Hochu-ekki-to consists of: the herbs Astragali radix, Atractylodis lanceae rhizoma, Ginseng radix, Angelicae radix, Bupleuri radix, Zizyphi fructus, Aurantii nobilis pericarpium, Glycyrrhizae radix, Cimicifugae rhizome, and Zingiberis rhizome.

Hochu-ekki-to has been found to reduce in vivo tumor activity in rodent cancer models and treated syngeneic animals have also demonstrated repression in tumor growth. The splenic natural killer cells of rats treated with Hochu-ekki-to revealed a heightened cytotoxicity against tumors, along with the discovery of a potent inhibitory mechanism on tumor growth via the enhancement of natural killer cell activity (Cho et al., 1991). Another study showed that Hochu-ekki-to inhibited the spread of hepatoma cell lines by stimulating apoptosis and halting G0/G1 (Kao et al., 2001). In addition to the inhibitory effect of Hochu-ekki-to on tumor growth, immunological outcomes have been reported. One study regarding the immunological effects of Hochu-ekki-to showed that it stimulated peripheral blood mononuclear cells (PBMNCs) to produce granulocyte-colony stimulating factor (G-CSF) and TNF-alpha (Kao et al., 2000). Also, the temporal dose stimulation of murine normal colonic epithelial cell lines caused a significant increase in the levels of granulocyte colony-stimulating (Matsumoto et al., 2010a).

Hochu-ekki-to has also demonstrated inhibitory effects on endometrial carcinogenesis due to a decrease in the expression of c-jun, TNF-alpha, and estrogen receptors alpha and beta (Onogi et al., 2006). The oral administration of this herbal compound has also been shown to increase IFN-gamma secretion from lymphocytes, which increases L-selectin positive B lymphocytes, which is associated with boosting IgA immune response against intestinal antigens (Matsumoto et al., 2010b). These studies suggest that Hochu-ekki-to possesses chemotherapeutic effects.

Dose-dependent use of Hochu-ekki-to suppresses DNA synthesis and induces apoptosis that inhibit the spread of human breast cancer cell lines. Additionally, Hochu-ekki-to stimulated the phosphorylation of c-Jun NH2-terminal kinase (JNK), and pretreatment of breast cancer cells with the JNK inhibitor SP600125 eradicated apoptosis (Volate et al., 2009). Furthermore, combined treatment of Hochu-ekki-to and 5-FU improved the apoptotic effectiveness of 5-FU in breast cancer cell lines (Volate et al., 2009). These data suggested that Hochu-ekki-to has chemotherapeutic effects (Volate et al., 2009).

Hochu-ekki-to was shown to ameliorate cachexia induced by colon-26 adenocarcinoma cells in mice. Although the controlled treatment study did not demonstrate reduced tumor growth, it showed significant mitigation in the reduction of carcass weight, food and water intake. Also, the weight of the gastrocnemius and fat tissue around the testes and a decrease in serum triglyceride level was noted (Yae et al., 2012). The mechanisms by which Hochu-ekki-to mediated these effects were proposed to involve a reduction in the serum IL-6 and expression level in macrophages (Yae et al., 2012).

Hochu-ekki-to has also been shown to have a preventive effect against chemically induced carcinoma of the biliary tract (Tsuneoka et al., 2009) and to reduce cancer-related fatigue (Jeong et al., 2010).

While findings thus far are encouraging, more rigorous trials are needed to confirm the efficacy of Hochu-ekki-to for use in cancer patients.

Juzen-taiho-to consists of the herbs: Astragali radix, Rehmanniae radix, Paeoniae radix, Angelicae radix, Poria radix, Glycyrrhizin radix, Ginseng radix, Cinnamomi cortex, Cnidii rhizoma, and Atractylodis lanceae rhizoma.

