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15 pages, 2821 KiB

Open AccessArticle

New Paradigms to Assess Consequences of Long-Term, Low-Dose Curcumin Exposure in Lung Cancer Cells

by Gintare Smagurauskaite, Jagdish Mahale, Karen Brown, Anne L. Thomas and Lynne M. Howells

Molecules 2020, 25(2), 366; https://doi.org/10.3390/molecules25020366 - 16 Jan 2020

Cited by 7 | Viewed by 2721

Curcumin has been investigated extensively for cancer prevention, but it has been proposed that long-term treatments may promote clonal evolution and gain of cellular resistance, potentially rendering cancer cells less sensitive to future therapeutic interventions. Here, we used long-term, low-dose treatments to determine [...] Read more.

Curcumin has been investigated extensively for cancer prevention, but it has been proposed that long-term treatments may promote clonal evolution and gain of cellular resistance, potentially rendering cancer cells less sensitive to future therapeutic interventions. Here, we used long-term, low-dose treatments to determine the potential for adverse effects in non-small cell lung cancer (NSCLC) cells. IC₅₀s for curcumin, cisplatin, and pemetrexed in A549, PC9, and PC9ER NSCLC cells were evaluated using growth curves. IC₅₀s were subsequently re-assessed following long-term, low-dose curcumin treatment and a three-month treatment withdrawal period, with a concurrent assessment of oncology-related protein expression. Doublet cisplatin/pemetrexed-resistant cell lines were created and the IC₅₀ for curcumin was determined. Organotypic NSCLC-fibroblast co-culture models were used to assess the effects of curcumin on invasive capacity. Following long-term treatment/treatment withdrawal, there was no significant change in IC₅₀s for the chemotherapy drugs, with chemotherapy-resistant cell lines exhibiting similar sensitivity to curcumin as their non-resistant counterparts. Curcumin (0.25–0.5 µM) was able to inhibit the invasion of both native and chemo-resistant NSCLC cells in the organotypic co-culture model. In summary, long-term curcumin treatment in models of NSCLC neither resulted in the acquisition of pro-carcinogenic phenotypes nor caused resistance to chemotherapy agents. Full article

(This article belongs to the Special Issue Curcumin)

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25 pages, 7340 KiB

Open AccessArticle

Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression

by Ikuko Nakamae, Tsumoru Morimoto, Hiroki Shima, Masafumi Shionyu, Hisayo Fujiki, Noriko Yoneda-Kato, Takashi Yokoyama, Shigehiko Kanaya, Kiyomi Kakiuchi, Tsuyoshi Shirai, Edy Meiyanto and Jun-ya Kato

Molecules 2019, 24(22), 4067; https://doi.org/10.3390/molecules24224067 - 10 Nov 2019

Cited by 34 | Viewed by 5014

Abstract

Background: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives [...] Read more.

Background: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives and examined their anti-proliferative and anti-tumorigenic properties. Methods and Results: Thirty-nine derivatives exhibited anti-proliferative activity toward human cancer cell lines, including CML-derived K562 leukemic cells, in a manner sensitive to an antioxidant, N-acetyl-cysteine (NAC). Some compounds exhibited lower GI₅₀ values than curcumin, some efficiently induced cell senescence, and others markedly increased ROS levels, efficiently induced cell death and suppressed tumor formation in a xenograft mouse model, without any detectable side effects. A clustering analysis of the selected compounds and their measurement variables revealed that anti-tumorigenic activity was most well-correlated with an increase in ROS levels. Pulldown assays and a molecular docking analysis showed that curcumin derivatives competed with co-enzymes to bind to the respective ROS metabolic enzymes and inhibited their enzymatic activities. Conclusions: The analysis of novel curcumin derivatives established the importance of ROS upregulation in suppression of tumorigenesis, and these compounds are potentially useful for the development of an anti-cancer drug with few side effects. Full article

(This article belongs to the Special Issue Curcumin)

