Therapeutic potential of curcumin and its nanoformulations for treating oral cancer

The global incidence of oral cancer has steadily increased in recent years and is associated with high morbidity and mortality. Oral cancer is the most common cancer in the head and neck region, and is predominantly of epithelial origin (i.e. squamous cell carcinoma). Oral cancer treatment modalities mainly include surgery with or without radiotherapy and chemotherapy. Though proven effective, chemotherapy has significant adverse effects with possibilities of tumor resistance to anticancer drugs and recurrence. Thus, there is an imperative need to identify suitable anticancer therapies that are highly precise with minimal side effects and to make oral cancer treatment effective and safer. Among the available adjuvant therapies is curcumin, a plant polyphenol isolated from the rhizome of the turmeric plant Curcuma longa. Curcumin has been demonstrated to have anti-infectious, antioxidant, anti-inflammatory, and anticarcinogenic properties. Curcumin has poor bioavailability, which has been overcome by its various analogues and nanoformulations, such as nanoparticles, liposome complexes, micelles, and phospholipid complexes. Studies have shown that the anticancer effects of curcumin are mediated by its action on multiple molecular targets, including activator protein 1, protein kinase B (Akt), nuclear factor κ-light-chain-enhancer of activated B cells, mitogen-activated protein kinase, epidermal growth factor receptor (EGFR) expression, and EGFR downstream signaling pathways. These targets play important roles in oral cancer pathogenesis, thereby making curcumin a promising adjuvant treatment modality. This review aims to summarize the different novel formulations of curcumin and their role in the treatment of oral cancer.     

Synthesis and anti-inflammatory evaluation of novel mono-carbonyl analogues of curcumin in LPS-stimulated RAW 264.7 macrophages

Curcumin is a multifunctional natural product with regulatory effects on inflammation. However, a major limitation for the application of curcumin is its poor bioavailability. We previously demonstrated that the mono-carbonyl analogues of curcumin possessed improved pharmacokinetic profiles. In this study, 33 novel mono-carbonyl analogues of curcumin were synthesized and their inhibition against TNF-α and IL-6 release was evaluated in LPS-stimulated RAW 264.7 macrophages. Based on the screening data, quantitative structure-activity relationship was conducted, indicating that electron-withdrawing groups in benzene ring are favourable to anti-inflammatory activities of B-class compounds. Furthermore, compounds AN1 and B82 demonstrated anti-inflammatory abilities in a dose-dependent manner. These raise the possibility that these compounds might serve as potential agents for the treatment of inflammatory diseases.     

Improving the Anticancer Activity of Curcumin Using Nanocurcumin Dispersion in Water

Curcumin is a highly potent, nontoxic bioactive agent found in turmeric and is known to have significant anticancer properties against different types of cancer cells. The major disadvantage associated with the use of curcumin, however, is its low systemic bioavailability due to its poor aqueous solubility. The focus of the present study was to generate nanoparticles of curcumin with improved aqueous phase solubility, and to investigate their efficacy in treating cancer cells. Curcumin nanoparticles having particle size in the range 2–40 nm and aqueous solubility of up to a maximum of 3 mg/mL were prepared. Evaluation of anticancer properties of curcumin nanodispersion was carried out in 3 different cancer cell lines: lung (A549), liver (HepG2), and skin (A431). The results demonstrated that under aqueous conditions curcumin nanoparticles exhibited similar or a much stronger antiproliferative effect on the cancer cells compared to normal curcumin in DMSO. Our results lead way toward unharnessed potential of curcumin in the form of its nanoparticles as an adjuvant therapy for clinical application in treating various cancers.     

