria are largely treated with antibiotics, but the struggle to defeat bacteria continues because bacteria are evolving and manifesting new resistance mechanisms [49]. Curcumin has shown the potential to solve drug resistance issues by inducing antibacterial effect through membrane disruption [30], inducing increased expression of ROS which can promote apoptosis-like response in bacteria [31, 50], and interrupting cell division [32].
Researchers are documenting more evidence about the antibacterial activities of curcumin against a wide range of bacteria [30, 51, 52]. Curcumin has been demonstrated to be potent against both gram-positive and gram-negative bacteria [30, 53]. An example of a gram-positive bacteria, Staphylococcus aureus (S. aureus), has been demonstrated to be vulnerable to curcumin-mediated inhibition. Staphylococcus aureus is a human pathogen that can cause a variety of diseases including infective endocarditis, a feared disease that affect young to middle-aged adults with heart disease [54, 55].
The antibacterial activity of curcumin against S. aureus has been thoroughly reviewed by Teow et al. [56]. The S. aureus bacteria have developed several mechanisms for evading the human immune system and to resist antibiotic treatment. To salvage S. aureus drug resistance, it has been shown that curcumin binds to FtsZ proteins, inhibiting protofilaments assembly, which then inhibits the formation of Z-rings, eliciting the suppression of cytokinesis and bacterial proliferation [32]. Furthermore, the binding of curcumin to peptidoglycans on S. aureus cell walls, could cause damage to the cell wall and membrane, hence triggering cell lysis [30, 56]. Mechanisms of curcumin on gram-negative bacteria and gram-positive bacteria are summarized in Table 2. In addition to showing its effectiveness as a standalone antibacterial agent, curcumin has also shown marked antibacterial activity when combined with various antibiotics at subinhibitory doses (12.5 and 25 μg/mL) [68, 69]. The collective antibacterial activity of curcumin with antibiotics against methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) is well demonstrated by many researchers [68, 69, 70, 71]. In tests of Helicobacter pylori infection that were done in-vivo, mice infected with this bacteria were eradicated by curcumin [72]. In order for curcumin to exert its bactericidal effects, it appears to cause cell membrane damage [30], thus inhibiting bacterial cell division through the improper assembly of the bacterial protofilament, which provides the framework for bacterial cell division apparatus [62, 73].
There were 19.3 million new cancer cases and 10.0 million cancer-related deaths reported in 2020, worldwide [74]. Considering the increasing cancer statistics and the cost of cancer treatments, finding effective and economically viable methods for patients in low- and middle-income countries is crucial. Cancer-related studies showed that curcumin-induced apoptosis and inhibited proliferation in cancer cells through the activation of the mitochondria-mediated pathway [75], ROS generation [76], and the activation of caspase-3 [77]. Other study suggested that curcumin compounds can prevent either the formation or spread of tumor by inducing apoptosis and inhibiting cell proliferation through antiangiogenic effects [78]. Inhibition of tumor invasion by curcumin is mediated by reducing the modification of the matrix metalloproteases (MMPs), the cell surface proteins NF-κβ, TNF-α, cyclooxygenase-2 (COX-2), chemokines, and growth factors (HER-2, EGFR) [79, 80]. In some tumors, curcumin inhibited angiogenesis by suppressing angiogenic cytokines such as IL-6, IL-23, and IL-1β [81].
Cancer and inflammation have a strong relationship, so the anti-inflammatory effects of curcumin would likely result in antitumor effects. According to Pulido-Moran et al. [81], curcumin prevented the development of several types of cancer by reducing the production of mediators of inflammation, such as COX-2 and lipoxygenase 2. The antitumor effect of curcumin has been shown in breast cancer [82], lung cancer [83], leukemia [84], gastric cancer [85], colorectal cancer [86], esophageal cancer [87] and prostate cancer [88]. Curcumin has been shown to regulate key processes involved in cancer development and progression (Figure 2).
Figure 2.
Cancer processes regulated by curcumin.
3.1 Induction of apoptosis
As a form of cell death, apoptosis is a highly regulated physiological process, which removes not only damaged, mutated, aged, and unrepairable cells, but also preserves the integrity and health of the entire organism. Apoptosis imbalances, either excessive or insufficient, may contribute to a variety of diseases including cancer [89, 90]. As a cancer cell growth inhibitor, curcumin modulates multiple cellular signaling pathways such as those that induce apoptosis in several cancers including breast [91], malignant pleural mesothelioma [92], gastric cancer [93], acute lymphoblastic leukemia [94], lung cancer [95], pancreatic cancer [96] and gallbladder carcinoma [97].
