Today, more than ever before, millions of people are seeking an approach to medicine and health care that is more comprehensive, more holistic and integrative, and more compassionate and sensitive to their needs as a whole person. This is particularly true for those dealing with cancer. Changing patient demographics, heightened consumer demand for complementary and alternative medicine (CAM) products and services, advances in medical science and technology, expanding access to the Internet and health information, and other factors have contributed to a wave of transformation that is unprecedented in its impact on the entire health care system. These trends have fueled the emerging fields of integrative medicine and oncology, which are growing rapidly. As these fields continue to evolve, they will move beyond the present integrative model to a broader vision of whole-person, multidimensional care that will more fully and coherently address and embrace all dimensions of the human experience. This article describes 6 major driving forces behind the wave of transformation presently under way in medicine and health care. It provides a brief, historical overview of integrative medicine and oncology and summarizes the present status of these emerging fields. It discusses the future of integrative medicine and oncology, including a multidimensional approach to care, and highlights 5 key elements that underlie this approach. Finally, it describes The Seven Levels of Healing— a model of multidimensional care—and concludes with a discussion of 3 important challenges and opportunities for medicine and health care that lie on the horizon.

There is no established protocol proven to be beneficial for treatment of hepatocellular carcinoma recurrence after liver transplantation. Only a few reports have shown direct treatment by surgery or ablation to be independent predictors of survival for localized recurrence. Moreover, the necessity of immunosuppression to prevent allograft rejection makes many physicians hesitate to administer systemic chemotherapy. This case report documents a case in which the administration of an herbal product, an extract of the lacquer tree, Rhus verniciflua Stokes, was associated with a decrease in the size of lung metastases in a patient with recurrent hepatocellular carcinoma after liver transplantation refractory to doxorubicin. This patient experienced prolonged survival compared with average survival times and little toxicity.

The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for chemoprevention against colon polyp formation. A total of 60 C57bl/6 mice were divided into 3 groups based on diet. One group received a low-fat, rodent chow diet (AIN76A). The second group received a high-fat "Western-style" diet (HFWD). The third group was fed the same HFWD with the mineral-rich extract included as a dietary supplement. Mice were maintained on the respective diets for 15 months. Autopsies were performed at the time of death or at the completion of the study. To summarize, the cumulative mortality rate was higher in mice on the HFWD during the 15-month period (55%) than in mice from the low-fat diet or the extract-supplemented high-fat diet groups (20% and 30%, respectively; P < .05 with respect to both). Autopsies revealed colon polyps in 20% of the animals on the HFWD and none in animals of the other 2 groups (P < .05). In addition to the grossly visible polyps, areas of hyperplasia in the colonic mucosa and inflammatory foci throughout the gastrointestinal tract were observed histologically in animals on the high-fat diet. Both were significantly reduced in animals on the low-fat diet and animals on the extract-supplemented HFWD.These data suggest that the mineral-rich algae extract may provide a novel approach to chemoprevention in the colon.

There is an increasing body of data showing that activated cancer therapy—the synergistic effect of "preloaded" molecules and a tuned energy source to produce cytopathogenic moieties—is a promising new modality for cancer treatment.The key activated therapies are photodynamic therapy (PDT), which involves the synergy between light and photosensitizer molecules, and ultrasound activated therapy (USAT; also referred to as sonodynamic therapy), which involves the synergy between ultrasound and sonosensitizer molecules. PDT is a well-known activated therapy with roots dating back to 1900. However, minimal data exist on USAT. One reason is the lack of suitable sonosensitizers for clinical USAT use. The authors present both LC₅₀ toxicity and cancer cell cytotoxicity studies on 2 dual activation agents. These compounds function as both sonosensitizers and photosensitizers, and are referred to as SonneLux agents, designated SF1 and SF2. The sensitizers are derived from chlorophyll and are metal centered porphyrins known to specifically accumulate in hyperproliferating tissue. LC₅₀ studies on both SF1 and SF2 as determined in zebra fish reveal that both are essentially nontoxic to zebra fish. In the worst case, 5% zebra fish death is noted at the maximum soluble concentration of the sensitizer. In the cytotoxicity studies, melanoma cell line WM-266-4, derived from a metastatic site of a malignant melanoma, was tested against SF1 and SF2. Both sensitizer systems showed marked efficacy in the destruction of the implanted melanoma cells. They show great promise for clinical use in the future.