Curcumin Nanotechnologies and Its Anticancer Activity

Cancer is one of the leading causes of death worldwide. Curcumin is a well-established anticancer agent in vitro but its efficacy is yet to be proven in clinical trials. Poor bioavailability of curcumin is the principal reason behind the lack of efficiency of curcumin in clinical trials. Many studies prove that the bioavailability of curcumin can be improved by administering it through nanoparticle drug carriers. This review focuses on the efforts made in the field of nanotechnology to improve the bioavailability of curcumin. Nanotechnologies of curcumin come in various shapes and sizes. The simplest curcumin nanoparticle that increased the bioavailability of curcumin is the curcumin–metal complex. On the other hand, we have intricate thermoresponsive nanoparticles that can release curcumin upon stimulation (analogous to a remote control). Future research required for developing potent curcumin nanoparticles is also discussed.     

Curcuma Longa,the “Golden Spice” to Counteract Neuroinflammaging and Cognitive Decline—What Have We Learned and What Needs to Be Done

Due to the global increase in lifespan, the proportion of people showing cognitive impairment is expected to grow exponentially. As target-specific drugs capable of tackling dementia are lagging behind, the focus of preclinical and clinical research has recently shifted towards natural products. Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways. These pathways have been shown to be critical for neurodegenerative disorders such as Alzheimer’s disease and more in general for cognitive decline. Despite the substantial preclinical literature on the potential biomedical effects of curcumin, its relatively low bioavailability, poor water solubility and rapid metabolism/excretion have hampered clinical trials, resulting in mixed and inconclusive findings. In this review, we highlight current knowledge on the potential effects of this natural compound on cognition. Furthermore, we focus on new strategies to overcome current limitations in its use and improve its efficacy, with attention also on gender-driven differences.     

Cytotoxic,Genotoxic and Senolytic Potential of Native and Micellar Curcumin

Background: Curcumin, a natural polyphenol and the principal bioactive compound in Curcuma longa, was reported to have anti-inflammatory, anti-cancer, anti-diabetic and anti-rheumatic activity. Curcumin is not only considered for preventive, but also for therapeutic, purposes in cancer therapy, which requires a killing effect on cancer cells. A drawback, however, is the low bioavailability of curcumin due to its insolubility in water. To circumvent this limitation, curcumin was administered in different water-soluble formulations, including liposomes or embedded into nanoscaled micelles. The high uptake rate of micellar curcumin makes it attractive also for cancer therapeutic strategies. Native curcumin solubilised in organic solvent was previously shown to be cytotoxic and bears a genotoxic potential. Corresponding studies with micellar curcumin are lacking. Methods: We compared the cytotoxic and genotoxic activity of native curcumin solubilised in ethanol (Cur-E) with curcumin embedded in micells (Cur-M). We measured cell death by MTT assays, apoptosis, necrosis by flow cytometry, senolysis by MTT and C12FDG and genotoxicity by FPG-alkaline and neutral singe-cell gel electrophoresis (comet assay). Results: Using a variety of primary and established cell lines, we show that Cur-E and Cur-M reduce the viability in all cell types in the same dose range. Cur-E and Cur-M induced dose-dependently apoptosis, but did not exhibit senolytic activity. In the cytotoxic dose range, Cur-E and Cur-M were positive in the alkaline and the neutral comet assay. Genotoxic effects vanished upon removal of curcumin, indicating efficient and complete repair of DNA damage. For inducing cell death, which was measured 48 h after the onset of treatment, permanent exposure was required while 60 min pulse-treatment was ineffective. In all assays, Cur-E and Cur-M were equally active, and the concentration above which significant cytotoxic and genotoxic effects were observed was 10 µM. Micelles not containing curcumin were completely inactive. Conclusions: The data show that micellar curcumin has the same cytotoxicity and genotoxicity profile as native curcumin. The effective concentration on different cell lines, including primary cells, was far above the curcumin concentration that can be achieved systemically in vivo, which leads us to conclude that native curcumin and curcumin administered as food supplement in a micellar formulation at the ADI level are not cytotoxic/genotoxic, indicating a wide margin of safety.     