Juzen-taiho-to was found to augment significantly the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) but did not augment that of G-CSF by cultured human PBMNCs (Kubota et al., 1992). It was also used to treat animals with liver tumors, where it showed a significantly higher survival rate without any side effects compared to the untreated controls (Tatsuta et al., 1994; Ohnishi et al., 1998). It has been suggested that oral administration of Juzen-taiho-to inhibits liver metastasis of cancer through a mechanism that is mediated by activation of the host immune system, including activation of: macrophages, T-cells, B-cells, and natural killer cells (Ohnishi et al., 1998).

The cytokine IL-18 was the most notable up-regulated of the high number of cytokines that were assayed in the serum of patients with liver function disorders under long-term Juzen-taiho-to administration (Fujiki et al., 2008). It was also found that the oral administration of Juzen-taiho-to might stimulate the expression of IL-12 in the early stage, and IL-18 in the chronic phase, followed by natural killer-T cell stimulation. The mechanism of activation following immunological restoration could contribute to the anti-tumor effects (Fujiki et al., 2008).

The oral administration of Juzen-taiho-to in mice with B16 melanoma was found to inhibit tumor metastasis in the lungs. The suggested mechanism was the increase in the production of IL-12, which is responsible for the activation of both natural killer cells and natural killer-T cells in the lungs, resulting in inhibition of B16 melanoma cell metastasis in the lungs (Matsuda et al., 2011).

Despite the emerging literature, it is still not clear which of the compounds in Juzen-taiho-to handle the stimulation of individual cell types. Recently, Takaoka et al. (2014) reported a “biomarker-guided screening” method that identified intercellular adhesion molecule-1 by using a DNA array for macrophages via the purification of compounds responsible for stimulating macrophage activity of Juzen-taiho-to. The screening method resulted in the distillation of a glycolipid mixture containing beta-glucosylceramides, which stimulated intercellular adhesion molecule-1 expression in primary dendritic cells and primary CD14+ macrophages.

A preventive effect was demonstrated by using Juzen-taiho-to on endometrial carcinogenesis via the suppression of estrogen-induced c-fos/jun-expression that created an inhibitory effect on E2-related endometrial carcinogenesis in mice (Niwa et al., 2001). It was also demonstrated that four herbs of Juzen-taiho-to attenuated these effects significantly, and Shimotsu-to handled the inhibition of estrogen-related endometrial carcinogenesis (Lian et al., 2002).

Juzen-taiho-to was shown to reduce oxidative DNA damage, inflammatory cell infiltration and cytokine expression, and these, in turn, inhibited the development of liver tumors and the recurrence of hepatocellular carcinoma after surgery (Tsuchiya et al., 2008). Suppression of Kupffer cell function leading to a decrease in pro-inflammatory cytokines and oxidants in the liver was proposed to mediate the protective effect of Juzen-taiho-to against hepatocarcinogenesis.

Kampo formulas may be beneficial for cancer patients treated with chemotherapy or radiation therapy (Yamada, 1989). The combination of Mitomycin C and Juzen-taiho-to showed significantly greater anti-cancer activity and longer survival times than Mitomycin C alone (Komiyama et al., 1989; Yamada, 1989).

Juzen-taiho-to has been shown to reduce some of the side effects associated with anticancer drugs when combined with UFT and TS-1 treatments that contain a five-fluorouracil derivative. Combined treatment with Juzen-taiho-to mitigated weight loss (Sakamoto et al., 1991) and improved bone marrow suppression (Ogawa et al., 2012) in UFT colon cancer treatment in rats and TS-1 related cancer treatments, respectively.

Juzen-taiho-to creates radioprotective and anti-tumor effects by increasing the number and size of splenic CFU-S (Ohnishi et al., 1990). This anti-tumor effect has been markedly demonstrated when combined with surgical excision or with chemotherapeutic drugs. For example, a study that used combined Juzen-taiho-to therapy with IFN-alpha on experimental lung metastasis of murine renal cell carcinoma, resulted in a dose-dependent inhibition of lung metastasis after five consecutive treatment doses in mice (Muraishi et al., 2000).

Ninjin-yoei-to consists of the herbs Rehmanniae radix, Astragali radix, Angelicae radix, Ginseng radix, Polygalae radix, Glycyrrhizae radix, Paeoniae radix, Atractylodis rhizome, Poria cortex, Cinnamomi cortex, Aurantii nobilis pericarpium, and Schisandrae fructus.

