Anticancer Properties of Curcumin and Interactions With the Circadian Timing System

Abstract

The phytochemical curcumin is a major component of turmeric. It has recognized activity against cancer cells and affects several intracellular signaling pathways. Many molecules targeted by curcumin also regulate the circadian timing system that has effects on carcinogenesis, tumor growth, and metastasis. Although the circadian clock within cells may be suppressed in tumors, cancer cells are subjected to daily hormonal and neural activity that should be considered when timing optimal curcumin treatments. Rapid curcumin degradation in blood and tissues provides a challenge to maintaining sustained levels suitable for inducing cancer cell death, increasing the need to identify when during the circadian cycle rhythmically expressed molecular targets are present. Curcumin is well tolerated by individuals ingesting it for possible cancer prevention or in combination with conventional cancer therapies, and it shows low toxicity toward noncancerous cells at low dosages. In contrast, curcumin is particularly effective against cancer stem cells, which are treatment-resistant, aggressive, and tumor-initiating. Although curcumin has poor bioavailability, more stable curcumin analogs retain the anti-inflammatory, antioxidant, antimitotic, and pro-apoptotic benefits of curcumin. Anticancer properties are also present in congeners of curcumin in turmeric and after curcumin reduction by intestinal microbes. Various commercial curcuminoid products are highly popular dietary supplements, but caution is warranted. Although antioxidant properties of curcumin may prevent carcinogenesis, studies suggest curcumin interferes with certain chemotherapeutic agents. This review delves into the complex network of curcuminoid effects to identify potential anticancer strategies that may work in concert with daily physiological cycles controlled by the circadian timing system.

The Many Cancer Cell Targets of Curcumin

Ideally, medically effective phytochemicals act primarily on a single cellular pathway, thereby minimizing detrimental off-target effects that could negate derived benefits. Any discussion of the highly promising anticancer properties of curcumin, derived from the Curcuma longa rhizome, and similar congeners present in turmeric ¹ needs to be balanced with a consideration of their multiple molecular targets and low bioavailability. ² Descriptions of the many signal transduction pathways, transcription factors, and cellular events suppressed by curcumin appear to have added to its appeal and much attention by researchers. It is conceivable that the ability of curcumin to act on multiple targets provides combined, if not synergistic, actions that may be behind its attractive anticancer properties. ³ Several studies describe its suppression of STAT3 and NF-κB pathways that promote cancer cell proliferation and cell survival. ⁴ Curcuminoids also act on pathways used in cancer cell autophagy, proliferation, invasion, and apoptosis that rely on PI3k/Akt-1/mTOR,^5-9 Ras/Raf/MEK/ERK, ¹⁰ GSK-3beta, ¹¹ and p53.^12,13 Along with these actions, curcumin causes mitotic arrest of many types of cancer cells, often at G1 or G2/M.

Curcumin crosses the blood-brain barrier and has potentially therapeutic effects on amyloid plaque formation and other chronic processes in Alzheimer’s disease. ¹⁴ Studies report differential molecular effects between curcumin delivered to healthy subjects at low dosages, for example, 80 mg/day, and higher dosages, 500 mg/day or more, which are often tested after a disease state or tissue damage has begun. ¹⁵ High curcumin levels may present a risk to healthy cells with both carcinogenic and pro-oxidant effects reported in vitro and in animal studies.^16-18 Rhythmic rather than sustained curcumin delivery may be important to avoid suppressing beneficial acute inflammatory and immune responses needed for healing and tissue maintenance while also minimizing exposure to continuous high dosages.

Cell signaling targets of curcumin that are also important for circadian rhythm generation and expression will be discussed in this article. These molecular pathways include components of epithelial-mesenchymal transition (EMT), endoplasmic reticulum (ER) stress, and inflammation. Molecules of particular interest are peroxisome proliferator-activated receptor-γ (PPAR-γ), sirtuin (SIRT) proteins, and components of the circadian clock timing mechanism, including PER2, BMAL1, and CLOCK. The impact of curcumin on circadian timing will also be considered through its effects on pluripotency genes and neurogenesis, which requires examination because of the stem-like state of neurons in the master circadian clock located in the hypothalamic suprachiasmatic nucleus (SCN). ¹⁹ The SCN receives retinal light signals through the retinohypothalamic tract that allow the circadian clock to entrain to daily cycles while synchronizing itself and regulating the phase of circadian clocks throughout the body through neural and endocrine routes. ²⁰

Interestingly, studies have shown that in most tissues and organ systems single cells have independently running circadian clocks that are synchronized to each other.^21,22 The molecular timing mechanism of these clocks regulates numerous cellular processes including cell division, differentiation, and cell death.^4,23-28 Neurogenesis in the dentate gyrus is under circadian control, and loss of core circadian clock gene BMAL1 directs differentiation into astrocytes rather than neurons. ²⁸ Molecular targets of curcumin rhythmically vary due to control by the circadian timing system, and curcumin can in turn alter this temporal organization by affecting circadian timing within the SCN or in tissues bearing tumors.