Curcumin potentiate apoptosis in cancer due to its ability to induce increased activation of Bax [92], cleavage of poly (ADP-ribose) polymerase (PARP) [92], blocking the PI3K-Akt–mTOR signaling pathway [98, 99], dephosphorylation of Bad [95] and the downregulation of Bcl-2 proteins [96].
3.2 Modulation of cell survival pathways
A number of signaling pathways have been shown to drive unregulated self-renewal and differentiation in cells leading to cancer [100, 101, 102]. The antitumor activities of curcumin have been studied extensively; a growing body of evidence indicates that curcumin is involved in the inhibition of growth/proliferation pathways and activation of cell death pathways [103, 104, 105, 106, 107]. The fact that curcumin acts through multiple signaling pathways makes it unlikely to develop resistance.
Curcumin regulates multiple cell survival signaling pathways including Wnt/β-catenin pathway [104], NF-κB signaling pathway [105], PI3K/Akt signaling pathway [106], and JAK-STAT3 pathway [107], which regulate different sets of target genes that are involved in cell proliferation, cell survival, and differentiation. The regulation of these cell survival pathways by curcumin has been demonstrated in breast cancer [99, 105], colon cancer [104], bladder cancer [106], lung cancer [108], and liver cancer [109].
3.3 Inhibition of metastasis
Relapse of cancer patients is commonly attributed to cancer invasion and migration, and researchers have been focusing their attention on invasion as an important step in metastasis [110]. Curcumin has shown promising potential for the treatment of cancer by inhibiting metastasis, previous studies have shown that curcumin reduces cancer metastasis by suppressing NF-kB and matrix metalloproteinases (MMPs) expression in cancer animal models [111, 112]. Tumor metastasis is promoted by NF-kB through modulation of cell adhesion molecules including selectins, integrins, and their ligands, NF-kB also induces epithelial-mesenchymal transition, which aids distant metastasis [113]. MMPs also show similar mechanisms by degrading extracellular matrix components resulting in tumor cell migration [114].
Research on the anti-metastasis effect of curcumin continues to pile up, and Sreenivasan et al. [115] showed that curcumin inhibited the metastasis of nasopharyngeal carcinomas (NPCs) by inhibiting miR-125a-5p as a consequence, increasing p53 expression. In prostate cancer, the anti-metastasis effect of curcumin was achieved by decreasing miR-21 and increasing phosphatase and tensin homolog (PTEN) [116]. A recent study of the anti-metastasis effect of curcumin is shown in gastrointestinal cancers, according to this study, curcumin inhibited cell invasion in these cells [117], these results suggest that curcumin inhibits metastasis in cancer by targeting multiple anticancer pathways.
Despite the advantages of curcumin in treating different diseases, the insolubility of curcumin contributes to its poor oral bioavailability and low chemical stability, which limits its application [13, 38, 39]. Moreover, the cellular uptake of curcumin is low, as a result of its hydrophobicity, curcumin penetrates into the cell membrane and binds to the fatty acyl chains of membrane lipids through hydrogen bonds and hydrophobic interactions, resulting in low curcumin levels inside the cytoplasm [56, 118]. These curcumin challenges are resolved by the use of nanoformulations.
Nanoparticles (NPs) have improved the main drawbacks associated with the use of curcumin in biomedical applications, these shortcomings include its rapid metabolism, low solubility, and poor bioavailability, which are considered major obstacles for the treatment of cancer [119], wound healing [120], Alzheimer’s disease [121], epilepsy [122] ischemia [123], and inflammatory diseases [124]. The delivery of therapeutic concentrations of curcumin using nanoparticles is emerging as one of the most useful alternatives to treat different diseases including cancer and microbial infections (Figure 3). Table 3 summarizes the therapeutic potential of curcumin-loaded nanoparticles on different diseases.
Figure 3.
Curcumin-loaded nanoparticles induce cell death in both cancer and bacterial cells.
Nanoparticle
Disease
Outcome
Reference/s
Gold
Prostate cancer Colorectal cancer Renal cancer
Improved solubility Augmented antioxidant and anticancer effects
Summary of the activities of curcumin-loaded nanoparticles for the treatment of different diseases.
4.1 Curcumin-loaded nanoparticles and their antibacterial activities
According to a study by Tyagi et al. [30], curcumin has greater effectiveness in controlling both gram-positive and gram-negative bacteria. Despite curcumin having potential antibacterial properties, its low solubility, low stability, and low bioavailability remain a debate [142]. Curcumin nanoparticles exhibit better biological activity, solubility, and stability than all other forms of curcumin [143]. When evaluated, it was found that the curcumin particles are smaller, which enhanced their toxicity and sensitization in bacterial cells, compared to curcumin alone [144].