The chloroform extract of Physalis minima produced a significant growth inhibition against human T-47D breast carcinoma cells as compared with other extracts with an EC₅₀ value of 3.8 µg/mL. An analysis of cell death mechanisms indicated that the extract elicited an apoptotic cell death. mRNA expression analysis revealed the coregulation of apoptotic genes, that is, c-myc , p53, and caspase-3. The c-myc was significantly induced by the chloroform extract at the earlier phase of treatment, followed by p53 and caspase-3. Biochemical assay and ultrastructural observation displayed typical apoptotic features in the treated cells, including DNA fragmentation, blebbing and convolution of cell membrane, clumping and margination of chromatin, and production of membrane-bound apoptotic bodies. The presence of different stages of apoptotic cell death and phosphatidylserine externalization were further reconfirmed by annexin V and propidium iodide staining. Thus, the results from this study strongly suggest that the chloroform extract of P minima induced apoptotic cell death via p53-, caspase-3 -, and c-myc-dependent pathways.

Tocotrienols of palm oil have been shown to possess potent neuroprotective, antioxidative, anticancer, and cholesterol-lowering activities. In this study, the authors examined the antiproliferative effects of -, - and -tocotrienols (T3, T3, and T3), and -tocopherol (T) in human cervical carcinoma (HeLa) cells. Their mechanism(s) of action on cell cycle signaling pathway were also investigated. Results showed that the antiproliferative effect of T3 (IC₅₀: 3.19 ± 0.05 µM) and T3 (IC ₅₀: 2.85 ± 0.07 µM) was more potent than T3 (IC ₅₀: >100 µM) and T (IC₅₀: 69.46 ± 3.01 µM). Both T3 and T3 also demonstrated a dose-dependent and time-dependent induction of cell death.They caused cell cycle arrest at G2/M phase and triggered apoptosis as displayed by the externalization of annexin V—targeted phosphatidylserine and accumulation of sub-G1 peak. At a concentration of 3 µM, T3 downregulated the expression of cyclin D3, p16, and CDK6, while having no effect on cyclin D1, p15, p21, p27, and CDK4 expression. However, T3 showed no effect on these proteins. The induction of HeLa cell apoptosis by T3 and T3 appeared to be associated with the expression of IL-6, but not the other cytokines (IFN-, IL-2, and IL-10).Taken together, the results suggest that T3 and T3 are more effective than T3 and T in inhibiting HeLa cell proliferation, and their mode of action could be through the upregulation of IL-6, and the downregulation of cyclin D3, p16, and CDK6 expression in the cell cycle signaling pathway.

The aim of this study was to determine the effects of ¹²⁵I seeds on prostate carcinoma (PC3) cells. The relative biological effectiveness of ¹²⁵I seeds on PC3 cells with respect to ⁶⁰Co rays was 1.4. Both 4 Gy of ⁶⁰Co ray and ¹²⁵I seed irradiation increased the percentage of cells in G₂ phase, but there was no significant difference between these 2 types of radiation. Significantly, ¹²⁵I seeds induced higher apoptotic rates of PC3 cells compared with ⁶⁰Co ray irradiation. Furthermore, Bcl-2 expression, but not caspase-3 activity, in PC3 cells was downregulated after irradiation with ¹²⁵I seed or ⁶⁰Co rays.