Curcumin Effects on EMT and Cancer Stem Cells

EMT precedes metastasis as cancer cells become more motile and aggressive and express genes typical of stem cells.^29,30 These cancer stem cells (CSCs) are important in tumor growth because of their resistance to anticancer chemotherapy and radiation treatments and because they differentiate and proliferate to form recurrent tumors. During metastasis, cancer cells that are dynamically transitioning to enhanced aggressive and migratory states through EMT also dedifferentiate to acquire stem cell properties and become CSCs. ³¹ Conventional anticancer therapies often fail to eradicate such cancer cells that have undergone EMT and acquired a CSC state. The mechanistic and functional links through which the EMT program triggers cancer cells to become stem-like are implicated in drug resistance. ³² CSCs are thus clinically important because of their resistance to treatments and their potential to form tumors.

Curcumin appears capable of killing CSCs while promoting differentiation of metastatic cells. ³³ For example, Wnt/β-catenin signaling, which elevates the stem cell protein OCT-4, ³⁴ is inhibited by curcumin in colon ³⁵ and gastric cancer cells. ³⁶ Curcumin also suppresses human cancer cell growth by binding to SIRT1, thereby facilitating its degradation. ³⁷ Rather than suppressing tumor growth by causing apoptosis, curcumin suppresses cell proliferation of human colon cancer cells in a mouse xenograft model. ³⁵ Curcumin appears to induce G1 cell-cycle arrest of colon cancer cells by interfering with CDK2 kinase activity. ³⁸ Curcumin also suppresses human colon cancer cell migration by inhibiting NF-κB activation of plasminogen activator and matrix metalloproteinase-9 (MMP-9) genes that are needed in cell invasion. ³⁹

Curcumin effectively suppresses invasive properties of breast cancer cells. Specifically, it interrupts the EMT program by downregulating expression of several EMT-related proteins including Slug, AXL, Twist1, N-cadherin, β-catenin, vimentin, and fibronectin. ⁴⁰ An in vitro study has revealed the anti-metastatic properties of curcumin where it perturbed MEKK3 and p-ERK signaling pathways and inhibited VEGF, MMP-2, and MMP-9 resulting in the suppression of invasion and migration of human non-small lung cancer cells. ⁴¹

Curcumin downregulates CXCR4, a protein serving in cell adhesion and migration, and upregulates one of the core clock proteins PER2 in human follicular lymphoma cells, which is otherwise downregulated in lymphoma cell lines and primary acute myeloid leukemia-derived cells. ⁴² PER2 has possible tumor suppressor functions and its downregulation is associated with poor prognosis in breast cancer patients. ⁴³ The same study also showed that PER2 functions as a transcriptional corepressor and epigenetically represses expression of EMT-related genes Twist1, Slug, and Snail in metastatic breast cancer cells. PER2 degradation induced by hypoxia promotes EMT in these cancer cells.

Curcumin might target CSCs through direct or indirect effects on CSC self-renewal pathways. ⁴⁴ Wnt/β-catenin, sonic hedgehog, and Notch are 3 major pathways considered to play pivotal roles in CSC self-renewal mechanisms in various cancers. Curcumin reduced the β-catenin/TCF transcriptional activity in intestinal and stomach cancer cell lines. ⁴⁵ Attenuation of Wnt receptor Frizzled-1 and induction of enhanced activity of the proapoptotic activating transcription factor 3 by curcumin resulted in increased apoptosis in metastasizing, poorly and moderately differentiated head and neck squamous carcinoma cells. ⁴⁶ Curcumin-induced cell death was observed in esophageal squamous carcinoma cells resulting in fewer CSCs in the surviving cell line after curcumin treatment. ⁴⁷ Interestingly, curcumin also induced apoptosis and decreased proliferation through reduced Notch-1 activation by downregulation of γ-secretase complex components in human and mouse esophageal adenocarcinoma cells. In the same study, curcumin targeted and decreased Notch-1 specific microRNAs miR-21 and miR-34a and upregulated tumor suppressor let-7a miRNA. ⁴⁸ A novel curcumin analogue diflourinated curcumin reduced expression of histone methyltransferase EZH2 (a major epigenetic regulator of CSC state) and enhanced concomitant expression of several tumor-suppressive miRNAs including let-7a in human pancreatic cancer cells. ⁴⁹ Surprisingly, curcumin was reported to cause one subtype of colon CSCs to proliferate while other CSCs were suppressed. ⁵⁰

