Anticancer Potential Of Curcumin Research Articles

In vitro and in vivo studies on the anticancer potential of curcumin and nanocurcumin

Purpose: Curcumin, a polyphenolic compound that obtained from the herb of Curcuma longa, has many anticancer effects. But, its effect is low due to poor water solubility. In order to improve its solubility and drug delivery, we have utilized a nano-curcumin. Methods: In vitro cytotoxicity and anti-tumor promoting effects of nanocurcumin and normal curcumin were investigated. Results revealed that nanocurcumin is able to inhibit the growth of two human cancer cell lines Hep-G2 and HCT116 with IC50 values of 5.68 and 6.53 µg ml−1, respectively,while free curcumin expresses the activity with IC50 values of 8.28 and 9.64µg ml−1. At the concentration of 40 µg ml−1. Nanocurcumin showed anti-tumor promoting effects in reducing tumor size by 59.8 % , while the percentages caused by curcumin was 41.4%, respectively. Mice were treated with equal concentration of nanocurcumin and curcumin showed an improvement in the antioxidant and anti-inflammatory cytokines. The level of improment in EC bearing mice treated with curcumin was lower than that of cells treated with nano curcumin (P=0.001). Conclusion:Results are suggesting that Nano curcumin can be more effective than free curcumin in inhibition of Elrich ascites carcinoma cell lines.

Enhanced drug retention, sustained release, and anti-cancer potential of curcumin and indole-curcumin analog-loaded polysorbate 80-stabilizied PLGA nanoparticles in colon cancer cell line SW480.

The major therapeutic limitation of curcumin and indole-incorporated curcumin analog is its low bioavailability. We hypothesized that nano-encapsulation of indole-incorporated curcumin analog and curcumin as a biodegradable polymeric nanoparticle may enhance its bioavailability with extended drug retention time. Indole-incorporated curcumin analog and curcumin loaded PLGA nanoparticles were synthesized by solvent evaporation technique. Physicochemical characterizations and anti-cancer potential of the nanoparticles were evaluated in human colon cancer cell line SW480. The synthesized NPs had a size range of 50-150nm diameter. The nano-formulation preserved the drug from degradation in wide ranges of pH environments. The nanoparticles treatment against SW480 cancer cell line triggered nuclear fragmentation, cell cycle blockade, inhibition of apoptosis and metastatic biomarkers. These drug-loaded nanoparticles may be potent nano-formulations against colon cancer because of its ability to tolerate extreme pH environments, thus having potential of oral drug-delivery.

Polymeric Nano-Encapsulation of Curcumin Enhances its Anti-Cancer Activity in Breast (MDA-MB231) and Lung (A549) Cancer Cells Through Reduction in Expression of HIF-1α and Nuclear p65 (Rel A).

The anti-cancer potential of curcumin, a natural NFκβ inhibitor, has been reported extensively in breast, lung and other cancers. In vitro and in vivo studies indicate that the therapeutic efficacy of curcumin is enhanced when formulated in a nanoparticulate carrier. However, the mechanism of action of curcumin at the molecular level in the hypoxic tumour micro-environment is not fully understood. Hence, the aim of our study was to investigate the mechanism of action of curcumin formulated as nanoparticles in in vitro models of breast and lung cancer under an hypoxic microenvironment. Biodegradable poly(lactic-co-glycolic acid) PLGA nanoparticles (NP), loaded with curcumin (cur-PLGA-NP), were fabricated using a solvent evaporation technique to overcome solubility issues and to facilitate intracellular curcumin delivery. Cytotoxicity of free curcumin and cur-PLGA-NP was evaluated in MDA-MB-231 and A549 cell lines using migration, invasion and colony formation assays. All treatments were performed under an hypoxic micro-environment and whole cell lysates from controls and test groups were used to determine the expression of HIF-1α and p65 levels using ELISA assays. A ten-fold increase in solubility, three-fold increase in anti-cancer activity and a significant reduction in the levels of cellular HIF-1α and nuclear p65 (Rel A) were observed for cur-PLGA-NP, when compared to free curcumin. Our findings indicate that curcumin can effectively lower the elevated levels of HIF-1α and nuclear p65 (Rel A) in breast and lung cancer cells under an hypoxic tumour micro-environment when delivered in nanoparticulate form. This applied means of colloidal delivery could explain the improved anti-cancer efficacy of curcumin and has further potential applications in enhancing the activity of anti-cancer agents of low solubility.