Background. Qingyihuaji formula (QYHJ) is a widely used herbal formula that has shown promising antitumor effect in the treatment of pancreatic cancer in the Cancer Hospital, Fudan University, Shanghai, China. Objective. This research was conducted to study whether Ski acts as a therapeutic target of QYHJ formula in the treatment of SW1990 pancreatic cancer. Methods. The expression changes of Ski mRNA and protein in SW1990 pancreatic cancer subcutaneously transplanted tumor treated with QYHJ were detected by real-time polymerase chain reaction and Western blot. Then, we established a stable transfection SW1990 cell with low expression of Ski through lentivirus-mediated RNA interference (RNAi) technique. The responses to QYHJ treatment on a subcutaneously transplanted tumor with different Ski expression statuses were evaluated. Finally, the effect of Ski downregulation on SW1990 cell biological behavior was also evaluated. Results. Expression of Ski mRNA and protein in SW1990 subcutaneously transplanted tumor decreased dramatically after the treatment with QYHJ. Stable transfection cells with low expression of Ski (SW1990/Ski RNAi) were created, and negative vector-transfected cells (SW1990/con RNAi) were used as controls. The tumor weight inhibitory rates of QYHJ on subcutaneously transplanted tumors formed by SW1990 or SW1990/con RNAi were 29.6% and 32.2%, respectively, whereas they were 16.0% to 17.8% when the tumors were formed by SW1990/Ski RNAi. Ski downregulation sensitized the response of SW1990 cells to TGF-β1-induced growth inhibition in vitro. Flow cytometric analyses revealed that the percentage of cells in the G1 phase increased from 40.4% to 62.9% when Ski was downregulated. The subcutaneously transplanted tumors formed by SW1990/Ski RNAi grew much more slowly than those formed by parental and control vector—transfected cells. Conclusion. Ski acts as therapeutic target of QYHJ in the treatment of SW1990 pancreatic cancer cells, and its expression status mediates different responses to QYHJ treatment.

An essential oil extract, derived from the rhizome of Curcuma wenyujin (CWE), possesses antioxidative, antimicrobial, and anti-inflammatory properties. However, it remains unknown how exactly CWE inhibits tumor growth. In this study, using human cervical cancer HeLa cells, the authors postulated that CWE has the ability to inhibit tumor growth. The study shows that CWE dose-dependently suppressed colony formation and inhibited the proliferation of HeLa cells through blockade of cell cycle progression at G1 phase and apoptosis. CWE-induced G1 arrest was associated with retinoblastoma protein dephosphorylation and reduced amounts of cyclins D1 and D3, and cyclin-dependent kinase 4 and 6 proteins. CWE treatment resulted in apoptosis in HeLa cells as evidenced by morphological changes, caspase activation and PARP cleavage, which can be reversed by a pan-caspase inhibitor. It was observed that CWE treatment activated the mitochondrial apoptotic pathway indicated by a decrease in Mcl-1 and Bcl-xL levels, resulting in mitochondrial membrane potential loss and caspases 9 activation. CWE-treated cells displayed reduced PTEN, AKT, and STAT3 phosphorylation and downregulation of NFB signaling, providing a mechanism for the G1 arrest and apoptosis observed. Furthermore, CWE inhibited tumor growth of HeLa in a xenograft mouse tumor model, suggesting that CWE inhibited tumorigenesis by inhibiting cell proliferation and inducing apoptosis. These findings are the first to reveal the molecular basis for the anticervical cancer action of CWE. The results suggest that CWE could be developed as a drug for the management of cervical cancer.

Background: After cardiovascular disease, cancer is the most common cause of death. HESA-A is a natural product of herbal and marine origin. The aim of this study was to investigate the beneficial effects of HESA-A in patients with end-stage metastatic cancers. Methods: In this clinical trial, 30 consecutive patients (18 men, 12 women) with end-stage cancers and liver metastasis at the Cancer Research Center of Tehran University of Medical Sciences were studied. Patients received HESA-A 50 mg/kg/d orally in 2 to 3 divided doses for 3 months. At the start and end of the 1st, 4th, 8th, and 12th weeks of the study, the patients were assessed and hematological and hepatic biochemical indices were measured. Also, the Karnofsky Performance Scale questionnaire was completed for each patient. Results: The mean age of patients was 56.23 ± 12.10 years. Mean Karnofsky Performance Scale scores of the patients increased from 48 ± 14.36 to 78.42 ± 15.37 after 12 weeks of treatment. A total of 90.4% of the patients who remained in the study were alive for 12 weeks. No significant hepatic or hematologic adverse effect was seen during the study. Conclusion: HESA-A appears to be an effective and safe anticancer compound that may increase survival of end-stage patients and can be used in selected cases. Further prospective controlled clinical trials with large sample size and longer follow-up period are warranted to understand the mechanisms of action of HESA-A and evaluate its long-term effects on the survival and quality of life of patients with cancer and as well as its unfavorable side effects.

