Targeting cancer stem cells by curcumin and clinical applications

Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric, an Indian spice. The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, sonic hedgehog) and specific microRNAs involved in acquisition of epithelial–mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments.     

New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors

Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. In clinical trials, highly selective or specific blocking of only one of the kinases involved in these signaling pathways has been associated with limited or sporadic responses. Improved understanding of the complexity of signal transduction processes and their roles in cancer has suggested that simultaneous inhibition of several key kinases at the level of receptors and/or downstream serine/threonine kinases may help to optimize the overall therapeutic benefit associated with molecularly targeted anticancer agents. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment based on preclinical and clinical data showing potent anti-tumor activity of single drugs inhibiting multiple molecular targets or combination therapies involving multiple drugs with selective or narrow target specificity. Preclinical and clinical studies point to molecules on vascular endothelial cells and pericytes as being important targets for anticancer therapies, as well as molecules on or within tumor cells themselves. This suggests that optimal therapeutic approaches to cancer may involve targeting multiple molecules found in both the tumor and supportive tissues. In this review, we will use the most recent preclinical and clinical data to describe this emerging paradigm for anticancer therapy involving targeting multiple signaling pathways with tyrosine or serine/threonine kinase inhibitors.     

Curcumin inhibits the migration and invasion of human A549 lung cancer cells through the inhibition of matrix metalloproteinase-2 and -9 and Vascular Endothelial Growth Factor (VEGF)

It is well known that matrix metalloproteinases (MMPs) act an important role in the invasion, metastasis and angiogenesis of cancer cells. Agents suppressed the MMPs could inhibited the cancer cells migration and invasion. Numerous evidences had shown that curcumin (the active constituent of the dietary spice turmeric) has potential for the prevention and therapy of cancer. Curcumin can inhibit the formation of tumors in animal models of carcinogenesis and act on a variety of molecular targets involved in cancer development. There is however, no available information to address the effects of curcumin on migration and invasion of human lung cancer cells. The anti-tumor invasion and migration effects of lung cancer cells induced by curcumin were examined. Here, we report that curcumin suppressed the migration and invasion of human non-small cell lung cancer cells (A549) in vitro. Our findings suggest that curcumin has anti-metastatic potential by decreasing invasiveness of cancer cells. Moreover, this action was involved in the MEKK3, p-ERK signaling pathways resulting in inhibition of MMP-2 and -9 in human lung cancer A549 cells. Overall, the above data shows that the anticancer effect of curcumin is also exist for the inhibition of migration and invasion in lung cancer cells.     

Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer

Bladder cancer is often associated with recurrence and progression to invasive metastatic disease that have palliative therapeutic options. The use of traditional chemotherapeutic agents for bladder cancer management often suffers from toxicity and resistance concerns. This emphasizes the need for development of safer, natural, nontoxic compounds as chemotherapeutic/chemopreventive agents. Curcumin (diferuloylmethane) is a natural compound that has been known to possess anticancer properties in various cancers, including bladder cancer. However, the biological targets of curcumin are not well defined. Recently, it has been proposed that curcumin may mediate epigenetic modulation of expression of microRNAs (miRNA). In this article, we define for the first time, that curcumin directly induces a tumor-suppressive miRNA, miR-203, in bladder cancer. miR-203 is frequently downregulated in bladder cancer due to DNA hypermethylation of its promoter. We studied the functional significance of miR-203 in bladder cancer cell lines and found that miR-203 has tumor suppressive properties. Also, we define Akt2 and Src as novel miR-203 targets in bladder cancer. Curcumin induces hypomethylation of the miR-203 promoter and subsequent upregulation of miR-203 expression. This leads to downregulation of miR-203 target genes Akt2 and Src that culminates in decreased proliferation and increased apoptosis of bladder cancer cells. This is the first report that shows a direct effect of curcumin on inducing epigenetic changes at a miRNA promoter with direct biological consequences. Our study suggests that curcumin may offer a therapeutic advantage in the clinical management of refractory bladder cancer over other standard treatment modalities.     

Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis

Carcinogenesis is a multi-step process which could be prevented by phytochemicals. Phytochemicals from dietary plants and other plant sources such as herbs are becoming increasingly important sources of anticancer drugs or compounds for cancer chemoprevention or adjuvant chemotherapy. Phytochemicals can prevent cancer initiation, promotion, and progression by exerting anti-inflammatory and anti-oxidative stress effects which are mediated by integrated Nrf2, NF-κB, and AP-1 signaling pathways. In addition, phytochemicals from herbal medicinal plants and/or some dietary plants developed in recent years have been shown to induce apoptosis in cancer cells and inhibition of tumor growth in vivo. In advanced tumors, a series of changes involving critical signaling molecules that would drive tumor cells undergoing epithelial–mesenchymal transition and becoming invasive. In this review, we will discuss the potential molecular targets and signaling pathways that mediate tumor onset and metastasis. In addition, we will shed light on some of the phytochemicals that are capable of targeting these signaling pathways which would make them potentially applicable to cancer chemoprevention, treatment and control of cancer progression.     

Dual anticancer role of metformin: an old drug regulating AMPK dependent/independent pathways in metabolic,oncogenic/tumorsuppresing and immunity context

Metformin has been known to treat type 2 diabetes for decades and is widely prescribed antidiabetic drug. Recently, its anticancer potential has also been discovered. Moreover, metformin has low cost thus it has attained profound research interest. Comprehensing the complexity of the molecular regulatory networks in cancer provides a mode for advancement of research in cancer development and treatment. Metformin targets many pathways that play an important role in cancer cell survival outcome. Here, we described anticancer activity of metformin on the AMPK dependent/independent mechanisms regulating metabolism, oncogene/tumor suppressor signaling pathways together with the issue of clinical studies. We also provided brief overwiev about recently described metformin’s role in cancer immunity. Insight in these complex molecular networks, will simplify application of metformin in clinical trials and contribute to improvement of anti-cancer therapy.     

Death by design: where curcumin sensitizes drug-resistant tumours

Chemotherapy remains the core of anticancer treatment. However, despite the tremendous strides made in the development of targeted anticancer therapies, emergence of resistance to chemotherapeutic drugs is still a major obstacle in the successful management of resistant tumours. Therefore, profound investigation into the in-depth molecular mechanisms of drug resistance is essential and may hopefully translate into effective therapies that can flip the switch from drug resistance to susceptibility. Mechanistically, resistance phenomena may be explained by (i) overexpression of drug efflux pumps, (ii) enhanced drug detoxification, (iii) rapid DNA repair efficiency, (iv) defects in apoptosis regulation, and (v) active cell survival signals. Several adverse effects associated with multidrug resistance and the need for safe multi-targeted anticancer drugs instigated the use of the phytochemical, curcumin, the yellow pigment of the spice turmeric, which has pleotropic activities. We performed a structured literature review using PubMed and Medline searches with secondary review of cited publications, identifying studies on the role of curcumin in conquering drug resistance in cancer. This review describes how curcumin sensitizes cancer cells through regulation of multiple multidrug resistance pathways, thus employing one drug for multiple targets. Curcumin helps the cancer cells to regain their 'forgotten' apoptosis, modulates drug-target interaction at different levels, restrains survival pathways when their proteins are overexpressed, and finds an alternate way to carry forward the process of sensitization of different resistant tumours. Additionally, the review dissects the role of curcumin, if any, in targeting the major culprit of drug resistance, cancer stem cells (CSC), thereby circumventing resistance. Taken together, this review strongly suggests that curcumin is a promising chemosensitizing agent and that the unique properties of curcumin may be exploited for successful management of resistant tumours.     

ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer

Gastric cancer is one of the leading causes of cancer mortality in the world, and finding novel agents and strategies for the treatment of advanced gastric cancer is of urgent need. Curcumin is a well-known natural product with anti-cancer ability, but is limited by its poor chemical stability. In this study, an analog of curcumin with high chemical stability, WZ35, was designed and evaluated for its anti-cancer effects and underlying mechanisms against human gastric cancer. WZ35 showed much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, our data showed that WZ35 induced reactive oxygen species (ROS) production, resulting in the activation of both JNK-mitochondrial and ER stress apoptotic pathways and eventually cell apoptosis in SGC-7901 cells. Blockage of ROS production totally reversed WZ35-induced JNK and ER stress activation as well as cancer cell apoptosis. In vivo, WZ35 showed a significant reduction in SGC-7901 xenograft tumor size in a dose-dependent manner. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human gastric cancer treatment.     

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

Background: Curcumin, a phenolic compound extracted from the rhizomes of Curcuma longa, has showncytotoxic effects against a variety of cancers. The aim of this study was to identify potential microRNA (miRNA)mediators of the anticancer effects of curcumin in ovarian cancer cells. Materials and Methods: SKOV3 ovariancancer cells were treated with curcumin (10-60 μM) and miR-9 expression, cell proliferation, and apoptosiswere assessed. The effects of miR-9 depletion on curcumin-mediated growth suppression were also examined.Phosphorylation of Akt and forkhead box protein O1 (FOXO1) was measured in cells with miR-9 overexpressionor curcumin treatment. Results: Curcumin caused a significant and dose-dependent increase of miR-9 expressionin SKOV3 cells, while significantly impeding cell proliferation and stimulating apoptosis. Depletion of miR-9significantly (p<0.05) attenuated the growth-suppressive effects of curcumin on SKOV3 cells, coupled withreduced percentages of apoptotic cells. In contrast, overexpression of miR-9 significantly enhanced the cleavageof caspase-3 and poly(ADP-ribose) polymerase and promoted apoptotic death in SKOV3 cells. Western blotanalysis showed that both miR-9 overexpression and curcumin similarly caused a significant (p<0.05) declinein the phosphorylation of Akt and FOXO1, compared to untreated cells. Conclusions: The present studyprovided evidence that curcumin exerts its cytotoxic effects against SKOV3 ovarian cancer cells largely throughupregulation of miR-9 and subsequent modulation of Akt/FOXO1 axis. Further studies are needed to identifydirect targets of miR-9 that mediate the anticancer effects of curcumin in ovarian cancer cells.     

Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice

Earlier studies using prostate cancer cells in culture showed that phenethyl isothiocyanate (PEITC) and curcumin have significant chemopreventive and possibly chemotherapeutic effects. However, their in vivo effects are still lacking. Hence, this study was undertaken to determine the possible in vivo efficacy of prostate cancer-prevention as well as cancer-therapeutic treatment by PEITC and curcumin alone or in combination. We evaluated the effects on tumor growth in vivo, using NCr immunodeficient (nu/nu) mice bearing s.c. xenografts of PC-3 human prostate cancer cells. Molecular biomarkers representing proliferation and apoptosis were determined. Continued i.p. injection of curcumin or PEITC (6 and 5 mumol; thrice a week for 28 days), beginning a day before tumor implantation significantly retarded the growth of PC-3 xenografts. Combination of i.p. administration of PEITC (2.5 mumol) and curcumin (3 mumol) showed stronger growth-inhibitory effects. Next, we evaluated the cancer-therapeutic potential of curcumin and PEITC in mice with well-established tumors, and the results showed that PEITC or curcumin alone had little effect, whereas combination of curcumin and PEITC significantly reduced the growth of PC-3 xenografts. Immunohistochemistry staining and Western blot analysis revealed that the inhibition of Akt and nuclear factor-kappaB signaling pathways could contribute to the inhibition of cell proliferation and induction of apoptosis. Taken together, our results show that PEITC and curcumin alone or in combination possess significant cancer-preventive activities in the PC-3 prostate tumor xenografts. Furthermore, we found that combination of PEITC and curcumin could be effective in the cancer-therapeutic treatment of prostate cancers.     

Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo

Curcumin (diferuloylmethane) is the major active ingredient of turmeric (Curcuma longa) used in South Asian cuisine for centuries. Curcumin has been shown to inhibit the growth of transformed cells and to have a number of potential molecular targets. However, the essential molecular targets of curcumin under physiologic conditions have not been completely defined. Herein, we report that the tumor cellular proteasome is most likely an important target of curcumin. Nucleophilic susceptibility and in silico docking studies show that both carbonyl carbons of the curcumin molecule are highly susceptible to a nucleophilic attack by the hydroxyl group of the NH(2)-terminal threonine of the proteasomal chymotrypsin-like (CT-like) subunit. Consistently, curcumin potently inhibits the CT-like activity of a purified rabbit 20S proteasome (IC(50) = 1.85 micromol/L) and cellular 26S proteasome. Furthermore, inhibition of proteasome activity by curcumin in human colon cancer HCT-116 and SW480 cell lines leads to accumulation of ubiquitinated proteins and several proteasome target proteins, and subsequent induction of apoptosis. Furthermore, treatment of HCT-116 colon tumor-bearing ICR SCID mice with curcumin resulted in decreased tumor growth, associated with proteasome inhibition, proliferation suppression, and apoptosis induction in tumor tissues. Our study shows that proteasome inhibition could be one of the mechanisms for the chemopreventive and/or therapeutic roles of curcumin in human colon cancer. Based on its ability to inhibit the proteasome and induce apoptosis in both HCT-116 and metastatic SW480 colon cancer cell lines, our study suggests that curcumin could potentially be used for treatment of both early-stage and late-stage/refractory colon cancer.     

Autophagy-associated Targeting Pathways of Natural Products during Cancer Treatment

It is well known that conventional chemotherapy and radiation therapy can result in toxicity to both normalcells and tumor cells, which causes limitations in the application of these therapeutic strategies for cancer control.Novel and effective therapeutic strategies for cancers with no or low toxicity for normal cells are a high priority.Therefore, natural products with anticancer activity have gained more and more attention due to their favorablesafety and efficacy profiles. Pre-clinical and clinical studies have demonstrated that several representative naturalcompounds such as resveratrol, epigallocatechin-3-gallate, curcumin, allicin and ginsenosides have obviousanticancer potential. In this article, we summarize autophagy-associated targeting pathways of such naturalproducts for inducing the death of cancer cells, and discuss the core autophagic pathways involved in cancertreatments. Recent advances in the discovery, evaluation and exploitation of natural compounds as therapeuticagents for cancers will provide references and support in pre-clinical and clinical application of novel naturaldrugs for the treatment of primary and metastatic tumors in the future.     

天然草药—癌症治疗中的潜在自噬诱导剂

自噬是一种维持细胞内稳态的重要代谢过程。近年来研究发现,自噬与肿瘤的发生发展密切相关,参与调控肿瘤的形成、增殖、转移以及能量代谢等过程。并且自噬在肿瘤的发生发展中发挥着不同的作用,它能抑制早期肿瘤的生成,促进晚期肿瘤的发展。目前,自噬已成为肿瘤药物靶向研究中的一个新热点。许多草药,包括中草药,已作为现行药物的补充和替代药物、保健品和营养品,以减轻癌症治疗中化疗药物的毒副反应。此外,许多草药及天然产物均可通过诱导自噬,进而导致细胞衰老、凋亡非依赖性细胞死亡途径或补体介导的细胞凋亡途径的激活,最终发挥着抗肿瘤作用。据此,本文将回顾分析天然自噬诱导剂在癌症治疗中的潜在作用机制。同时,我们着重探讨白藜芦醇、姜黄素和16-羟基克罗烷-3,13-二烯-15,16-内酯这三种天然化合物作为候选自噬诱导剂在癌症治疗中的研究进展,旨在为研发靶向自噬的新型抗肿瘤药物提供方向。     

Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with beta-phenylethyl isothiocyanate and curcumin