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20 pages, 4718 KiB

Open AccessArticle

Dietary Curcumin Prevented Astrocytosis, Microgliosis, and Apoptosis Caused by Acute and Chronic Exposure to Ozone

by Sendar Daniel Nery-Flores, Mario Alberto Ramírez-Herrera, María Luisa Mendoza-Magaña, Marina María de Jesús Romero-Prado, José de Jesús Ramírez-Vázquez, Jacinto Bañuelos-Pineda, Hugo Alejandro Espinoza-Gutiérrez, Abraham Alberto Ramírez-Mendoza and Mariana Chávez Tostado

Molecules 2019, 24(15), 2839; https://doi.org/10.3390/molecules24152839 - 05 Aug 2019

Cited by 14 | Viewed by 4138

Abstract

Ozone is the most oxidant tropospheric pollutant gas, causing damage through the formation of reactive oxygen and nitrogen species. Reactive species induce the nuclear factor-kappa B (NF-κB) activation leading to neuroinflammation characterized by astrocytosis, microgliosis, and apoptotic cell death. There is interest in [...] Read more.

Ozone is the most oxidant tropospheric pollutant gas, causing damage through the formation of reactive oxygen and nitrogen species. Reactive species induce the nuclear factor-kappa B (NF-κB) activation leading to neuroinflammation characterized by astrocytosis, microgliosis, and apoptotic cell death. There is interest in evaluating the pharmacological activity of natural antioxidants to confer neuroprotection against the damage caused by ozone in highly polluted cities. Curcumin has been proven to exert a protective action in the central nervous system (CNS) of diverse experimental models, with no side effects. The aim of this work is to evaluate the effect of curcumin in a preventive and therapeutic manner against the astrocytosis, microgliosis, and apoptosis induced by ozone in rat hippocampus. Fifty Wistar rats were distributed into five experimental groups: The intact control, curcumin fed control, ozone-exposed group, and the preventive and therapeutic groups receiving the curcumin supplementation while exposed to ozone. Ozone caused astrocytosis and microgliosis, as well as apoptosis in the hippocampus. Meanwhile, curcumin was able to decrease the activation of microglia and astrocytes, and apoptotic cell death in both periods of exposure. Therefore, we propose that curcumin could be used as a molecule capable of counteracting the damage caused by ozone in the CNS. Full article

(This article belongs to the Special Issue Curcumin)

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19 pages, 3658 KiB

Open AccessArticle

Curcumin Nanoparticles Protect against Isoproterenol Induced Myocardial Infarction by Alleviating Myocardial Tissue Oxidative Stress, Electrocardiogram, and Biological Changes

by Paul-Mihai Boarescu, Ioana Boarescu, Ioana Corina Bocșan, Raluca Maria Pop, Dan Gheban, Adriana Elena Bulboacă, Cristina Nicula, Ruxandra-Mioara Râjnoveanu and Sorana D. Bolboacă

Molecules 2019, 24(15), 2802; https://doi.org/10.3390/molecules24152802 - 01 Aug 2019

Cited by 52 | Viewed by 5474

Abstract

Curcumin from Curcuma longa is a nutraceutical compound reported to possess strong antioxidant activity that makes it a candidate for use in counteracting oxidative stress-induced damage. The effect of pre-treatment with curcumin nanoparticles (nC) compared to conventional curcumin (Cs) on blood pressure, electrocardiogram, [...] Read more.