Calebin A, a novel component of turmeric, suppresses NF-κB regulated cell survival and inflammatory gene products leading to inhibition of cell growth and chemosensitization

BackgroundWhile the anti-inflammatory and anticancer potential of curcumin, which is derived from turmeric (Curcuma longa), has been studied extensively, very little is known about Calebin A, another novel compound from the same source. PurposeTo determine whether Calebin A exhibits anti-inflammatory and anticancer potential. MethodsWe examined the anti-inflammatory potential of Calebin A by DNA binding of NF-κB. Anticancer properties of Calebin were determined by MTT and FACS analysis and NF-κB regulated expression of proteins was assessed by western blotting. ResultsCalebin A suppressed NF-κB activation induced by various stimuli. This inhibition of NF-κB activation was mediated through the suppression of direct binding of NF-κB/p65 to the DNA. This inhibitory effect was reversed by a reducing agent, and mutation of the Cys38 of p65 to serine abolished the effect of Calebin A on this binding. Suppression of NF-κB activation by Calebin A resulted in the down-regulation of the expression of proteins involved in tumor cell survival, proliferation, inflammation, and metastasis. Furthermore, Calebin A inhibited proliferation and induced apoptosis in a wide variety of tumor cells, as examined by various assays. It enhanced apoptosis induced by chemotherapeutic agents. ConclusionOur results demonstrate that Calebin A inhibits NF-κB activation pathway through interaction with p65 and potentiates apoptosis in cancer cells; thus, it has potential in the treatment of cancer. However, further in vivo studies are warranted to define its anti-inflammatory and anticancer potential.

Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings.

Antimutagenic and cancer preventive potential of culinary spices and their bioactive compounds

Spices significantly contribute to human health through their bioactives. They exert multiple health-beneficial influences including anti-cancer potential. Among natural chemopreventive bioactives capable of inhibiting, retarding, or reversing the multi-stage carcinogenesis, considerable attention has been focused in recent decades on spice derived phytochmicals. Spices with proven anticarcinogenic effects in animal models of cancer include turmeric, garlic, ginger, and black cumin. These spices showed chemopreventive effects against cancers of the skin, forestomach, pancreas, liver, colon, and oral cancer in experimental models. Bioactives of these spices reduce oxidative stress by decreasing free radicals concentration, impede cell division and promote apoptosis in cancerous cells. Additionally, they regulate inflammation and immunocompetence, contributing to cancer prevention. The anticancer potential of curcumin has also been evidenced in clinical studies. Curcumin of turmeric is understood to impede carcinogenesis at all three stages. Curcumin’s anticarcinogenic effect is partly mediated through its inhibition of the transcription factor NFkB and inhibition of proinflammatory pathways. Curcumin induces apoptosis, suppress proliferation and angiogenesis. Use of spices as food adjuncts is a promising approach to reduce the risk of cancer. Although the cancer preventive effects have not been conclusively proven in humans, these spices deserve to be considered as nutraceuticals for deriving anticancer influences.

Curcumin-loaded chitosan-cholesterol micelles: evaluation in monolayers and 3D cancer spheroid model.

To improve the bioavailability and anticancer potential of curcumin by using a cholesterol-conjugated chitosan micelle. Methods & methods: Cholesterol was conjugated to chitosan (15 kDa) to form self-assembled micelles, which loaded curcumin. Physicochemical characterization and formulation optimization of the drug-loaded micelles (curcumin-loaded chitosan-cholesterol micelles [C-CCM]) were performed. In vitro cellular uptake and viability of C-CCM were investigated in melanoma and breast cancer cell lines. The antitumor efficacy was evaluated in 3D lung cancer spheroid model. The optimized C-CCM had size of approximately 162 nm with loading efficiency of approximately 36%. C-CCM was taken up efficiently by the cells, and it reduced cancer cell viability significantly compared with free curcumin. C-CCM enhanced the antitumor efficacy in spheroids, suggesting that C-CCM could be used as an effective chemotherapy in cancer.