Curcumin and Melanoma: From Chemistry to Medicine

Melanoma is the most deadly form of skin cancer, with about 48,000 deaths each year worldwide. Growing evidence suggests that individual nutrients or dietary patterns might have important roles in the prevention of melanoma. Considering that melanoma is a potentially life-threatening cancer, novel protective and adjuvant treatments are needed to improve its prognosis. Curcumin is a bioactive substance extracted from rhizome of Curcuma longa L. Its global market is expected to grow in the next few years, especially in the pharmaceutical industry, due to its numerous physiological and pharmacological properties. For this review, we collected the available data on the protective and therapeutic role of curcumin against melanoma. We also discuss the chemistry, dietary sources, bioavailability, and metabolism of curcumin, and the mechanisms of action of its potential anticancer effects at the molecular level. Current challenges and future directions for research are also critically discussed.     

Curcumin content of turmeric and curry powders

Curcumin, derived from the rhizome curcuma longa, is one of the primary ingredients in turmeric and curry powders that are used as spices in Middle Eastern and Asian countries, especially on the Indian subcontinent. More recently, laboratory studies have demonstrated that dietary curcumin exhibits various biological activities and significantly inhibits colon tumorigenesis and tumor size in animals. Curcumin displays both anti-inflammatory and antioxidant properties, giving it the potential to be considered in the development of cancer preventive strategies and applications in clinical research. Experimental studies have shown the biological activities of the compound, but much more information on pharmacokinetics, bioavailability, and food content are needed. Whether the amount of curcumin in turmeric and curry powders is sufficient to suggest effects on biological activities and cancer risk is unknown. To determine and compare the quantitative amounts of curcumin that are present in several brands of turmeric and curry powders, a high performance liquid chromatography technique was used to analyze 28 spice products described as turmeric or curry powders and two negative controls. Pure turmeric powder had the highest curcumin concentration, averaging 3.14% by weight. The curry powder samples, with one exception, had relatively small amounts of curcumin present, and the variability in content was great. The curcumin content of these seasoning products that are consumed as a component of the diet should be considered in evaluating baseline tissue concentration and response to curcumin supplementation, which is under study in chemoprevention trials.     

Potential Health Benefits of Curcumin on Female Reproductive Disorders: A Review

Curcumin is one of the main polyphenolic compounds in the turmeric rhizome. It possesses antioxidant, anti-inflammatory, anti-cancer, anti-arthritis, anti-asthmatic, anti-microbial, anti-viral and anti-fungal properties. This review aims to provide an overview of the potential health benefits of curcumin to treat female reproductive disorders, including polycystic ovary syndrome (PCOS), ovarian failure and endometriosis. Comprehensive information on curcumin was retrieved from electronic databases, which were MEDLINE via EBSCOhost, Scopus and Google Scholar. The available evidence showed that curcumin reduced the high level of androgen in PCOS. Studies in rodents suggest that curcumin resulted in the disappearance of cysts and the appearance of healthy follicles and corpora lutea. Furthermore, animal studies showed curcumin improved the overall function of the ovary in ovarian diseases and reversed the disturbance in oxidative stress parameters. Meanwhile, in vitro and in vivo studies reported the positive effects of curcumin in alleviating endometriosis through anti-inflammatory, anti-proliferative, anti-angiogenic and pro-apoptotic mechanisms. Thus, curcumin possesses various effects on PCOS, ovarian diseases and endometriosis. Some studies found considerable therapeutic effects, whereas others found no effect. However, none of the investigations found curcumin to be harmful. Curcumin clinical trials in endometriosis and ovarian illness are still scarce; thus, future studies need to be conducted to confirm the safety and efficacy of curcumin before it could be offered as a complementary therapy agent.     

Curcumin and muscle wasting—A new role for an old drug?