Curcumin from Curcuma longa is a nutraceutical compound reported to possess strong antioxidant activity that makes it a candidate for use in counteracting oxidative stress-induced damage. The effect of pre-treatment with curcumin nanoparticles (nC) compared to conventional curcumin (Cs) on blood pressure, electrocardiogram, and biological changes on isoproterenol (ISO)-induced myocardial infarction (MI) in rats had been investigated. The Cs doses of 150 and 200 mg/kg bw and all nC doses (100, 150 and 200 mg/kg bw) significantly reduced heart rate before ISO administration and prevented QRS complex enlargement after MI induction (p < 0.026). All doses of Cs and nC prevented prolongation of the QT and QT corrected (QTc) intervals, with better results for higher doses (p < 0.048). The nC solution had more significant results than Cs in all metabolic parameters assessed (lactate dehydrogenase, glycaemia, aspartate transaminase, and alanine transaminase, p < 0.009). nC was more efficient than Cs in limiting myocardial oxidative stress and enhancing antioxidative capacity (p < 0.004). Compared to Cs, nC better prevented myocardial damage extension, reduced interstitial oedema, and inflammation. Curcumin nanoparticles as compared to conventional curcumin exert better antioxidative effects. Moreover, nC better prevent cardiomyocytes damage, and electrocardiogram alterations, in the case of ISO-induced MI in rats. Full article

(This article belongs to the Special Issue Curcumin)

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12 pages, 2992 KiB

Open AccessArticle

Biological Effects of EF24, a Curcumin Derivative, Alone or Combined with Mitotane in Adrenocortical Tumor Cell Lines

by Loris Bertazza, Susi Barollo, Maria Elena Mari, Irene Faccio, Maira Zorzan, Marco Redaelli, Beatrice Rubin, Decio Armanini, Caterina Mian and Raffaele Pezzani

Molecules 2019, 24(12), 2202; https://doi.org/10.3390/molecules24122202 - 12 Jun 2019

Cited by 18 | Viewed by 3151

Abstract

Background: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or [...] Read more.

Background: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. Method and Results: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 ± 2.4 μM and 4.9 ± 2.8 μM for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/β-catenin, NF-κB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. Conclusion: This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models. Full article

(This article belongs to the Special Issue Curcumin)

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14 pages, 1494 KiB

Open AccessArticle

Curcumin and Resveratrol Regulate Intestinal Bacteria and Alleviate Intestinal Inflammation in Weaned Piglets

by Zhending Gan, Wenyao Wei, Yi Li, Jiamin Wu, Yongwei Zhao, Lili Zhang, Tian Wang and Xiang Zhong

Molecules 2019, 24(7), 1220; https://doi.org/10.3390/molecules24071220 - 28 Mar 2019

Cited by 63 | Viewed by 5552

Abstract

Human infants or piglets are vulnerable to intestinal microbe-caused disorders and inflammation due to their rapidly changing gut microbiota and immaturity of their immune systems at weaning. Resveratrol and curcumin have significant anti-inflammatory, bacteria-regulating and immune-promoting effects. The purpose of this study was [...] Read more.

Human infants or piglets are vulnerable to intestinal microbe-caused disorders and inflammation due to their rapidly changing gut microbiota and immaturity of their immune systems at weaning. Resveratrol and curcumin have significant anti-inflammatory, bacteria-regulating and immune-promoting effects. The purpose of this study was to investigate whether dietary supplementation with resveratrol and curcumin can change the intestinal microbiota and alleviate intestinal inflammation induced by weaning in piglets. One hundred eighty piglets weaned at 21 ± 2 d were fed a control diet (CON group) or supplemented diet (300 mg/kg of antibiotics, ANT group; 300 mg/kg of resveratrol and curcumin, respectively, HRC group; 100 mg/kg of resveratrol and curcumin, respectively, LRC group; 300 mg/kg of resveratrol, RES group; 300 mg/kg of curcumin, CUR group) for 28 days. The results showed that compared with the CON group, curcumin alone and antibiotics decreased the copy numbers of Escherichia coli. Both curcumin and resveratrol down-regulated the level of Toll-like-receptor 4 mRNA and protein expression in the intestine to inhibit the release of critical inflammation molecules (interleukin-1β, tumor necrosis factor-α), and increase the secretion of immunoglobulin. Our results suggested that curcumin and resveratrol can regulate weaned piglet gut microbiota, down-regulate the TLR4 signaling pathway, alleviate intestinal inflammation, and ultimately increase intestinal immune function. Full article