EMT in noncancerous cells is initiated by inflammation, ³⁰ suggesting a connection with cancer cells that tend to develop and reside in a pro-inflammatory microenvironment. ⁵¹ Curcumin also suppresses EMT in noncancerous cells ⁷ and during peritoneal fibrosis. ⁵² It also acts on noncancerous tumor stromal cells to repress pancreatic cancer cell EMT. ⁵³ CSC sensitivity to curcumin encourages caution because curcumin might accelerate differentiation of normal mesenchymal stem cells found in organs and tissues. Curcumin increases adult neurogenesis in the dentate gyrus of the hippocampus.^54-56 The hippocampus also expresses daily rhythms in cell proliferation and neural synapse strength,^57,58 suggesting that the phase of the cycle most sensitive to curcumin could be identified for use in minimizing potential disruption. Neurons may be particularly sensitive to curcumin. High curcumin concentrations have toxic effects on neural stem cells in vitro, ⁵⁹ and a mouse lupus model shows greater brain atrophy in the presence of curcumin. ⁶⁰

Possible Curcumin Effects on Stem-Like Cells of the SCN

Like curcumin, anticancer agents developed to exploit the stem-like properties of CSCs may also affect important mesenchymal stem cells within multiple organs that have potential for tissue regeneration and repair. There are proteomic and transcriptomic similarities between CSCs and mesenchymal stem cells of adult animals. The SCN clock might be particularly sensitive to curcuminoids because many SCN neurons have an immature phenotype, expressing stem cell-associated proteins. ¹⁹ In particular, RORα and Six3 genes are expressed distinctly in early SCN development, which persists into adult ages. ⁶¹ The stem-like state of mature neurons in the master circadian clock includes expression of Sox2, a transcription factor with an established function in neural development.^62,63 In addition to Sox2, a fraction of adult human SCN cells express nestin, vimentin, and glutamate-aspartate transporter that are considered as neural stem and progenitor cell markers. ⁶⁴ The adult SCN also contains cells expressing doublecortin and doublecortin-like proteins that are usually found in neuroblasts undergoing a final differentiation into neurons.^65,66 Interestingly, SCN cells express high levels of at least 3 genes prominent in cancer cells (Blcap, Msi2, and Zfhx3), suggesting that curcumin may alter circadian clock properties of these cells. ¹⁹

Curcumin uses a comprehensive and a diverse range of mechanisms to exert its anticancer effects. One such mechanism is by suppressing oncogenic pluripotency genes such as Oct4, Sox2, and NANOG. ⁶⁷ Oct4 and Sox2 are expressed in adult SCN neurons, ⁶⁸ and because curcumin crosses the blood-brain barrier it might alter these stem-like cells. Curcumin has been shown to induce apoptotic cell death by Oct-4 inhibition in NCCIT human embryonic carcinoma cells. ¹¹ To inhibit these pluripotency genes, curcumin upregulates tumor-suppressive microRNAs such as the let-7 family, miR-26a, miR-101, miR-146a, and miR-200b as shown in pancreatic cancer. ⁶⁹ CSC targeting was also observed in studies using curcumin-loaded nanoparticles. ⁷⁰ As mentioned above, curcumin is also known to inhibit EMT in breast cancer cell lines by suppressing multiple EMT- and CSC-related genes, thereby preventing cancer cell invasion. ⁴⁰ Additionally, curcumin was shown to induce the differentiation of glioma-initiating cells evident by a reduction in nestin expression. ⁷¹

