Antiproliferative Effects Of Curcumin Research Articles

Targeting the Hippo and Rap1 signaling pathways: the anti-proliferative effects of curcumin in colorectal cancer cell lines.

CRC has the third-highest cancer incidence and death. Many human cancers, including colorectal cancer, are connected to abnormal signaling pathway gene expression. Many human malignancies include Hippo and Rap1 signaling. This research examined curcumin's therapeutic effects on colorectal cancer cell lines' Hippo and Rap1 signaling pathway genes. The role of the above signaling pathways is considered in colorectal cancer development. No research has examined curcumin's influence on key genes in these pathways; thus, this work ismeant to uncover its more precise mechanism. First, the gene expression omnibus database is queried to discover GSE8671, a dataset that contains differentially expressed genes associated in CRC formation. DAVID was used to discover the corporation of these genes and signaling pathways (Hippo and Rap1), and the cancer genome atlas (TCGA) database was utilized to select genes and assess their expression and biomarker potential. MTT, apoptosis, and quantitative PCR were used to assess whether curcumin is therapeutic for colorectal cancer cell lines. An in-silico analysis identified the dysregulation of several critical genes AXIN2, MYC, TEAD4, MET, LPAR1, and ADCY9 in colorectal cancer, highlighting their involvement in the Hippo and Rap1 signaling pathways. Experimental assessments, including MTT assays, apoptosis assays, and quantitative PCR (qPCR) analysis, demonstrated that the targeted modulation of these genes effectively inhibits cancer cell proliferation. Specifically, treatment with curcumin resulted in a significant reduction in cell viability in HT-29 and HCT-116 colorectal cancer cell lines, thereby facilitating apoptotic cell death. Furthermore, curcumin administration was associated with the upregulation of LPAR1 and ADCY9 gene expression, while concurrently downregulating AXIN2, MYC, TEAD4, and MET in both cell lines. This study reveals compelling evidence of curcumin's potent anticancer properties, highlighting its transformative influence on the Hippo and Rap1 signaling pathways within colorectal cancer cells. These findings not only underscore curcumin's potential as a therapeutic agent but also pave the way for innovative strategies in the fight against colorectal cancer.

Abstract 1811: Anti-proliferative effects of curcumin, silibinin, and combination of curcumin plus silibinin on gastric cancer

Abstract 1811: Anti-proliferative effects of curcumin, silibinin, and combination of curcumin plus silibinin on gastric cancer

Targeted anticancer prodrug therapy using dextran mediated enzyme–antibody conjugate and β-cyclodextrin-curcumin inclusion complex

A targeted and controlled drug delivery system based on β-cyclodextrin (β-CD) for encapsulation and controlled release of hydrophobic drugs in the presence of maltogenic amylase (MAase), as a cyclodextrin-hydrolyzing enzyme, and trastuzumab antibody has been developed. In this study, the inclusion complex of curcumin (CUR), as a model anticancer compound, with β-CD was prepared and we constructed an antibody-enzyme bioconjugate (dextran mediated MAase–Trastuzumab bioconjugate) for controlled and targeted release of CUR at HER2 positive cancer cells (including SKBR3 and BT474). Immunocytochemistry analysis indicated that the MAase–Trastuzumab bioconjugate had significant binding affinities to HER2 positive cancer cells and demonstrated high enzyme activity to degrade β-CD in order to rapid release of CUR on targeted cell surface. Fluorescence microscopy images and cytotoxicity studies represent significantly greater cellular uptake and anti-proliferative effects of CUR by β-CD-CUR/MAase-Trastuzumab bioconjugate compared to free CUR and β-CD-CUR in presence and absence of MAase in HER2 positive cells. The results from flow cytometric assay suggest that the β-CD-CUR/MAase-Trastuzumab conjugate exhibited higher cytotoxic and apoptotic effects on cancer cells compared to other formulation. We demonstrate that this formulation has a potential application for targeted and controlled release of drugs in cancer therapy with increased therapeutic efficiency.

Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells

Curcumin is a natural non-toxic phenol which is isolated from Curcumin longa L. Mounting evidence has revealed the anticancer properties of curcumin in various tumors, but the underlying molecular mechanisms of this suppression in cervical cancer is still remained unclear. Here we assessed the antitumor effects of curcumin compared with 5-Fluorouracil in Hella cells in spheroids models and monolayer cell cultures.The anti-proliferative effects of curcumin and 5-Fluorouracil were as examined in spheroid and monolayer models. The expression levels of Wnt/β-catenin and NF-kB pathways as well as the influence of the cell cycle were evaluated. Curcumin inhibited cell growth in Hella cells through the regulation of NF-kB and Wnt pathways. Also, cells developed a G2/M cell cycle arrest followed by sub-G1 apoptosis with 5-Fluorouracil and curcumin. It was also shown that curcumin either considerably affects the Wnt/β-catenin and NF-kB pathways. We showed that curcumin inhibits invasion and proliferation of cervical cancer cells via impairment of NF-kB and Wnt/β-catenin pathways, proposing further studies on the potential impacts of this compound on cancer therapy.

Curcumin: A Natural Multitarget Treatment for Pancreatic Cancer.

ucts. Among its numerous health benefits, 1 curcumin has been particularly the focus of increasing research for its strong antitumor effects. 2 Several lines of preclinical evidence have shown the chemopreventive and antitumor effects of curcumin against different types of cancer. 1 With respect to pancreatic cancer (PC), in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, BxPC-3, and Pan02. 2-6 Mechanistic evaluations have shown that the antiproliferative effects of curcumin are due to induction of apoptosis and inhibition of oxidative stress and angiogenesis. 1 At the molecular level, treatment of PC models with curcumin has been associated with reduced clonogenicity, spherical growth, invasiveness and migration of tumor cells, inhibition of cancer stem cell function, reversal of epithelial-mesenchymal transition, and suppression of NF-κB, miR-221, COX-2 and their effectors such as PTEN, p27, p57, and pro-inflammatory cytokines. 4-6 Curcumin can also block STAT1 and STAT3 phosphorylation and EGFR and Notch-1 signaling pathways, which are all essential for the growth of pancreatic tumors. 7 Notably, a novel curcumin analogue, namely, 3,4-difluorobenzylidene curcumin (CDF), has recently emerged as a potential drug for PC owing to its enhanced pharmacokinetic and cytotoxic properties compared with the parent compound. CDF has a preferential accumulation in pancreas, with a tissue concentration that is twice as much as that of curcumin. 8 CDF has been shown to enhance disintegration of pancreatospheres and possess greater cytotoxic effects on both resistant and nonresistant pancreatic tumor cell lines compared with curcumin. The low aqueous solubility of CDF is, however, still a limitation since it may necessitate dose escalation of the compound for intravenous injections and increase the risk of adverse reactions. To address this limitation, several nanosized delivery systems have been developed. These include hyaluronic acid 9 and styrene-maleic acidengineered 10 nanomicelles, and hyaluronic acid (HA)conjugated polyamidoamine dendrimers of CDF. 11 These

Curcumin AntiCancer Studies in Pancreatic Cancer.

Pancreatic cancer (PC) is one of the deadliest cancers worldwide. Surgical resection remains the only curative therapeutic treatment for this disease, although only the minority of patients can be resected due to late diagnosis. Systemic gemcitabine-based chemotherapy plus nab-paclitaxel are used as the gold-standard therapy for patients with advanced PC; although this treatment is associated with a better overall survival compared to the old treatment, many side effects and poor results are still present. Therefore, new alternative therapies have been considered for treatment of advanced PC. Several preclinical studies have demonstrated that curcumin, a naturally occurring polyphenolic compound, has anticancer effects against different types of cancer, including PC, by modulating many molecular targets. Regarding PC, in vitro studies have shown potent cytotoxic effects of curcumin on different PC cell lines including MiaPaCa-2, Panc-1, AsPC-1, and BxPC-3. In addition, in vivo studies on PC models have shown that the anti-proliferative effects of curcumin are caused by the inhibition of oxidative stress and angiogenesis and are due to the induction of apoptosis. On the basis of these results, several researchers tested the anticancer effects of curcumin in clinical trials, trying to overcome the poor bioavailability of this agent by developing new bioavailable forms of curcumin. In this article, we review the results of pre-clinical and clinical studies on the effects of curcumin in the treatment of PC.

Curcumin induces the apoptosis of non-small cell lung cancer cells through a calcium signaling pathway.

