Astragalus, an herb used in traditional Chinese medicine, possesses significant immune-stimulating properties. Preclinical studies found that astragalus can promote anti-tumor immune responses in tumor-bearing mice, likely by restoring T cell function, an important component of the immune system (Cho 2007a; Cho 2007b).
There is also some clinical evidence suggesting that astragalus may improve survival rates in patients with advanced-stage NSCLC. Specifically, researchers found that patients who received 60 mL intravenous astragalus daily for 3 months combined with conventional treatment had a 1-year survival rate of 46.8% compared to a survival rate of 30% in the conventional treatment only group (Zou 2003). An analysis of 12 studies involving 940 patients with advanced NSCLC investigated the effects of astragalus in combination with platinum-based chemotherapy; researchers found an average 33% increase in 1-year survival rates in the astragalus groups compared to patients receiving platinum-based chemotherapy alone (McCulloch 2006). In another study, 136 patients with NSCLC received either vinorelbine and cisplatin or both chemotherapy drugs in combination with astragalus. Researchers noted significant improvement in patients’ overall quality of life, physical function, fatigue, nausea and vomiting, pain, and loss of appetite (Guo 2012).
A study assessed B-vitamin (B2, B6, B9, and B12) and methionine levels in blood samples of 899 patients with lung cancer, then compared them to a healthy group. People with the highest blood levels of B6 had a 56% reduced risk of lung cancer, while those with the highest levels of methionine had a 48% reduced risk, compared to those with the lowest levels (Johansson 2010).
Vitamin B6 appears to regulate the response of lung cancer cells to cisplatin by depleting glutathione within the cell, as well as exacerbating intracellular stress. The mechanism may be related to levels of pyridoxal kinase (PDXK), an enzyme required to make B6 biologically active. Evaluation of patients with NSCLC found that those with low PDXK expression had markedly worse disease-free and overall survival (Galluzzi 2012).
An increasing body of evidence suggests that vitamin D may be chemoprotective against several types of cancer (Fleet 2012; NCI 2013b). Skin cells naturally produce vitamin D in the presence of ultraviolet radiation from sunlight. However, relying on sunshine alone is often insufficient to achieve optimal blood levels of vitamin D. It is also difficult to obtain adequate levels of vitamin D from diet alone (Nair 2012).
An epidemiological study found that patients with NSCLC who underwent surgery during the summer and had higher vitamin D intake (greater than 596 IU daily) had a significantly longer period of recurrence-free survival and overall survival than those who underwent surgery during the winter and had low vitamin D intake (less than 239 IU daily and no vitamin D supplements) (Zhou, Suk 2005). In addition, analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) found that higher blood levels of vitamin D in people with lung cancer was associated with a 47% reduced risk of death in former and never smokers as well as a 69% reduced risk in distant-former (quit ≥20 years) and never smokers (Cheng 2012).
Made from the leaves of Camellia sinensis, green tea contains a variety of antioxidant phytochemicals called polyphenols. Epigallocatechin gallate (EGCG), the principal active ingredient in green tea, appears to possess significant growth-inhibitory effects on lung cancer cells, particularly in conjunction with chemotherapy (Yamauchi 2009; Shim 2010; Wang, Bian 2011; Anderson 2008; Suganuma 2011). Several mechanisms are responsible for its anti-cancer properties in lung cancer, primarily its ability to suppress the EGFR signaling pathway, suppressing EGFR, AKT, and ERK1/2 activation, all of which are associated with lung cancer development (Ma 2014). It also appears to reduce VEGF (vascular endothelial growth factor) expression (Li 2013), increase expression of the tumor suppressor protein p53, and inhibit COX-2 expression (Lu 2012). Another laboratory study found that it inhibited tumor migration as well as increased the effectiveness of docetaxel (Deng 2011). In addition, topical application of green tea may help radiation burns heal faster (Fritz 2013). However, a 2009 study found that green tea blocked the anticancer effects of certain types of chemotherapy agents, boronic acid-based proteasome inhibitors, with bortezomib (Velcade) being the most prominent in this category. The research found no negative effects with non–boronic acid proteasome inhibitors they studied (Golden 2009).
Melatonin, a hormone produced by the pineal gland, is integral to the proper regulation of sleep. Several studies have found that melatonin may slow tumor progression thanks to its ability to protect cells from oxidation, induce cell death, and stimulate the immune system. It also protects red blood cell precursors during chemotherapy (Srinivasan 2008).