Hypothesis: Anorexia and cancer cachexia produce significant loss of adipose tissue and muscle mass and eventually reduce survival in cancer patients. Study design: This phase II study was conducted to assess the efficacy and the safety of an herbal decoction with Astragali Radix in patients with anorexia in advanced cancer. Methods: All patients with histologic evidence of an incurable malignancy had a weight loss of at least 5% during the preceding 6 months and a patient-estimated severe anorexia.The herbal decoction was administered 30 minutes after meals, three times a day for 3 weeks.The score of appetite, body weight, the cytokines, IL-1β, IL-6, TNF-, and anthropometric measurements were assessed. For the assessment of anorexia, a visual analog scale (VAS: 0 mm = no anorexia, 100 mm = maximal anorexia) was used. Results: Eleven patients were recruited from January, 2007 to January, 2009. The mean age was 59.8 years old. The change in anorexia from baseline with the herbal decoction was significantly different and anorexia was improved (anorexia VAS score, 60mm vs. 40mm, p = 0.008). The mean value of the maximal body weight was 55.6 kg and differed significantly from the 54.6 kg at baseline (p = 0.009). Changes in cytokine levels and anthropometric measurements from baseline to the 3rd week were not significant. All toxicities were manageable. Conclusion: Appetite and body weight were improved with the herbal decoction. This herbal decoction shows some potential for management of cancer-related anorexia.

Background. Taiwan’s National Health Insurance (NHI) is a comprehensive and universal program, providing Western medicine (WM) and Chinese medicine (CM). This study aims to explore CM use among prostate cancer patients in NHI. Methods. A cross-section retrospective analysis was conducted using registration and claim data sets from the NHI Research Database. In 2007, 22 352 prostate cancer patients with 265 497 visits of CM and WM ambulatory services were identified. Patient demographics, patterns of therapies, and costs were analyzed. Results. In 2007, 592 prostate cancer patients (2.6%) had 4141 CM outpatient visits (7.0 on average). The median age was 73.9. The majority (90.5%) of CM users also used WM ambulatory services. About one third of CM outpatient services were provided by private clinics. The most frequently used CM therapies were Chinese herbal medication (93.6%), followed by acupuncture/traumatology manipulative therapies (7.0%). CM accounted for 0.2% expenditure ($87 500) and 1.6% visits of ambulatory services. The average cost per visit for WM was 6.3 times higher than that for CM ($133.6 vs $21). Conclusions. The prevalence and costs of insurance-covered CM among prostate cancer patients were low. Most prostate cancer patients did not use insurance-covered CM. The majority of CM users also used WM. CM appeared to play a complementary rather than an alternative role.

Numerous botanical agents, many of which are used in whole medical system practices (i.e. traditional Chinese medicine, Ayurvedic medicine, etc.), have been shown to exhibit radiomodifying effects on tumors and normal tissues in-vitro and invivo studies. Some of these agents can enhance the therapeutic gain of radiation therapy by either acting as a radiosensitizer to tumor cells and/or as a radioprotector to normal cells. Botanical agents are comprised of multiple phytochemical compounds that may work individually or synergistically to not only improve radiation therapy outcomes, but may also exhibit a variety of anti-cancer effects as well. It will be important to evaluate these botanicals for efficacy, tumor specificity, and safety profiles before they can be recommended during radiation therapy.

Therapeutic gain by radiotherapy can be achieved through improved targeting, selectively sensitizing malignant cells, or protecting normal tissue. The majority of synthetic chemical radiation sensitizers and normal tissue protectors have proved to be too toxic at effective clinical doses. However, Asian botanicals (from both Chinese and Ayurvedic medicine) are being evaluated for their ability to improve therapeutic gain through the modulation of reactive oxygen species. An increase in the efficacy of radiotherapy on tumor tissue allows a reduction in the dose applied to normal tissues. In addition, some botanicals may selectively protect normal tissue or increase its repair following radiation therapy. The results are promising enough to consider clinical trials.

The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF_kB, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.

L-Glutamine (L-GLN) is considered a nonessential amino acid that has a variety of applications in naturopathic medicine. It has been postulated that in the critically ill patient, GLN becomes an essential amino acid for recovery, restoration, and repair at a cellular level. Mucositis is an intestinal mucosal damage of the gastrointestinal tract—mouth, throat, stomach, intestines, rectum, and anus—that is caused directly by chemotherapies and radiotherapies. Cancer cachexia is a significant biochemical event, which is characterized by weight loss, fatigue, and indicative of depletion of skeletal muscle GLN—a hypercatabolic state. There has been some question as to the use of GLN in this patient population because of its role as a preferred energy source not only for enterocytes and lymphocytes but for malignant cells as well.This article will address the questions of safety, efficacy, dosing, and toxicity of GLN used as an integrative therapeutic in ongoing integrative cancer treatment.