Furthermore, an evaluation of curcumin nanoparticle’s effectiveness in inhibiting bacteria like Shigella dysenteriae, Staphylococcus aureus, Escherichia coli, and Streptococcus pneumonia was observed to be greater than amoxicillin, a commercial antibiotic [52]. In order to manifest antibacterial properties, curcumin-loaded nanoparticles attach to the cell wall of the bacterial cell, break it, and penetrate inside the cell, disrupting the structure of cellular organelles [143]. Since curcumin-loaded nanoparticles are effective on the broad spectrum of microorganisms and human cancer cell lines, therefore targeting curcumin-loaded nanoparticles for therapeutic purpose is a promising strategy.
4.2 Curcumin-loaded nanoparticles and their anticancer activities
Over the years, different nanoformulations have been investigated in order to enhance the delivery of curcumin to tumor sites [128, 145, 146]. Different nanoparticle-based approaches have been explored, such as solid-lipid microparticles based on bovine serum albumin [147, 148], encapsulation in liposomes [149], and chitosan [150]. These nanoparticles are tailored in a precise dimension for the purpose of increasing absorption and permeation, which then result in more bio-distribution and longer circulation in the body [151]. Nanoformulations are used primarily for enhancing the solubility of curcumin in water [152]. To enhance solubility, curcumin is prepared using pH-driven loading method, in this method, hydrophobic phytochemicals such as curcumin are deprotonated and dissolved under alkaline conditions to overcome solubility challenges [152, 153].
Preferably, curcumin nanoformulation would exhibit increased anticancer activity over free curcumin, while remaining nontoxic to normal cells. Chabib et al. [154] compared the anticancer activity of pure curcumin with curcumin-loaded nanoparticles, and found that curcumin-loaded nanoparticles were more effective than curcumin on its own against breast cancer cells T47D. A study by Bisht et al. [155] had previously demonstrated that pancreatic cancer can be effectively treated with polymer-based curcumin-loaded nanoparticles, which induced apoptosis and obstructed the activation of NFκB in BxPC3 pancreatic cancer cells. Recently, the use of curcumin-loaded nanoparticles in combination with anticancer drugs have been shown to enhance their chemotherapeutic effect in ovarian carcinoma by inhibiting proliferation via modulation of JAK/STAT3 and PI3K/Akt signaling pathways [156].
Curcumin-loaded nanoparticles showed increased anticancer effect in lung cancer [157], prostate cancer [158], breast cancer [154], colon cancer [159], brain cancer [160] and oral cancer [161]. Additionally, curcumin-loaded nanoparticles have been shown to interact with plasma proteins, providing a new platform for improving cancer treatment [162]. Based on these results, it is not surprising that the usage of curcumin-loaded nanoparticles is gaining momentum in anticancer therapeutics [163].
4.3 Strategies to improve curcumin nanoparticles
Numerous in vitro and in vivo studies have shown that nanoparticles may enhance the anticancer effects of curcumin [164, 165]. However, there are still some concerns about the cost, safety, side-effects, and long-term toxicity of curcumin-loaded nanoparticles, leading to the development of a new field of study called nanotoxicology [166].
To improve curcumin nanoparticles, curcumin-loaded nanoparticles should be tested in a larger population to determine their toxicity and efficacy. Furthermore, clinical trials are necessary to evaluate their anticancer activities and determine side effects and toxicity in human subjects [167]. The safety concerns associated with nanomedicine-based delivery systems include neuroinflammation, excitotoxicity, and DNA damage [168]. Although they are methods that are currently explored to reduce the toxicity of nanoparticles [169], developing DNA/RNA nano-carriers to eliminate cancer cells can be a promising plan of action.
The safety profile of curcumin is exceptional, and it has multiple health benefits including anti-inflammatory, antioxidant, antitumor, antibacterial, and anti-diabetic properties. However, the poor stability in the body fluids, rapid clearance, and low aqueous solubility limit curcumin’s clinical use. Nano-based drug delivery systems are currently opening a new world of possibilities for solving these problems. Nanoparticles have been shown to improve the solubility and stability of some substances including curcumin and amend its curative index. Therefore, targeting curcumin-loaded nanoparticles for therapeutic purpose is a promising strategy.
The authors wish to thank the Department of Biochemistry, Microbiology and Biotechnology (University of Limpopo) for support.
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Written By
Lilian Makgoo and Zukile Mbita
Submitted: 26 January 2022Reviewed: 07 February 2022Published: 20 June 2022
Open access peer-reviewed chapter