In a study of 12 lung cancer patients, researchers assessed urinary markers of melatonin and found that low levels were associated with faster cancer growth (Bartsch 1997). A study of 100 patients with lung cancer found significantly higher 5-year survival rates and tumor regression rates in those who received 20 mg of melatonin each evening while undergoing chemotherapy compared to those who received chemotherapy alone (Lissoni 2003). Other studies also found that daily oral doses of melatonin between 10 and 50 mg for 3-5 weeks with chemotherapy seemed to enhance the response to chemotherapy and even demonstrated some disease stabilization and tumor regression (Vijayalaxmi 2002).
Traditionally used in the treatment of certain liver diseases, silymarin is a mixture of flavonoids from the medicinal plant milk thistle. Several studies show that silymarin’s primary active ingredient, silibinin, possesses potent antioxidant properties that may prevent the formation of reactive oxygen species, subsequent DNA damage, and the growth of tumor cells (Kaur 2010; Dagne 2011; Li 2011). Studies have found that silibinin inhibits the growth of lung cancer cells in the laboratory and in mice, with one study reporting that it worked as well as the targeted biologic drug gefitinib (Mateen 2010; Chittezhath 2008; Cufi 2013). It also appears to enhance apoptosis, or programmed cell death, of SCLC cells and reverse resistance to the chemotherapy drugs etoposide and doxorubicin (Adriamycin), as well as EGFR inhibitors gefitinib and erlotinib (Sadava 2013; Rho 2010). Silibinin has been noted to suppress nuclear factor-kappa B (NF-κB), which is involved in numerous steps of carcinogenesis and which contributes to chemotherapy and radiotherapy resistance (Chen 2012). It also appears to reduce the activity of EGFR-related proteins and has an anti-angiogenesis effect, preventing or slowing the growth of vascular tissue (Rho 2010; Tyagi 2009).
Isoflavones are a class of plant polyphenols found in soy and other plants. A study of 444 women with lung cancer found that those whose diets were high in soy products and isoflavones (average 31.4 g of soy foods daily) before diagnosis had mortality rates during the 2-year follow-up that were 81% lower than those with the lowest intake (average 6.3 g soy foods daily) (Yang 2013).
In addition, studies in mice found that soy isoflavones given before and after radiation can make NSCLC cells more sensitive to radiotherapy and protect against radiation-related lung tissue injury and other side effects, while laboratory studies in human lung cancer cells show that soy increased radiation-related cell death (Hillman 2013; Hillman 2011; Singh-Gupta 2011). A study of 1674 patients with lung cancer found that those with the highest dietary intake soy bioactives, including phytosterols, isoflavones, lignans, and phytoestrogens, were 21-46% less likely to develop lung cancer than those consuming the least (Schabath 2005).
N-acetylcysteine (NAC) is often used to counteract acetaminophen poisoning. It is also used to treat certain respiratory conditions such as COPD given its ability to break up mucus (Millea 2009). Numerous laboratory and animal studies also support its ability to prevent cancer, including lung cancer in smokers, through a variety of mechanisms, including antioxidant activity, changes in gene expression, effects on chemical pathways related to cell survival and apoptosis, anti-inflammatory activity, and anti-angiogenetic activity (De Flora 2001). In addition, a clinical study revealed that NAC, at a dose of 600 mg twice daily for 6 months, inhibited the formation of certain toxic compounds that are known to be responsible for cigarette smoke-mediated lung damage (Van Schooten 2002). There is also research in an animal model where the combination of NAC with doxorubicin had a synergistic effect on reducing cancer metastases (De Flora 1996).
Pomegranate extract, containing high levels of antioxidants, has been shown to possess anti-lung cancer properties in experimental models of lung cancer in mice. A study in mice found that combining pomegranate fruit extract (in water) with chemotherapy reduced tumor growth 61.6-65.9% more than chemotherapy alone. The authors speculated that pomegranate’s anti-inflammatory effects are due to its actions on several biochemical pathways related to cellular proliferation (Khan, Afaq 2007; Khan, Hadi 2007). Specifically, daily consumption of pomegranate extract was associated with a 66% reduction in the incidence of lung tumor formation in mice exposed to carcinogenic compounds (Khan, Afaq 2007).