This article reviews updates and provides some data related to nutritional and orthomolecular supplementation in oncology patients with an emphasis on lung cancer, a commonly diagnosed tumor with significant nutritional disturbances. Cancer and its treatment play a significant role in nutritional imbalance which likely has negative impact on the patient both in terms of quality and quantity of life. Nutritional supplementation may correct these imbalances with significant clinical benefit both physiologically and psychologically. This review will help assist in providing clinically useful data to assess the cancer patient’s nutritional status and to guide nutritional intervention to assist these patients’ recovery.

Life has evolved on this planet with regular daily spans of direct solar energy availability alternating with nocturnal spans of dark. Virtually every earth-borne life form has factored this circadian pattern into its biology to ensure the temporal coordination with its resonating environment, a task essential for its individual survival and that of its species. The first whole genome inspections of mutations in human colon and breast cancer have observed specific retained clock gene mutations. Single nucleotide polymorphisms within the genes of clock, clock-controlled, and melatonin pathways have been found to confer excess cancer risk or protection from cancer. Experimental studies have shown that specific core clock genes (Per2 and Per1) are tumor suppressors because their genetic absence doubles tumor numbers, and decreasing their expression in cancer cells doubles cancer growth rate, whereas their overexpression decreases cancer growth rate and diminishes tumor numbers. Experimental interference with circadian clock function increases cancer growth rate, and clinical circadian disruption is associated with higher cancer incidence, faster cancer progression, and shorter cancer patient survival. Patients with advanced lung cancer suffering greater circadian activity/sleep cycle disruption suffer greater interference with function, greater anxiety and depression, poorer nighttime sleep, greater daytime fatigue, and poorer quality of life than comparable patients who maintain good circadian integration. We must now determine whether strategies known to help synchronize the circadian clocks of normal individuals can do so in advanced cancer patients and whether doing so allows cancer patients to feel better and/or live longer. Several academic laboratories and at least 2 large pharmaceutical firms are screening for small molecules targeting the circadian clock to stabilize its phase and enhance its amplitude and thereby consolidate and coordinate circadian organization, which in turn is likely to help prevent and control human cancer. These drugs and strategies can, in turn, be used to make cancer patients with advanced disease feel and function more normally.

Practical circadian therapy for the cancer patient involves 3 spheres of intervention—improving lifestyle, optimizing internal biochemical milieu, and adjusting treatment times. The potential value of improving overall circadian functioning is shown in the work of Mormont et al in which pronounced rest—activity rhythms were associated with better survival in colorectal cancer patients receiving chronomodulated chemotherapy. Lifestyle interventions that may improve circadian functioning involve diet, physical activity, and mind—body therapies. A diet that is anti-inflammatory and has appropriate carbohydrate intake, as well as regular meal timing, encourages normal circadian cycles. Adequate daytime physical activity encourages restful sleep, and morning light exposure during exercise may entrain melatonin rhythms. Meditation and other mind—body therapies can reduce anxiety and depression that may disrupt sleep. Aspects of the biochemical milieu that specifically disrupt circadian functioning are inflammation and stress hormones. Inflammation and cytokine disruption can be addressed with diet, herbs, and other natural substances. Chronomodulation of chemotherapy in a US clinical setting will be discussed. A series of 12 cases will be presented of patients who experienced grade 3 to 4 toxicities with various chemotherapy regimens for colorectal cancer. When rechallenged with the same regimens administered chronotherapeutically, none of the patients experienced grade 3 to 4 toxicity. Integrating all the above treatment modalities has the potential to improve both the quality of life and disease outcomes in cancer patients.