Sepsis, severe injury, and cancer are associated with loss of muscle mass. Muscle wasting in these conditions is mainly caused by increased proteolysis, at least in part regulated by nuclear factor-κB. Despite recent progress in the understanding of mediators and mechanisms involved in muscle wasting, effective and universally accepted treatments by which muscle atrophy can be prevented or reversed are still lacking. We review recent evidence suggesting that curcumin (diferuloylmethane), a component of the spice turmeric, may prevent loss of muscle mass during sepsis and endotoxemia and may stimulate muscle regeneration after traumatic injury. Curcumin has been part of the traditional Asian medicine for centuries, mainly because of its anti-inflammatory properties. Studies suggest that inhibition of nuclear factor-κB is one of the mechanisms by which curcumin exerts its ant-inflammatory effects. Curcumin is easily accessible, inexpensive, and non-toxic even at high doses, and may therefore offer an important treatment modality in muscle wasting and injury. It should be noted, however, that the muscle-sparing effects of curcumin are not universally accepted, and more studies are therefore needed to further test the role of curcumin in the prevention and treatment of muscle wasting.     

Curcumin Protects against Cadmium-Induced Vascular Dysfunction,Hypertension and Tissue Cadmium Accumulation in Mice

Curcumin from turmeric is commonly used worldwide as a spice and has been demonstrated to possess various biological activities. This study investigated the protective effect of curcumin on a mouse model of cadmium (Cd)—induced hypertension, vascular dysfunction and oxidative stress. Male ICR mice were exposed to Cd (100 mg/L) in drinking water for eight weeks. Curcumin (50 or 100 mg/kg) was intragastrically administered in mice every other day concurrently with Cd. Cd induced hypertension and impaired vascular responses to phenylephrine, acetylcholine and sodium nitroprusside. Curcumin reduced the toxic effects of Cd and protected vascular dysfunction by increasing vascular responsiveness and normalizing the blood pressure levels. The vascular protective effect of curcumin in Cd exposed mice is associated with up-regulation of endothelial nitric oxide synthase (eNOS) protein, restoration of glutathione redox ratio and alleviation of oxidative stress as indicated by decreasing superoxide production in the aortic tissues and reducing plasma malondialdehyde, plasma protein carbonyls, and urinary nitrate/nitrite levels. Curcumin also decreased Cd accumulation in the blood and various organs of Cd-intoxicated mice. These findings suggest that curcumin, due to its antioxidant and chelating properties, is a promising protective agent against hypertension and vascular dysfunction induced by Cd.     

姜黄素灌胃不同时间和剂量对小鼠胃肠蠕动的影响

【目的】 探讨姜黄素作用不同时间和剂量对胃肠蠕动的影响,寻找姜黄素作用的最佳时间和剂量。 【方法】 昆明种小鼠,随机分组,每组8只。姜黄素[200 mg/(kg·d)]预先灌胃分为1、5、10 d和15 d组;姜黄素灌胃10 d,每公斤体重100、200、300、400 mg组。采用阿托品腹腔注射减弱胃肠运动模型,用墨汁灌胃法分别测量各组小鼠胃残留率和小肠推进率。 【结果】 阿托品导致小鼠胃残留率增加,小肠推进率显著下降。姜黄素灌胃1和5 d组,小鼠胃残留率和小肠推进率与阿托品组比均无明显变化,而姜黄素灌胃10和15 d组,小鼠胃残留率显著下降,小肠推进率明显提高(P<0.01),10 d和15 d组间差异无统计学意义。100~400 mg/kg姜黄素灌胃10 d,对阿托品小鼠胃残留率和小肠推进率均有显著改善,各组间无明显差异。 【结论】 姜黄素100 mg/(kg·d)、灌胃10 d可以显著提高阿托品减弱的小鼠胃肠动力。     