Curcumin is known for its anti-proliferative effects in lung cancer cells. Studies have demonstrated that an increase in the levels of intracellular free calcium ([Ca2+]i) is involved in curcumin-induced apoptosis. In this study, we aimed to investigate the involvement of calcium overload in the anti-proliferative effects of curcumin on lung cancer cells and the possible mechanisms involved. A549 and H1299 lung cancer cells were incubated with serial diluted curcumin. MTT assay was used to assess the cytotoxic effects of curcumin on the lung cancer cells; the inositol 1,4,5-trisphosphate receptor (IP3R, a key regulator of [Ca2+]i signaling) was blocked by its specific inhibitor, xestospongin C (XSC). Hoechst 33342, Fura-2/AM and rhodamine 123 fluorescence staining was employed to detect the apoptosis, the [Ca2+]i level and mitochondrial potential in the lung cancer cells. The expression levels of B-cell lymphoma-2 (Bcl-2), cleaved caspase-3 and cleaved caspase-9, and the phosphorylation level of IP3R were evaluated by western blot analysis. Our results revealed that curcumin inhibited cell growth, increased the [Ca2+]i level and increased the apoptosis of the lung cancer cells in a concentration-dependent manner. However, XSC attenuated the increase in the [Ca2+]i level and apoptosis, and also reversed the curcumin-induced loss of mitochondrial potential potential. Treatment with curcumin downregulated the expression of Bcl-2, and elevated the phosphorylation level of IP3R in a concentration-dependent manner. However, this effect was not reversed by treatment with XSC. In conclusion, the cytotoxic effects of curcumin on lung cancer cells were induced by calcium overload, which involves Bcl-2 mediated IP3R phosphorylation.

Immunoliposome encapsulation increases cytotoxic activity and selectivity of curcumin and resveratrol against HER2 overexpressing human breast cancer cells

Natural compounds have been studied as a source of countless bioactive compounds with diverse activities. Among them, many dietary phytochemicals have been thoroughly studied for their cytotoxic or apoptotic effects in several cellular models in order to explain their anticancer capacity. Curcumin and resveratrol are two natural compounds with a large body of evidence showing their cytotoxic activity against a wide variety of cancer cells; however, their poor absorption, bioavailability, and low selectivity have limited their clinical use. With the aim of improving bioavailability and selectivity, the antiproliferative effects of free-, liposomed-, and immunoliposomed-curcumin and/or resveratrol formulations have been compared in two human breast cancer cell lines with different HER2 expression levels. The results demonstrate that when HER2-targeted immunoliposomes are coupled to trastuzumab there is a dramatic increase in the antiproliferative effects of curcumin and resveratrol in HER2 positive human breast cancer cells in comparison to regular liposomed or free forms, indicating an increase of its therapeutic effect. The enhancement of the cytotoxic effects was also correlated to the uptake of curcumin at intracellular level, as shown by using ImageStream technique. The striking efficacy of the immunoliposomed formulation containing both resveratrol and curcumin suggests a multitargeted mechanism of action that deserves further study. These findings show the potential of HER2-targeted nanovesicles to develop new drug delivery systems for cancer therapy based on these compounds and justify further preclinical trials.

Topical Curcumin-Based Cream Is Equivalent to Dietary Curcumin in a Skin Cancer Model

Skin squamous cell carcinoma (SCC), the most common cancer in the USA, is a growing problem with the use of tanning booths causing sun-damaged skin. Antiproliferative effects of curcumin were demonstrated in an aggressive skin cancer cell line SRB12-p9 (P < 0.05 compared to control). Topical formulation was as effective as oral curcumin at suppressing tumor growth in a mouse skin cancer model. Curcumin at 15 mg administered by oral, topical, or combined formulation significantly reduced tumor growth compared to control (P = 0.004). Inhibition of pAKT, pS6, p-4EBP1, pSTAT3, and pERK1/2 was noted in SRB12-p9 cells post-curcumin treatment compared to control (P < 0.05). Inhibition of pSTAT3 and pERK1/2 was also noted in curcumin-treated groups in vivo. IHC analysis revealed human tumor specimens that expressed significantly more activated pERK (P = 0.006) and pS6 (P < 0.0001) than normal skin samples. This is the first study to compare topical curcumin to oral curcumin. Our data supports the use of curcumin as a chemopreventive for skin SCC where condemned skin is a significant problem. Prevention strategies offer the best hope of future health care costs in a disease that is increasing in incidence due to increased sun exposure.