Integration of circadian clock theory into cancer prevention and therapy remains a novel approach.^72-75 Cancer growth was shown to be inhibited by circadian reprogramming of the tumor transcriptome with meal timing ⁷⁶ or with agents that synchronize circadian clocks directly including dexamethasone. ⁷⁷ There are few reports describing effects of curcumin on the SCN or circadian clocks. One study claims that dietary curcumin lowers SCN serotonin levels in rats after ethanol exposure. ⁷⁸ Serotonin modulates the phase-shifting effects of retinal light exposure on the SCN circadian clock,^79,80 suggesting an additional possible influence of curcumin on circadian timing mechanisms. Reviews by Kuol et al^81,82 provide a compelling argument that the nervous system can alter carcinogenesis and cancer progression, particularly through its interaction with the immune system. These key influences include growth factor release, control of cancer cell EMT, metastasis regulated by vagal nerve activity, and neurogenesis induced by intestinal resident stem cells.

Because of its antioxidant effects curcumin at high levels might also unfavorably alter the redox balance of cells. The binding of transcription factors BMAL1 and CLOCK as a dimer to promoter elements of clock-controlled genes is sensitive to cellular redox state as shown by circadian clock responses to cellular metabolism. ⁸³ Consequently, these potential curcumin effects on the SCN or other circadian timing structures could have an indirect impact on cancer.

Coupling Between the Circadian Timing and Immune Systems

Circadian clocks within immune cells and cytokine oscillations in the circadian timing system produce rhythmic immune activity^84,85 in part by regulating the NF-κB transcription factor pathway, which has been reviewed elsewhere. ⁸⁶ Curcumin is an effective anti-inflammatory agent and blocks signaling through the canonical NF-κB pathway by acting on I-κB. Curcumin increases PPAR-γ activity in reactive astrocytes, thereby inhibiting inflammation through NF-κB. ⁸⁷ NF-κB activity is commonly elevated in cancer cells, providing them an anti-apoptotic benefit, which is then lost following curcumin exposure.

The circadian timing system and immune system are tightly intermeshed, feeding back on each other. ⁸⁶ SIRT1 is a histone deacetylase that controls the circadian clock by downregulating NF-κB and modifying 2 critical circadian clock proteins, BMAL1 and PER2.^37,88-90 Therefore, curcumin has converging effects on genes controlled by NF-κB—directly and indirectly through SIRT1 and PPAR-γ and through genes serving in the internal timing mechanism of the clock. Although SIRT1 alters acetylation and stability of BMAL1 and PER2, computer modeling suggests PER2 is the major target. ⁹¹ This complexity affects any scheme for optimal timing of curcumin dosing but could be simplified by limiting consideration to only the target organ’s internal timing or any circadian rhythms within the tumor.

Curcumin Effects on ER Stress and the Unfolded Protein Response

Cancer cells respond to chemotherapy and resulting ER stress with an unfolded protein response (UPR) that promotes survival by minimizing harm to the cell. Nevertheless, cancer cells do succumb to overwhelming ER stress. For example, curcumin induces apoptosis of prostate cancer cells through an ER stress response that produces sufficiently disrupted protein folding, as indicated by increased expression of the Ca²⁺-binding protein calreticulin and additional markers of ER stress. ⁹² Similarly, curcumin causes apoptosis of lung, gastric, colon, thyroid, and cervical cancer through ER stress.^93-96 Curcumin has also been shown to inhibit the proliferation of hepatocellular carcinoma cells through ER stress caused by the UPR, which upregulates calreticulin expression and downregulates the expression of calnexin and other proteins. ⁹⁷

Calreticulin is a calcium-binding ER chaperone protein assisting in protein folding that is upregulated during periods of ER stress. ⁹² It is also expressed on the cell surface as the dominant pro-phagocytic signal in a variety of human cancers.^98-100 Calreticulin expression is also increased in tumors compared with normal tissue,^101,102 and it has been shown that calreticulin expression can be a biomarker for bladder urothelial cancer. ¹⁰³ Calreticulin may be an effective target for immune-based drug development to treat a variety of cancers,^98,99 and it can be used as a marker for the prognosis of various cancers, which can provide a new clinical tool for physicians. ¹⁰²

Modified curcuminoids with improved bioavailability may also be a useful target for immune-based drug development. One curcumin derivative shows promising effects on mouse colon cancer cells by inducing cell death through ER stress. ¹⁰⁴ Another curcumin analog, C-150, was shown to be more potent than curcumin and increased the survival rate in treated rats with glioblastoma compared with controls, while also decreasing tumorigenesis in the eyes of a Drosophila cancer model. ¹⁰⁵ In addition, novel delivery systems increase curcumin bioavailability, and many curcumin analogs have been studied to determine their potency against a number specific cancers. ¹⁰⁶ Thus, curcumin and various analogs have much potential for treating various types of cancer by increasing UPR. Furthermore, because calreticulin is upregulated by UPR and its cell-surface expression is increased in numerous cancers, it may also be a therapeutic target or a biomarker to study the efficacy of curcumin in cancer treatment.