There have been a few investigations that have demonstrated the potential benefits of Ninjin-yoei-to. Researchers discovered that the compound increased natural killer cell activity after 2 days and lasted for a 1-week period in healthy people (Kamei et al., 1998). A case study reported decreased tumor CEA and CA19-9 markers in an older female with lung cancer after a 7-weeks treatment. And her cough was eliminated along with an improvement in appetite (Kamei et al., 2000). Cultured human PBMNCs in the presence of Ninjin-yoei-to in vitro demonstrated marked augmentation of GM-CSF production but not G-CSF (Okamura et al., 1991).

Seisho-ekki-to consists of the herbs: Atractylodis lanceae rhizoma, Ginseng radix, Ophiopogonis tuber, Astragali radix, Aurantii nobilis pericarpium, Angelicae radix, Phellodendri cortex, Glycyrrhizae radix, and Schisandrae fructus.

Seisho-ekki-to has been shown to have above average anti-oxidation activity. The effects of the combination of Seisho-ekki-to and Scutellaria baicalensis were evaluated in cancer-induced cachectic mice upon receiving chemotherapy with 5-FU. The combined application resulted in a significant decrease in tumor masses and losses of carcass and/or gastrocnemius muscles (Wang et al., 2012) and increases in both the Th1/Th2 ratio, NK cytotoxicity, and decreases in the expression of NF-kappaB and muscle RING finger protein-1 (MuRF-1) in the gastrocnemius muscle.

Rikkunshi-to has been used to treat various gastrointestinal tract disorders and includes the herbs: Atractylodis lanceae rhizoma, Ginseng radix, Pinelliae tuber, Poria cocos, Zizyphi fructus, Aurantii nobilis pericardium, Radix Glycyrrhizae, Zingiberis rhizome, and Atractylidis lanceae rhizoma.

Tominaga et al. (2011) clarified the mechanism of Rikkunshi-to activity that underlies its clinical effect. It has been shown that it enhances gastric motility by causing an antagonistic effect on the 5-HT3 receptor. The hypothesis is that this may occur due to a singular transmission path that differs from that facilitated by the 5-HT3 receptor-antagonist (Tominaga et al., 2011). In a clinical study, Rikkunshi-to was demonstrated to significantly attenuate gastrointestinal symptoms after gastrectomy (Takiguchi et al., 2013). In use with animals and patients with cancer, it showed a reduction in anorexia, GI dysmotility, muscle wasting, anxiety and extended survival time (Fujitsuka et al., 2011). In a double-blind controlled trial in rats with cancer, it significantly ameliorated dysmotility-like dyspepsia and improved upper gastrointestinal symptoms (Hattori, 2010).

The combination of Rikkunshi-to with an anti-emetic drug has demonstrated some effectiveness against anorexia and vomiting induced by chemotherapy. It was recently indicated that it ameliorates cisplatin-induced anorexia by facilitating an increase in circulating ghrelin concentration (Yakabi et al., 2010). A recent RCT was conducted on advanced esophageal cancer patients who received combined chemotherapy with docetaxel/5-FU/CDDP and Rikkunshi-to. The combined treatment was effective in reducing the symptomatic occurrence of vomiting, nausea and anorexia. It also improved the quality of life, mood and activities of daily living (Seike et al., 2011). Another clinical study also showed that Rikkunshi-to reduced cisplatin-induced anorexia (Ohno et al., 2011).

In rats with tumors, a CRF receptor antagonist was shown to mitigate cancer anorexia–cachexia syndrome, and administration of the 5-HT2cR antagonist or Rikkunshi-to reduced hypothalamic CRF levels along with behaviors that are generally associated with anxiety that may lead to better quality of life (Fujitsuka et al., 2011). Another study found that the antrum and duodenum contraction rates in rats were improved after Rikkunshi-to treatment, owing to selective serotonin re-uptake inhibitor improvement via the enhancement of the circulating ghrelin and signaling (Terawaki et al., 2013).