A disruption of the circadian timing system, as identified by monitoring of marker biorhythms, is common in cancer patients. The recording of the rest—activity rhythm with a wrist actigraph has been commonly used. This noninvasive monitoring allows a robust estimation of circadian disruption. The authors have previously found that altered patterns of circadian rest—activity rhythms are significantly and independently associated with the severity of fatigue and anorexia in patients with metastatic colorectal cancer. Elevated proinflammatory cytokines could partly account for this circadian disruption and its associated constitutional symptoms. Here, the authors present and discuss the data supporting the hypothesis that circadian disruption is often associated with fatigue and anorexia, which in turn further alter and dampen circadian synchronization, thus, creating a vicious cycle. This body of evidence paves the path for innovative therapeutic approaches targeting the circadian timing system in an effort to diminish constitutional symptoms induced by cancer and some anticancer treatments.

In industrialized countries, certain types of cancer, most notably, breast and prostate, are more frequent than in poorly developed nations. This high cancer frequency is not explained by any of the conventional causes. Within the past decade, numerous reports have appeared that link light at night with an elevated cancer risk. The three major consequences of light at night are sleep deprivation, chronodisruption, and melatonin suppression. Each of these individually or in combination may contribute to the reported rise in certain types of cancer. In this article, the potential mechanisms underlying the basis of the elevated cancer risk are briefly discussed. Finally, if cancer is a consequence of excessive nighttime light, it is likely that other diseases/conditions may also be exaggerated by the widespread use of light after darkness onset.

The circadian production of melatonin by the pineal gland during the night provides an inhibitory signal to tissue-isolated steroid receptor SR+ and — MCF-7 human breast cancer xenografts in female nude rats. A pivotal mechanism for melatonin’s anticancer effects in vivo involves a melatonin receptor-mediated inhibition of linoleic acid (LA) uptake and its metabolism to mitogenically active 13-hydroxyoctadecadienoic acid (13-HODE). Exposure of (SR-) xenograft-bearing rats to increasing intensities of polychromatic white light at night suppresses melatonin while increasing tumor growth rates, DNA content, [3H]thymidine incorporation into DNA, LA uptake, 13-HODE formation, cAMP levels and ERK1/2 activation a dose-dependent manner. Similar effects occur in SR- human breast cancer xenografts perfused in situ with melatonin-depleted blood from healthy female subjects after their exposure to a single bright intensity (2800 lux) of polychromatic light at night. Additionally, SR- human breast cancer xenografts exhibit robust circadian rhythms of LA uptake, 13-HODE formation and proliferative activity. Exposure of xenograft-bearing rats to dim light at night results in the complete elimination of these rhythms which culminates in unfettered, high rates of tumor metabolism and growth. The organization of tumor metabolism and growth within circadian time structure by the oncostatic melatonin signal helps create a balance between the cancer and its host that is disrupted by host exposure to light at night. This biological mechanism may partially explain the higher risk of breast and other cancers in women working rotating night shifts and possibly others who also experience prolonged exposure to light at night.

The authors have shown that, via activation of its MT1 receptor, melatonin modulates the transcriptional activity of various nuclear receptors and the proliferation of both ER+ and ER- human breast cancer cells. Employing dominant-negative (DN) and dominant-positive (DP) G proteins, it was demonstrated that G _i2 proteins mediate the suppression of estrogen-induced ER transcriptional activity by melatonin, whereas the G_q proteins mediate the enhancement of retinoid-induced RAR transcriptional activity by melatonin. In primary human breast tumors, the authors’ studies demonstrate an inverse correlation between ER and MT1 receptor expression, and confocal microscopic studies demonstrate that the MT1I receptor is localized to the caveoli and that its expression can be repressed by estrogen and melatonin. Melatonin, via activation of its MT1 receptor, suppresses the development and growth of breast cancer by regulation of growth factors, regulation of gene expression, regulation of clock genes, inhibition of tumor cell invasion and metastasis, and even regulation of mammary gland development. The authors have previously reported that the clock gene, Period 2 (Per2), is not expressed in human breast cancer cells but that its reexpression in breast cancer cells results in increased expression of p53 and induction of apoptosis. The authors demonstrate that melatonin, via repression of ROR transcriptional activity, blocks the expression of the clock gene BMAL1 . Melatonin’s blockade of BMAL1 expression is associated with the decreased expression of SIRT1, a member of the Silencing Information Regulator family and a histone and protein deacetylase that inhibits the expression of DNA repair enzymes (p53, BRCA1 & 2, and Ku70) and the expression of apoptosis-associated genes. Finally, the authors developed an MMTV-MT1-flag mammary knock-in transgenic mouse that displays reduced ductal branching, ductal epithelium proliferation, and reduced terminal end bud formation during puberty and pregnancy. Lactating female MT1 transgenic mice show a dramatic reduction in the expression of β-casein and whey acidic milk proteins. Further analyses showed significantly reduced ER expression in mammary glands of MT1 transgenic mice. These results demonstrate that the MT1 receptor is a major transducer of melatonin’s actions in the breast, suppressing mammary gland development and mediating the anticancer actions of melatonin through multiple pathways.

Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentrations (IL-6, TNF-alpha, gamma-INF, IL-1ra, IL-1-beta, VEGF) were compared among patients with high and low scores for fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory II), or sleep disruption (Pittsburgh Sleep Quality Index), or among patients with different Per3 clock gene variants. Poor sleep was associated with elevated VEGF, and fatigue-related reduced activity was associated with elevated TNF-alpha concentrations. Participants with the 4/5 or 5/5 Per3 variable tandem repeat sequence had elevated IL-6 concentrations compared to those with the 4/4 genotype. Biological processes linking circadian disruption with cancer remain to be elucidated. Increased inflammatory cytokine secretion may play a role.

Nuclear receptor subfamily 1, group D member 1 (Nr1d1), also known as Rev-erb-, belongs to the family of "orphan receptors" and functions as a member of clock gene family. In addition to being an important member of clock circuitry, Nr1d1, also regulates cell proliferation, lipid metabolism, and inflammation and is also touted as a tumor suppressor. Our focus on Nr1d1 was stimulated by data from a genome-wide search for mRNA correlates of cigarette smoke (CS) sensitive—whole smoke (WS) and filtered smoke (FS)—lung transcriptomes in tumor-resistant C57BL6 and tumor-susceptible AJ mice strains. Differential analysis of ~15 000 genes using Affymetrix 430A 2.0 high-density oligonucleotide arrays identified modulation of genes related to circadian pathways by CS in lungs of both mouse strains. Nr1d1 expression was downregulated by both WS and FS irrespective of mouse strain as compared to respective air-breathing controls. WS was more effective than FS on decreasing Nr1d1 expression. The present data suggest that transcriptional regulation of Nr1d1 by CS may affect circadian rhythmicity and thus may play a complementary role in CS-induced lung respiratory tract pathobiology and/or lung tumorigenesis.

Circadian rhythms are endogenous biological clocks that govern fundamental physiological and behavioral functions. Consequently, perturbations of these rhythms have been associated with pathogenic conditions, such as depression, diabetes, and cancer. CCAAT/enhancer-binding proteins (C/EBPs) are a family of transcription factors that regulate cell growth and differentiation in various tissues and have also been implicated in many cancer types. Using expression profiling studies, we found that the levels of 2 core components of the circadian network, Per2 and Rev-Erb, are significantly altered by C/EBPs. Further studies showed that levels of Per2 were reduced in lymphoma and acute myeloid leukemia patient samples, as well as in lymphoma cell lines. Overexpression of Per2 in hematopoietic cancer cell lines resulted in growth inhibition, cell cycle arrest, apoptosis and loss of clonogenic ability. These results support the emerging role of circadian genes in tumor suppression.

The mammalian core clock genes, Periods (Per1 and Per2), have tumor suppressor properties. Decreased expression of Per1 and Per2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or Per2 inhibits cancer cell growth in culture. The authors have shown that downregulation of Per1 or Per2 enhances cancer growth in vitro. These genes also regulate the amount of cell proliferation—related molecules, many of which are therapeutic targets. In animals, tumors grow with clear circadian organization, and Per1 and Per2 exert their tumor suppressor functions in a circadian time-dependent manner. Downregulation of Per1 or Per2 increases tumor growth only at certain specific times of the day. Per1 and Per2 differentially regulate tumor growth rhythm in vivo. These data suggest that the therapeutic efficacy of antiproliferation agents depends on the time of day of drug delivery. The optimal times of day may be shifted in tumors that have mutant Period genes.

Period genes ( Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate β-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal β-catenin levels and colon polyp formation. Per2 mutation also increases Apc^Min/+-mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased β-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc^Min/+ mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered β-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.