Curcumin Suppresses Proliferation and Migration of MDA-MB-231 Breast Cancer Cells through Autophagy-Dependent Akt Degradation.

Previous studies have evidenced that the anticancer potential of curcumin (diferuloylmethane), a main yellow bioactive compound from plant turmeric was mediated by interfering with PI3K/Akt signaling. However, the underlying molecular mechanism is still poorly understood. This study experimentally revealed that curcumin treatment reduced Akt protein expression in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells, along with an activation of autophagy and suppression of ubiquitin-proteasome system (UPS) function. The curcumin-reduced Akt expression, cell proliferation, and migration were prevented by genetic and pharmacological inhibition of autophagy but not by UPS inhibition. Additionally, inactivation of AMPK by its specific inhibitor compound C or by target shRNA-mediated silencing attenuated curcumin-activated autophagy. Thus, these results indicate that curcumin-stimulated AMPK activity induces activation of the autophagy-lysosomal protein degradation pathway leading to Akt degradation and the subsequent suppression of proliferation and migration in breast cancer cell.

Abstract B42: Nelfinavir potentiates the anti-cancer efficacy of curcumin by subverting endoplasmic reticulum stress toward apoptosis: A promising chemoprevention approach

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Despite the availability of treatments against localized PCa, the clinical management of advanced PCa remains a significant challenge in relation to both patient morbidity and escalating healthcare costs. Therefore, the ability to suppress cancer growth using safe natural compounds as chemopreventive agents, e.g. Curcumin (CUR), is emerging as a promising and cost-effective approach. The anti-cancer effects of CUR have been associated with its ability to suppress crucial survival pathways in cancer cells, e.g. PI3K/Akt and NF-κB signaling. However, clinical trials investigating the anti-cancer potential of CUR have clearly indicated that this phytochemical will be of limited efficacy when used alone. Aggressive cancer cells utilize multiple master regulatory pathways to dictate their growth, survival and death decisions, which need to be simultaneously targeted towards an effective anti-cancer approach. Indeed, recent findings demonstrate that the control of cell survival and apoptosis is exquisitely regulated via the endoplasmic reticulum (ER) stress cascades. Numerous recent studies have shown that the clinically approved HIV-1 protease inhibitor drug, Nelfinavir (NFV) is an well-tolerated oral drug with promising anti-cancer properties. The antitumor effects of NFV is believed to be via the suppression of PI3K/Akt and the induction of ER-stress. Therefore, we hypothesized that the constitutive ER-stress in aggressive cancer cells can be subverted towards apoptosis by chronic exposure to CUR and NFV, which will be a novel chemoprevention approach. In vitro studies (MTT cytotoxicity-assays) in two aggressive PCa cell lines, i.e. C4-2B and PC-3, showed significant (p<0.05) increases in cytotoxicity following coexposure to physiologically achievable concentrations of CUR & NFV (5 μM each). However, this drug combination did not show comparable toxicity in the non-tumorigenic RWPE-1 cell line, or in the primary prostate epithelial cells (PrEC) and bone-marrow mesenchymal stem cells (MSC). Western immunoblot studies showed that combined exposure to CUR & NFV acted in a synergistic manner (combination index<1) to suppress Akt activation (phosphorylated form) and significantly (p<0.05) increased the levels of early ER-stress markers, Grp78 and phospho-eIF2α. The ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3 were also upregulated following acute (12 hr) exposure to CUR & NFV combination. More importantly, chronic exposure (3 wks; replenished every third day) to a much lower concentration of CUR & NFV combination (0.5 μM each) was able to drastically reduce the clonogenic ability of C4-2B and PC-3 cells, as evident from colony forming unit (CFU) assays. Therefore, our in vitro studies showed that NFV can potentiate the anti-cancer effects of CUR and this combination may be a promising approach against PCa growth. In vivo studies using mice containing C4-2B tumor xenografts (<50 mm) are currently in progress to document the safety and anti-tumor efficacy of chronic treatment with the CUR & NFV combination. Initial evidence of the in vitro efficacy of this combination suggests a safe chemoprevention strategy that specifically targets the constitutive ER-stress in aggressive cancer cells. Citation Format: Aditi Mathur, Mikhail L. Kostochka, Asim B. Abdel-Mageed, Debasis Mondal. Nelfinavir potentiates the anti-cancer efficacy of curcumin by subverting endoplasmic reticulum stress toward apoptosis: A promising chemoprevention approach. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B42.