(This article belongs to the Special Issue Curcumin)

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17 pages, 1100 KiB

Open AccessArticle

Liposomal Curcumin is Better than Curcumin to Alleviate Complications in Experimental Diabetic Mellitus

by Adriana Elena Bulboacă, Alina S. Porfire, Lucia R. Tefas, Paul Mihai Boarescu, Sorana D. Bolboacă, Ioana C. Stănescu, Angelo Corneliu Bulboacă and Gabriela Dogaru

Molecules 2019, 24(5), 846; https://doi.org/10.3390/molecules24050846 - 27 Feb 2019

Cited by 43 | Viewed by 5647

Abstract

Curcumin (CC) is known to have anti-inflammatory and anti-oxidative properties and has already been tested for its efficiency in different diseases including diabetes mellitus (DM). New formulations and route administration were designed to obtain products with higher bioavailability. Our study aimed to test [...] Read more.

Curcumin (CC) is known to have anti-inflammatory and anti-oxidative properties and has already been tested for its efficiency in different diseases including diabetes mellitus (DM). New formulations and route administration were designed to obtain products with higher bioavailability. Our study aimed to test the effect of intraperitoneal (i.p.) administration of liposomal curcumin (lCC) as pre-treatment in streptozotocin(STZ)-induced DM in rats on oxidative stress, liver, and pancreatic functional parameters. Forty-two Wistar-Bratislava rats were randomly divided into six groups (seven animals/group): control (no diabetes), control-STZ (STZ-induced DM —60 mg/100g body weight a single dose intraperitoneal administration, and no CC pre-treatment), two groups with DM and CC pre-treatment (1mg/100g bw—STZ + CC1, 2 mg/100g bw—STZ + CC2), and two groups with DM and lCC pre-treatment (1 mg/100g bw—STZ + lCC1, 2 mg/100g bw—STZ + lCC1). Intraperitoneal administration of Curcumin in diabetic rats showed a significant reduction of nitric oxide, malondialdehyde, total oxidative stress, and catalase for both evaluated formulations (CC and lCC) compared to control group (p < 0.005), with higher efficacy of lCC formulation compared to CC solution (p < 0.002, excepting catalase for STZ + CC2vs. STZ + lCC1when p = 0.0845). The CC and lCC showed hepatoprotective and hypoglycemic effects, a decrease in oxidative stress and improvement in anti-oxidative capacity status against STZ-induced DM in rats (p < 0.002). The lCC also proved better efficacy on MMP-2, and -9 plasma levels as compared to CC (p < 0.003, excepting STZ + CC2 vs. STZ + lCC1 comparison with p = 0.0553). The lCC demonstrated significantly better efficacy as compared to curcumin solution on all serum levels of the investigated markers, sustaining its possible use as adjuvant therapy in DM. Full article

(This article belongs to the Special Issue Curcumin)

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Review

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23 pages, 2490 KiB

Open AccessReview

Curcumin and Its Derivatives as Potential Therapeutic Agents in Prostate, Colon and Breast Cancers

by Zintle Mbese, Vuyolwethu Khwaza and Blessing Atim Aderibigbe

Molecules 2019, 24(23), 4386; https://doi.org/10.3390/molecules24234386 - 30 Nov 2019

Cited by 94 | Viewed by 9170

Abstract

Cancer is a life-threatening disease and is the second leading cause of death around the world. The increasing threats of drug-resistant cancers indicate that there is an urgent need for the improvement or development of more effective anticancer agents. Curcumin, a phenolic compound [...] Read more.