姜黄素通过上调miR-637抑制肾癌786-O细胞的增殖、迁移和侵袭

目的 探讨姜黄素对肾癌786-O细胞的增殖、迁移和侵袭的影响及其可能的分子机制。方法 体外培养人正常肾小管上皮细胞HK-2和肾癌786-O细胞,将786-O细胞分为对照组、低剂量姜黄素组、中剂量姜黄素组、高剂量姜黄素组、miR-NC组、miR-637组、高剂量姜黄素+anti-miR-NC组、高剂量姜黄素+anti-miR-637组。分别进行实时荧光定量PCR（qRT-PCR）、MTT、Transwell和蛋白质印迹（Western blot）实验来检测各组的miR-637表达量、细胞活力、迁移侵袭能力和相关蛋白表达水平。结果 与人正常肾小管上皮细胞HK-2比较,肾癌786-O细胞中miR-637的表达水平降低（P<0.05）。与对照组比较,中、高剂量姜黄素组786-O细胞的活力、迁移和侵袭细胞数、CyclinD1、MMP-2及MMP-9表达水平均显著降低,p21表达显著升高,miR-637的表达水平均显著升高（均P<0.05）。与miR-NC组比较, miR-637组的miR-637表达水平提高,miR-637组的细胞活力、迁移和侵袭细胞数、CyclinD1、MMP-2和MMP-9表达均显著降低,p21表达升高（均P<0.001）。与高剂量姜黄素+anti-miR-NC组比较,高剂量姜黄素+anti-miR-637组的miR-637表达水平降低,786-O细胞的活力、迁移和侵袭细胞数、CyclinD1、MMP-2和MMP-9表达均升高,p21表达降低（均P<0.05）。结论 姜黄素可能通过上调miR-637发挥肾癌抑制作用。     

姜黄素对S180荷瘤小鼠TNF-α的作用研究

目的观察姜黄素（curcumin）对S180荷瘤小鼠的作用。方法建立S180荷瘤小鼠模型,给予姜黄素治疗后,观察其抗肿瘤作用及其对小鼠血清肿瘤坏死因子-α（TNF-α）水平的影响。结果姜黄素对S180荷瘤有显著抑制作用,可提高荷瘤小鼠的脾脏指数及胸腺指数;能显著提高血清TNF-α水平。结论姜黄素对S180荷瘤有显著抑制作用,其作用机制可能与升高机体细胞因子,调节小鼠免疫功能有关。     

姜黄素通过Notch途径抑制人宫颈癌细胞株HeLa细胞增殖

目的:探讨姜黄素对人宫颈癌细胞株HeLa细胞体外增殖抑制及凋亡诱导作用及相关机制。方法:MTT法检测不同浓度姜黄素对HeLa细胞的增殖抑制作用;RT-PCR法检测HeLa细胞Notch1、Notch2、Jagged1、Bcl-2、Bax基因表达情况。结果:姜黄素对HeLa细胞具有增殖抑制作用,且呈时间-剂量依赖性。随着姜黄素剂量的增加,Notch1、Notch2、Bcl-2mRNA的表达逐渐下降,Bax mRNA的表达逐渐升高,Bcl-2/Bax亦逐渐减小,Jagged1mRNA无明显变化。结论:姜黄素可能通过Notch信号途径改变凋亡蛋白的表达,抑制HeLa细胞增殖。     

A Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin Formulation with 95% Curcumin: A Randomized,Double-Blind,Crossover Study

Objective: Curcumin exhibits many beneficial health-promoting characteristics. However, its poor oral absorption precludes its general use. This study assessed the bioavailability of a novel curcumin formulation compared to 95% curcumin and published results for various other curcumin formulations.

Methods: A randomized, crossover, double-blind, comparator-controlled pharmacokinetic study was performed in 12 healthy adult subjects to determine the appearance of free curcumin and its metabolites curcumin sulfate and curcumin glucuronide in plasma after a single dose of a novel proprietary curcumin liquid droplet micromicellar formulation (CLDM) and unformulated 95% curcumin powder in capsule form. An equivalent 400-mg dose of each product was administered. The 95% curcumin contained 323 mg curcumin, and the CLDM contained 64.6 mg curcumin. Blood samples were drawn and plasma was analyzed for curcumin and its 2 conjugates without enzymatic hydrolysis by liquid chromatography–tandem mass spectroscopy.