Multifunctional polymeric nanocurcumin for cancer therapy.

Nanotechnology-based drug delivery systems have the potential to enhance the efficacy of poorly soluble systemic drugs. Curcumin, a yellow pigment isolated from turmeric, possesses a wide range of pharmacological activities, including anticancer effects. The anticancer potential of curcumin is mediated through the inhibition and modulation of several intracellular signaling pathways, as confirmed in various in vitro and in vivo cancer studies. However, clinical application of dietary curcumin for the treatment of cancer and other chronic diseases have been hindered by poor bioavailability, due to low systemic solubility as well as rapid metabolism and elimination from the body. Different techniques for sustained and efficient curcumin delivery, including nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles are the focus of this study. Previous studies have shown that nanocurcumin has improved anticancer effects as compared to normal curcumin formulations. Among nanoformulations, few composite nanosystems have the simultaneous properties of therapeutic activity and multifunctional nanoparticles as enhanced image contrast agents. We also address the challenges to the development of nanocurcumin delivery platforms by enhancing a steady aqueous dispersion state. Further studies are needed using preclinical and clinical cancer models to recommend nanocurcumin as a drug of choice for cancer therapy.

Abstract 4227: Curcumin in cyclodextrin in liposome as a delivery vehicle against osteosarcoma

Abstract The delivery of curcumin, a broad spectrum anticancer drug, has been explored in the form of liposomal nanoparticles to treat osteosarcoma. Osteosarcoma (OS) accounts for approximately 20% of all bone cancers and it develops during the period of rapid growth in adolescence. Anti-cancer potential of curcumin has not been fully explored in the form of nanoformulations against OS. The drug is water insoluble and an effective delivery route is through encapsulation in cyclodextrins followed by a second encapsulation in liposomes. Liposomal curcumin's potential evaluated against OS and breast cancer. The resulting 2-Hydroxypropyl-gamma-cyclodextrin/curcumin-liposome complex shows promising anticancer potential against cancer of mesenchymal and epithelial origin when tested against KHOS and MCF-7 cell lines with IC50 value of 5.4 and 10.2 µg/ml respectively. The anticancer potential of curcumin in the form of DCL (drug-in-cyclodextrin-in-liposome) preparation has been explored first time for OS. DMSO-curcumin (free drug) induced autophagic cell death in KHOS whereas liposomal curcumin initiates the caspase cascade that leads to apoptotic cell death in vitro and in vivo also. The in vivo study was performed using human osteosarcoma xenograft model in mice. Interestingly, liposomal curcumin was less toxic on normal cells. In this study, the objective to cause cancer cell death by apoptosis and not by autophagy was achieved through liposomal curcumin formulations alone. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4227. doi:10.1158/1538-7445.AM2011-4227

Perspectives on Chemopreventive and Therapeutic Potential of Curcumin Analogs in Medicinal Chemistry

Curcumin is a natural polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over past 50 years has indicated that this polyphenol is highly pleiotropic molecule capable of preventing and treating various cancers. The anticancer potential of Curcumin is severely affected by its limited systemic and target tissue bioavailability and rapid metabolism. In the present review article, we provide a summarized account of different drug delivery systems employed for tackling the problem of cucumin's bioavailability such as liposomes, phospholipid complexes and nanoparticles. Concomitantly we have reviewed the large volume of literature reports describing structural modifications of Curcumin and the anticancer potential of its analogs. Some of the difluorocurcumin analogs allowing longer circulation times and preferential accumulation in the pancreas seem to offer promising leads for conducting first in-depth animal studies and subsequently clinical trials for the use of these analogs for prevention of tumor progression and/or treatments of human malignancies.