Many naturally occurring compounds, including beta-phenylethyl isothiocyanate (PEITC) and curcumin, exhibit significant anti-cancer chemopreventive effects. In this study, we investigated the combined effects of PEITC and curcumin in PC-3 human prostate cancer cells and in PC-3 cells that were stably transfected with an NF-kappaB luciferase plasmid (PC-3 C4). We found an additive effect of PEITC and curcumin for the induction of apoptosis. To elucidate the potential mechanisms of this effect, we studied several critical cellular signaling pathways, including the critical NF-kappaB cell survival signal that is hyper-activated in PC-3 cells and many other cancers. PEITC and curcumin additively inhibited NF-kappaB luciferase activity. Furthermore, the combined treatment significantly increased the activity of poly(ADP-Ribose) polymerase and cleavage of caspase-3 in correlation with apoptotic cell death. Studying upstream signaling events, we found that the phosphorylations of IkappaBalpha and Akt (Ser473, Thr308) were significantly attenuated by the combination of PEITC and curcumin. As these events can be downstream of the activation of epidermal growth factor receptor (EGFR), we pretreated PC-3 cells with PEITC and curcumin and then stimulated them with EGF. EGFR phosphorylations (Y845 and Y1068) were dramatically suppressed by PEITC or curcumin, and more so by the combination. Importantly, the degree of Akt and PI3K phosphorylations induced by EGF were also significantly suppressed. We conclude that the simultaneous targeting of EGFR, Akt and NF-kappaB signaling pathways by PEITC and curcumin could be the molecular targets by which PEITC and curcumin exert their additive inhibitory effects on cell proliferation and ultimately lead to programmed cell death of tumor cells.     

MicroRNA-326 sensitizes human glioblastoma cells to curcumin via the SHH/GLI1 signaling pathway

Glioblastoma multiforme is the most malignant and common brain tumor in adults and is characterized by poor survival and high resistance to chemotherapy and radiotherapy. Among the new chemotherapy drugs, curcumin, a popular dietary supplement, has proven to have a potent anticancer effect on a variety of cancer cell types; however, it remains difficult to achieve a satisfactory therapeutic effect with curcumin using the traditional single-drug treatment. In this study, we found that expression of miR-326, a tumor suppressor microRNA in various tumor types, resulted in a marked increase of curcumin-induced cytotoxicity and apoptosis and a decrease of proliferation and migration in glioma cells. Moreover, we found that combination treatment of miR-326 and curcumin caused significant inhibition of the SHH/GLI1 pathway in glioma cells compared with either treatment alone, independent of p53 status. Furthermore, in vivo, the curcumin-induced increase in miR-326 expression altered the anti-glioma mechanism of this combination treatment, which further reduced tumor volume and prolonged the survival period compared to either treatment alone. Taken together, our data strongly support an important role for miR-326 in enhancing the chemosensitivity of glioma cells to curcumin.     

Dendrosomal Curcumin Suppresses Metastatic Breast Cancer in Mice by Changing M1/M2 Macrophage Balance in the Tumor Microenvironment

Curcumin, a lipid-soluble compound extracted from the plant Curcuma Longa, has been found to exertimmunomodulatory effects via macrophages. However, most studies focus on the low bioavailability issue ofcurcumin by nano and microparticles, and thus the role of macrophages in the anticancer mechanism of curcuminhas received little attention so far. We have previously shown the potential biocompatibility, biodegradabilityand anti-cancer effects of dendrosomal curcumin (DNC). In this study, twenty-seven BALB/c mice were equallydivided into control as well as 40 and 80 mg/kg groups of DNC to investigate the involvement of macrophagesin the antitumor effects of curcumin in a typical animal model of metastatic breast cancer. At the end ofintervention, the tumor volume and weight were significantly reduced in DNC groups compared to control(P<0.05). Histopathological data showed the presence of macrophages in tumor and spleen tissues. Real-timePCR results showed that DNC increased the expression of STAT4 and IL-12 genes in tumor and spleen tissues incomparison with control (P<0.05), referring to the high levels of M1 macrophages. Furthermore treatment withDNC decreased STAT3, IL-10 and arginase I gene expression (P<0.05), indicating low levels of M2 macrophage.The results confirm the role of macrophages in the protective effects of dendrosomal curcumin against metastaticbreast cancer in mice.