Curcumin Inhibits Carcinogen and Nicotine-Induced Mammalian Target of Rapamycin Pathway Activation in Head and Neck Squamous Cell Carcinoma

Curcumin appears to be a safe, bioactive food compound that is a potential chemopreventive for patients at a high risk for head and neck squamous cell carcinoma (HNSCC). Identification and validation of intermediate endpoints is an important step in evaluating chemopreventive agents. AKT/MTOR pathway biomarkers are intrinsic to the carcinogenic process as well as the mechanism of intervention with curcumin. Antiproliferative effects of curcumin were assayed in 9 HNSCC and a keratinocyte cell line. Nicotine, a genotoxic alkaloid involved in tobacco addiction, forms DNA adducts and has been implicated in upper aerodigestive tract cancer promotion. The antiproliferative effects of curcumin were associated with inhibition of the AKT/MTOR pathway in presence and absence of nicotine, which also induced this pathway. Curcumin was highly effective at suppressing growth of SCC40 xenografts and its activity is associated with modulation of MTOR's downstream target pS6. Curcumin at 15 mg significantly increased survival (286 ± 37 vs. 350 days) in the 4NQO carcinogenic model survival study. A major cause of lethal progression of HNSCC is local regional migration and invasion of malignant cells, and curcumin significantly inhibited cancer cell migration and invasion in vitro and in vivo where downregulation of pS6 was associated with a significant decrease in MMP-9. This is the first study to demonstrate that curcumin inhibits the adverse effects of nicotine by blocking nicotine-induced activation of the AKT/MTOR pathway in HNSCC, which retards cell migration. These studies indicate that inhibiting the AKT/MTOR pathway with curcumin may be useful as an oral chemopreventive agent.

Effect of curcumin on cell cycle progression and apoptosis in vascular smooth muscle cells.

1. The possible mechanisms of the antiproliferative and apoptotic effects of curcumin (diferuloylmethane), a polyphenol in the spice turmeric, on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line (A7r5). 2. The proliferative response was determined from the uptake of [3H]-thymidine. Curcumin (10(-6)-10(-4) M) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured vascular smooth muscle cells in a concentration-dependent manner. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 10(-6) to 10(-5) M in A7r5 cells. However, the number of viable cells after 10(-4) M curcumin treatment was less than the basal value (2 x 10(5) cells). 3. To analyse the various stages of the cell cycle, [3H]-thymidine incorporation into DNA was determined every 3 h. After stimulation with foetal calf serum, quiescent A7r5 cells started DNA synthesis in 9 to 12 h (G1/S phase), then reached a maximum at 15 to 18 h (S phase). Curcumin (10(-6)-10(-4) M) added during either the G1/S phase or S phase significantly inhibited [3H]-thymidine incorporation. 4. Following curcumin (10(-6)-10(-4) M) treatment, cell cycle analysis utilizing flow cytometry of propidium iodide stained cells revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 10(-4) M also induced cell apoptosis. It is suggested that curcumin arrested cell proliferation and induced cell apoptosis, and hence reduced the [3H]-thymidine incorporation. 5. The apoptotic effect of 10(-4) M curcumin was also demonstrated by haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling (TUNEL), and DNA laddering. Curcumin (10(-4) M) induced cell shrinkage, chromatin condensation, and DNA fragmentation. 6. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin at the concentration range 10(-5) to 10(-4) M. On the other hand, the cytosolic protein kinase C activity stimulated by phorbol ester was reduced by 10(-4) M curcumin, but unaffected by lower concentrations (10(-6)-10(-5) M). 7. The levels of c-myc, p53 and bcl-2 mRNA were analysed using a reverse transcription-polymerase chain reaction (RT-PCR) technique. The level of c-myc mRNA was significantly reduced by curcumin (10(-5)-10(-4) M) treatment. And, the level of bcl-2 mRNA was significantly reduced by 10(-4) M curcumin. However, the alteration of the p53 mRNA level by curcumin (10(-5)-10(-4) M) treatment did not achieve significance. The effects of curcumin on the levels of c-myc and bcl-2 mRNA were then confirmed by Northern blotting. 8. Our results demonstrate that curcumin inhibited cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells. Curcumin may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis. Our results suggest that the antiproliferative effect of curcumin may partly be mediated through inhibition of protein tyrosine kinase activity and c-myc mRNA expression. And, the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase activity, protein kinase C activity, c-myc mRNA expression and bcl-2 mRNA expression.