Opportunities for Timed Optimal Curcuminoid Delivery

Interactions between curcuminoids and their circadian and noncircadian targets are complex, but it may be possible to identify an optimal phase for curcumin delivery that maximizes efficacy while minimizing potentially negative effects. Twice-daily curcumin dosing would be expected to maintain more sustained tissue levels, which is particularly important to offset the fast degradation of curcumin. However, greater efficacy may result from a single high dose that targets molecules or cellular processes that are available within a limited phase of the circadian cycle, as shown with 5-fluorouracil, ¹⁰⁷ roscovitine, ¹⁰⁸ temozolomide, ¹⁰⁹ and interferon treatments. ¹¹⁰ Melatonin is one of the most important hormones released in a daily rhythm that should be considered in relationship to timing of curcumin. ¹¹¹ This pineal gland hormone is released in darkness and under circadian clock control. Curcumin delivery at night would be expected to augment the ability of melatonin to prevent EMT and cancer cell migration, as has been described in bladder cancer cells in culture and in mouse xenograft studies. ¹¹² Because curcumin typically targets CSCs, nighttime curcuminoid delivery should be considered when designing medical treatments for cancer patients at risk of metastasis or cancer cell infiltration. On the other hand, morning curcumin delivery might complement melatonin effects by suppressing CSCs after melatonin levels have declined.

For individuals taking turmeric or curcumin as a cancer preventative, the challenge is to find a phase that maximizes circadian system effects on curcumin pharmacokinetics while maintaining curcumin benefits to functioning of the circadian system. Few studies suggest how circadian clocks in intestinal epithelia might modulate curcumin absorption. Optimal bioavailability may result from taking curcumin with meals, in line with its consumption in traditional cuisines where dietary fats help solubilize curcumin and may protect it from degradation. ²³ Curcuminoids do not appear to act directly on products of the core circadian clock genes. Indirect effects have been described that may weaken or strengthen clock stability, amplitude, period, or phase relationships between circadian clocks of neighboring cells. Because curcumin alters SIRT1 and PPAR-γ levels, which in turn modify circadian clock proteins,^37,87-90 oral curcumin delivery may affect circadian timing, particular by acting on clocks of the gastrointestinal tract. Nevertheless, additional studies are needed to determine when during daily cycles curcumin and other phytochemicals are beneficial or detrimental.

Another relevant question of concern is how to identify an optimal phase that minimizes possible off-target curcumin effects on neurogenesis in young and older cancer patients. Because curcumin induces differentiation of CSCs it may also affect immature cells such as neuroblasts more effectively than differentiated ones. In cancer patients there is the additional concern of compatibility of curcumin with chemotherapeutic agents. Interaction of curcumin with treatments in some cases augments the anticancer agent’s effects such as with 5-fluorouracil and esophageal squamous cell carcinoma ¹¹³ and colon cancer cells.^33,114 There are also reports of curcumin interfering with cancer treatments ¹¹⁵ and concerns that curcumin can cause oxidative damage at high concentrations. ¹¹⁶

As cancer progresses to late stages, the circadian timing system can be highly disturbed,^117,118 perhaps by altered sleep patterns, pain, cachexia, and possibly cytokine release initiated by tumors acting on the circadian timing mechanism. The SCN circadian clock, for example, is altered by cytokines, ¹¹⁹ but circadian clocks in cells near the tumor might be more profoundly influenced. Studies indicate that circadian timing disruption, such as from light exposure at night during late work schedules, significantly increases risk of breast, prostate, non-Hodgkin lymphoma, and other cancers.^120-123 Loss of circadian rhythms within cells is also considered a causal factor in carcinogenesis and aggressive tumor growth.^124-126 Therefore, the ability of curcumin to act on circadian clock proteins could provide a way to reestablish proper circadian timing before cancer initiation and in late stage cancer patients, possibly suppressing cancer cells while improving sleep cycles, mood, and quality of life. Curcumin may in this way prove beneficial during advanced cancer stages, along with its more direct anticancer properties.