These findings show that Rikkunshi-to may be useful for treating anorexia and may provide a new strategy for improvement of upper gastrointestinal dysfunction (Terawaki et al., 2014). Several studies have demonstrated that ghrelin or ghrelin receptor agonists were effective in the treatment of cancer cachexia (Fujitsuka et al., 2012). Rikkunshi-to has been shown to stimulate endogenous ghrelin secretion by blocking the 5-HT 2b/2c receptor pathway and enhancing ghrelin receptor activity (Fujitsuka et al., 2012). A study in rodents with tumors clarified that the active component hesperidin improved the effectiveness of ghrelin secretion while atractylodin improved receptor signaling and extended survival (Fujitsuka et al., 2011). Thus, Rikkunshi-to may provide a potential treatment method for anorexia, muscle wasting, and may prolong survival (Fujitsuka et al., 2012).

A large number of studies have suggested a relationship between stress, coping factors and cancer (Monjan and Collector, 1977; Sklar and Anisman, 1979; Laudenslager et al., 1983; Chilvers and Peto, 1986; Chrousos, 1995). A recent study showed that chronic stress might cause social aversion via the glucocorticoid receptor in dopaminoceptive neurons (Barik et al., 2013). There are two major pathways activated by stressors: the HPA axis and the sympathetic-adrenal-medullary (SAM) axis (Chrousos, 1995; Glaser and Kiecolt-Glaser, 2005). CRF and ACTH found in high concentrations during stress, have a critical role in decreasing the production of many cytokines and inflammation mediators. Both mental stress and depression are considered to be associated with NK cell activities and decreased T-cell that affect processes of immune surveillance of tumors (Reiche et al., 2004).

The links between psychological states and cancer progression have been studied. The response of the HPA axis to stressors impairs the immune response by provoking the release of pituitary and adrenal hormones such as ACTH, cortisol, catecholamines, growth hormone and prolactin. The levels of these hormones are influenced by negative events or emotions (Glaser and Kiecolt-Glaser, 2005). The HPA axis and the SAM axis act directly or indirectly on cell surface receptors by inducing dysregulation of the production of cytokines such as IL-6, IFN-γ, IL-1, and TNF-alpha. Many studies suggest that psychological stress affects various aspects of the immune response at cellular, molecular and genetic levels via the CNS, hormones, cytokines, several neurotransmitters and neuropeptides. The neuroendocrine and immune system share several mediators and receptors, and they regulate the immune system. CRF has a major role in regulating psychoneuroimmunology. CRF affects the HPA axis and stimulates elevation in stress hormone levels, which in turn leads to deregulated immune function (Glaser and Kiecolt-Glaser, 2005). In turn, CRF activities in HPA are stimulated by proinflammatory cytokines (Shintani et al., 1993; Chen et al., 2010).

Serotonin also plays a key role in the progress of cancer anorexia (Rossi-Fanelli and Laviano, 2003). Increased levels of the serotonin precursor, plasma and brain tryptophan may be related to the increased serotonergic activity seen in the cancer anorexia–cachexia syndrome. A recent study revealed the role of hypothalamic 5-HT-CRF receptor pathway, which regulates ghrelin secretion in cancer anorexia–cachexia (Fujitsuka et al., 2011; Suzuki et al., 2013). Both 5-HT(1a) and 5-HT(2c) receptors influence anxiety-like behavior (Holmes et al., 2003; Heisler et al., 2007). Currently, the effect of elevated ghrelin is unclear. Some studies report that it may induce anxiety while others state that it may produce an anxiolytic-like response in animals that enables coping with stress (Chuang and Zigman, 2010).

Proinflammatory cytokines may be related to the risk of depressive symptoms, shown in patients with cancer (Numakawa et al., 2014). The responses of cortisol to stress show crucial psychosomatic effects on the central nervous and immune systems as well as other tissues in the body. A cortisol treatment study also demonstrated a significant reduction in the production of IL-6 and generated an association with the impairment of memory recovery caused by emotional distress (Rohleder et al., 2009).