Cancer is a life-threatening disease and is the second leading cause of death around the world. The increasing threats of drug-resistant cancers indicate that there is an urgent need for the improvement or development of more effective anticancer agents. Curcumin, a phenolic compound originally derived from turmeric plant (Curcuma longa L. (Zingiberaceae family)) widely known as a spice and a coloring agent for food have been reported to possess notable anticancer activity by inhibiting the proliferation and metastasis, and enhancing cell cycle arrest or apoptosis in various cancer cells. In spite of all these benefits, the therapeutic application of curcumin in clinical medicine and its bioavailability are still limited due to its poor absorption and rapid metabolism. Structural modification of curcumin through the synthesis of curcumin-based derivatives is a potential approach to overcome the above limitations. Curcumin derivatives can overcome the disadvantages of curcumin while enhancing the overall efficacy and hindering drug resistance. This article reports a review of published curcumin derivatives and their enhanced anticancer activities. Full article

(This article belongs to the Special Issue Curcumin)

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19 pages, 2000 KiB

Open AccessReview

The Effect of Curcumin on the Differentiation of Mesenchymal Stem Cells into Mesodermal Lineage

by Armita Mahdavi Gorabi, Nasim Kiaie, Saeideh Hajighasemi, Tannaz Jamialahmadi, Muhammed Majeed and Amirhossein Sahebkar

Molecules 2019, 24(22), 4029; https://doi.org/10.3390/molecules24224029 - 07 Nov 2019

Cited by 42 | Viewed by 4252

Abstract

Curcumin has been placed at the forefront of the researcher’s attention due to its pleiotropic pharmacological effects and health benefits. A considerable volume of articles has pointed out curcumin’s effects on the fate of stem cell differentiation. In this review, a descriptive mechanism [...] Read more.

Curcumin has been placed at the forefront of the researcher’s attention due to its pleiotropic pharmacological effects and health benefits. A considerable volume of articles has pointed out curcumin’s effects on the fate of stem cell differentiation. In this review, a descriptive mechanism of how curcumin affects the outcome of the differentiation of mesenchymal stem cells (MSCs) into the mesodermal lineage—i.e., adipocyte, osteocyte, and chondrocyte differentiation—is compiled from the literature. The sections include the mechanism of inhibition or induction of MSCs differentiation to each lineage, their governing molecular mechanisms, and their signal transduction pathways. The effect of different curcumin doses and its structural modifications on the MSCs differentiation is also discussed. Full article

(This article belongs to the Special Issue Curcumin)

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21 pages, 688 KiB

Open AccessReview

Curcumin Combination Chemotherapy: The Implication and Efficacy in Cancer

by Bee Ling Tan and Mohd Esa Norhaizan

Molecules 2019, 24(14), 2527; https://doi.org/10.3390/molecules24142527 - 10 Jul 2019

Cited by 150 | Viewed by 13206

Abstract

Many chemotherapeutic drugs have been used for the treatment of cancer, for instance, doxorubicin, irinotecan, 5-fluorouracil, cisplatin, and paclitaxel. However, the effectiveness of chemotherapy is limited in cancer therapy due to drug resistance, therapeutic selectivity, and undesirable side effects. The combination of therapies [...] Read more.

Many chemotherapeutic drugs have been used for the treatment of cancer, for instance, doxorubicin, irinotecan, 5-fluorouracil, cisplatin, and paclitaxel. However, the effectiveness of chemotherapy is limited in cancer therapy due to drug resistance, therapeutic selectivity, and undesirable side effects. The combination of therapies with natural compounds is likely to increase the effectiveness of drug treatment as well as reduce the adverse outcomes. Curcumin, a polyphenolic isolated from Curcuma longa, belongs to the rhizome of Zingiberaceae plants. Studies from in vitro and in vivo revealed that curcumin exerts many pharmacological activities with less toxic effects. The biological mechanisms underlying the anticancer activity of co-treatment curcumin and chemotherapy are complex and worth to discuss further. Therefore, this review aimed to address the molecular mechanisms of combined curcumin and chemotherapy in the treatment of cancer. The anticancer activity of combined nanoformulation of curcumin and chemotherapy was also discussed in this study. Taken together, a better understanding of the implication and underlying mechanisms of action of combined curcumin and chemotherapy may provide a useful approach to combat cancer diseases. Full article

(This article belongs to the Special Issue Curcumin)

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