Although little is known about circadian cycles within cancer cells of tumors, in vitro studies have characterized circadian rhythms in cell lines derived from cancers of brain, breast, colon, and lung.^127-133 Furthermore, circadian timing within acute myeloid leukemia cells promotes rather than impedes their proliferation. ¹³⁴ The presence of circadian rhythms in some cancer cells and tumors^135,136 raises the possibility that there are rhythmic targets within tumors that could be exploited by strategically timed delivery of curcumin. The ability of a noncancer cell to use its internal circadian clock to predict when nutrients will be available from a meal, or after daily awakening from sleep, appears to be synchronized with cell cycle growth and mitotic phases. In cancer cells that have their own circadian timing these potentially selective advantages could be extended to an ability to predict when cancer cell DNA replication occurs or daily immune surveillance is maximal. ⁸⁴ In fact, evidence from animal models does challenge the generally held view that disrupted circadian timing enhances cancer cell survival and proliferation, particularly during chemotherapy. ⁷⁵

Whether cancer cells of a specific tumor are intrinsically rhythmic or not, they are exposed to the usual daily rhythms of numerous hormones including melatonin at night and corticosteroids that reach a peak during the morning ¹³⁷ and persist in cancer patients.^138,139 Daily serum corticosteroid rhythms likely induce the core clock gene Per1. ¹⁴⁰ Dexamethasone is in fact often used to synchronize circadian clocks in tumor-derived and non-cancer cell cultures. ⁷⁷

Cortisol has immune suppressive effects ¹⁴¹ and, in the absence of unusual stressors, is minimal at night when adaptive immune functions show greatest activity. ¹⁴² Like cortisol, ¹⁴³ curcumin inhibits pathways dependent on NF-κB, indicating it too should be delivered when possible during the morning if the goal is to avoid immune system suppression. On the other hand, it may be desirable to use curcumin to suppress excessive inflammation at night. It is recommended that glucocorticoid treatments when used to treat rheumatoid arthritis by restoring temporal order in the circadian system are best applied near the normal time of morning elevated cortisol. ¹⁴¹ Because it has similar effects on the immune system, curcumin should therefore be applied in the morning to have the least disruptive effect on the circadian system. Like cortisol treatments, curcumin delivered at this phase might also be beneficial in maintaining proper phase relationships between the circadian clocks of the body.

Along with circadian clocks in normal tissue, circadian behavior of cancer cells should be considered in any optimal dosing strategy for curcumin. Evidence described above that EMT and metastasis are timed by the circadian system indicates that cancer patients with undisturbed circadian rhythms should take curcumin when these events are most likely to occur. Research is beginning to characterize when EMT is most likely in cancers of specific tissues, which have circadian rhythms that vary in phase with the SCN and with each other. Circadian rhythms in tissues and organs also vary between cancer patients and between healthy individuals. This additional complexity is being addressed by customizing cancer therapies to better match the circadian timing systems of individuals as a type of personalized medicine. ¹⁴⁴

Finally, some individuals who have survived cancer or are maintaining cancer remission, such as some leukemia patients, may consume curcumin near maximum tolerable limits. One caution that should be considered is the potential disruptive effects on the circadian system. Limiting the highest dosing to only part of the day may be more beneficial, although additional research is needed to identify when particular cancer cell types are most easily suppressed.

Conclusions

Considering the multiple cellular actions of curcumin, it is not surprising that optimal dosing strategies relative to the circadian system are also complex. Along with the many potential benefits of curcumin, potential harm should be addressed, particularly at high dosages, as shown by effects on normal stem cells, neurogenesis, and immune functions. Timing of curcumin delivery for cancer prevention or in combination with cancer therapies to target CSCs is likely to be most favorable when it is taken in the morning to minimize suppression of immune functions and possible disruption of the circadian timing system. Curcumin delivery in the morning might prolong the cancer cell EMT inhibition provided by melatonin at night, thereby enabling more sustained control throughout the day. Alternatively, when higher dosages are needed for immune suppression, anti-inflammation or aggressive cancer treatment, including enhanced CSC inhibition, multiple curcumin doses throughput the day can be warranted because of rapid curcumin clearance from the blood. Clearly, additional translational and clinical studies are needed to understand interactions between circadian clocks and curcuminoids.