It has also been reported that central administration of IL-1 beta caused sickness and depressive-like behaviors with the increase of IL-6 in an animal model, whereas the administration of IL-6 resulted in depressive-like behavior (Sukoff Rizzo et al., 2012). These studies suggest that different cytokines are involved in both depression and sickness behaviors. Particularly elevated IL-6 may play a key role in the development of depression.

It has also been reported that a negative emotiogenic exposure can be related to specific immune reactions (Kalinichenko et al., 2014a). Furthermore, reduction of pro-inflammatory cytokine levels in active rats exposed to stress was less pronounced after intraperitoneal preinjection of melatonin. In passive animals, exogenous melatonin inverted the post-stress changes in the serum levels of the pro-inflammatory IL-2 cytokine and anti-inflammatory IL-4 and IL-10 cytokines (Kalinichenko et al., 2014b).

It was shown in a clinical study that emotional symptoms are related to the levels of several cytokines, such as IL-6, in several diseases, including rheumatoid arthritis and hemodialysis patients (Montinaro et al., 2010). Colorectal cancer patients had increased serum levels of IL-6, IL-1beta, TNF-alpha, and IL-8 but lower IL-10 concentrations. A correlation analysis of the Hospital Anxiety and Depression Scale score and cytokine levels revealed positive associations with the domain of anxiety/depression with IL-6, IL-1beta and TNF-alpha and a negative correlation with IL-10. These results suggested that circulating proinflammatory cytokines might be involved in the pathophysiology of anxiety and depression in cancer patients (Oliveira Miranda et al., 2014).

Yoga is a mind-body exercise that combines mind, body and breath, and users tend to be female with higher levels of education (Park et al., 2013). One study found that despite the interest in a yoga therapy program for cancer survivors, there were implementation barriers (Slocum-Gori et al., 2013).

Yoga therapy has demonstrated beneficial effects on improvement of components of health-related quality of life and symptom indices in survivors of breast cancer, survivors of non-small cell lung cancer and in patients undergoing radiotherapy (Mustian et al., 2013; Chandwani et al., 2014; Fouladbakhsh et al., 2014; Martin and Keats, 2014). Components of health-related quality of life were evaluated using the FACT-B survey and the breast cancer-specific well-being and Trial Outcome Index. Significant improvement was found in physical, social, emotional, and functional well-being but not social well-being (Levine and Balk, 2012). In a 12-weeks restorative yoga intervention, inflammation-related gene expression was reduced in breast cancer survivors (Bower et al., 2014). Other studies suggested the effectiveness of yoga for women with secondary arm lymphoedema from breast cancer treatment (Loudon et al., 2012, 2014). While there may be some apparent benefits in cancer patients that use yoga therapy, more research remains to be done, and the mechanisms by which yoga induces these effects need to be understood.

“Mindfulness” can be described as an engagement in a special form of meditation and a state of consciousness, depicted as a broadminded moment-to-moment awareness and a curious experiential openness and acceptance toward one’s own experiences (Bishop et al., 2004). The origin of mindfulness techniques, as used in psychosocial care, is derived from Siddhartha Gautama, the historical Buddha. Today the most commonly used mindfulness-based interventions are the mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (Baer, 2003). The evidence that MBSR supports patients with cancer has been explored. Many outcomes support the effect of MBSR in improvement of mood, stress, anxiety, fear of recurrence, adjustment, HRQoL, and locus of control (Lengacher et al., 2012, 2014). The mechanism that has been suggested to underlie these effects is that MBSR reduces cortisol levels and the levels of cytokines such as IL-6 (Carlson et al., 2007; Witek-Janusek et al., 2008; Lengacher et al., 2012). A study demonstrated that MBSR participants versus non-participants had re-established levels of immunoregulatory factors, such as PBMNC natural killer cell activity and cytokine regulation, and the study additionally demonstrated a reduction in cortisol levels, improved HRQoL, and increased coping effectiveness (Witek-Janusek et al., 2008).