Results: Plasma levels of curcumin sulfate and curcumin glucuronide after 1.5 hours from CLDM were approximately 20 and 300 ng/mL, respectively, whereas the levels for 95% curcumin were near baseline. Free curcumin reached a maximum level of 2 ng/mL for CLDM and 0.3 ng/mL for 95% curcumin at 1.5 hours. For the CLDM, a small secondary free curcumin peak occurred at 12 hours and a tertiary 1.5-ng/mL peak occurred at 24 hours. The total curcumin absorbed as represented by the area under the curve (AUC)/mg administered curcumin for CLDM was 522 times greater than for the 95% curcumin.

Conclusions: The novel CLDM formulation facilitates absorption and produces exceedingly high plasma levels of both conjugated and total curcumin compared to 95% curcumin. A comparison of the C_max/mg curcumin and AUC/mg of administered curcumin for CLDM with data from pharmacokinetic studies of various enhanced absorption formulations indicate that the greatest absorption and bioavailability are produced with the novel CLDM formulation.     

Post-Ischemic Brain Neurodegeneration in the Form of Alzheimer’s Disease Proteinopathy: Possible Therapeutic Role of Curcumin

For thousands of years, mankind has been using plant extracts or plants themselves as medicinal herbs. Currently, there is a great deal of public interest in naturally occurring medicinal substances that are virtually non-toxic, readily available, and have an impact on well-being and health. It has been noted that dietary curcumin is one of the regulators that may positively influence changes in the brain after ischemia. Curcumin is a natural polyphenolic compound with pleiotropic biological properties. The observed death of pyramidal neurons in the CA1 region of the hippocampus and its atrophy are considered to be typical changes for post-ischemic brain neurodegeneration and for Alzheimer’s disease. Additionally, it has been shown that one of the potential mechanisms of severe neuronal death is the accumulation of neurotoxic amyloid and dysfunctional tau protein after cerebral ischemia. Post-ischemic studies of human and animal brains have shown the presence of amyloid plaques and neurofibrillary tangles. The significant therapeutic feature of curcumin is that it can affect the aging-related cellular proteins, i.e., amyloid and tau protein, preventing their aggregation and insolubility after ischemia. Curcumin also decreases the neurotoxicity of amyloid and tau protein by affecting their structure. Studies in animal models of cerebral ischemia have shown that curcumin reduces infarct volume, brain edema, blood-brain barrier permeability, apoptosis, neuroinflammation, glutamate neurotoxicity, inhibits autophagy and oxidative stress, and improves neurological and behavioral deficits. The available data suggest that curcumin may be a new therapeutic substance in both regenerative medicine and the treatment of neurodegenerative disorders such as post-ischemic neurodegeneration.     

Anticancer Mechanism of Curcumin on Human Glioblastoma

Glioblastoma (GBM) is the most malignant brain tumor and accounts for most adult brain tumors. Current available treatment options for GBM are multimodal, which include surgical resection, radiation, and chemotherapy. Despite the significant advances in diagnostic and therapeutic approaches, GBM remains largely resistant to treatment, with a poor median survival rate between 12 and 18 months. With increasing drug resistance, the introduction of phytochemicals into current GBM treatment has become a potential strategy to combat GBM. Phytochemicals possess multifarious bioactivities with multitarget sites and comparatively marginal toxicity. Among them, curcumin is the most studied compound described as a potential anticancer agent due to its multi-targeted signaling/molecular pathways properties. Curcumin possesses the ability to modulate the core pathways involved in GBM cell proliferation, apoptosis, cell cycle arrest, autophagy, paraptosis, oxidative stress, and tumor cell motility. This review discusses curcumin’s anticancer mechanism through modulation of Rb, p53, MAPK, P13K/Akt, JAK/STAT, Shh, and NF-κB pathways, which are commonly involved and dysregulated in preclinical and clinical GBM models. In addition, limitation issues such as bioavailability, pharmacokinetics perspectives strategies, and clinical trials were discussed.