Quercetin, a flavonoid found in certain fruits, vegetables and grains, possesses significant antioxidant and anti-inflammatory properties that have been proposed to prevent the biological effects caused by many cancer-causing chemicals (Kamaraj 2007; Zheng 2012; Yang 2006; Jeong 2009; Saponara 2002).
In addition, epidemiological studies found that consumption of quercetin-rich foods was associated with a significant reduction in smoking-related cancer risk. A review of 35 studies found that smokers with the highest daily intake of quercetin-containing foods had an approximately 34% lower risk of developing lung cancer than those with the lowest intake (Woo 2013). Potential mechanisms include its ability to scavenge free radicals, modify signal transduction pathways that control cellular growth and apoptosis, and inhibit enzymes that activate carcinogens while inducing enzymes that break down carcinogens (Lam 2010).
A large study on 29 133 male smokers found that those whose blood levels of alpha-tocopherol were in the top 20% of the distribution had a 19% reduction in the risk of developing lung cancer compared to those whose levels were in the bottom 20% of the distribution (Woodson 1999). Another study showed that vitamin E (alpha-tocopherol; 300 mg twice daily during radiation therapy followed by 300 mg once daily for 3 months) when combined with the anti-inflammatory drug pentoxifylline (Trental) (400 mg three times daily during radiation therapy followed by 400 mg once daily for 3 months) helped reduce toxicity due to radiation therapy in lung cancer patients (Misirlioglu 2007). This same combination may also confer a survival advantage for patients with advanced-stage NSCLC; in a group of these patients undergoing radiotherapy, use of pentoxifylline along with alpha-tocopherol increased median survival to 12 months compared to 8 months in a control group receiving radiation alone (Misirlioglu 2006). The gamma-tocopherol form of vitamin E demonstrated impressive results in an animal model of lung cancer. In this study, a tocopherol mixture rich in gamma-tocopherol that was incorporated into the diet reduced tumor growth up to 80% in mice after 50 days of treatment. Moreover, microscopic analysis of tumor samples revealed that the gamma-tocopherol-enriched mixture increased the death rate of lung cancer cells up to 240% compared to the control (Lambert 2009).
Zinc is an important component in several enzymes that help maintain normal DNA replication. A study of 1676 people with lung cancer compared to an equal number of healthy individuals found that those with the highest dietary intake of zinc (greater than 12 mg daily) had a 43% lower risk of lung cancer (Mahabir 2006). A similar study found a 33% reduced risk (Zhou, Park 2005). Another study analyzed hair samples of lung cancer patients and healthy control subjects. Individuals with lung cancer were found to have significantly lower zinc levels in their hair samples compared to control subjects (Piccinini 1996).
Curcumin is an active constituent of the Indian culinary spice turmeric. It has been extensively studied and shown to possess considerable antioxidant and anti-inflammatory properties (Aggarwal 2013; Prasad 2014). Curcumin has also generated interest among cancer researchers due to its apparent chemopreventive properties (Gupta 2013). A number of studies have investigated curcumin’s activity against lung cancer in experimental models. One intriguing aspect of curcumin’s bioactivity is its ability to inhibit a signaling pathway called Stat3. Stat3 has been shown to be active in nearly 50% of lung cancers, and curcumin was shown in preclinical in vitro and animal experiments to function as a potent suppressor of the Stat3 pathway (Alexandrow 2012; Yang 2012). Other evidence shows that pretreating lung cancer cells with curcumin may enhance sensitivity to the chemotherapy drug cisplatin. It is thought to accomplish this by downregulating a protein called Bcl-2, which interferes with programmed cell death (Chanvorachote 2009). Additional evidence from a preclinical model shows that curcumin may reduce the invasive potential of lung cancer (Chen 2008).
Fish oil, a rich source of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), significantly increased the efficacy of first-line chemotherapy in patients with advanced NSCLC in one trial. The dose of fish oil used was sufficient to supply 2.5 g of EPA plus DHA daily. The study also found that fish oil increased the 1-year survival rate by about 20% compared to standard-of-care, although the difference was not statistically significant (Murphy 2011a). In another study by the same primary researcher, supplementation with 2.2 g of EPA daily was shown to help NSCLC patients receiving chemotherapy maintain their body weight and muscle mass more effectively than standard-of-care (Murphy 2011b). An experimental laboratory study showed that incubation of lung cancer cells with EPA and DHA dose- and time-dependently decreased the viability of the cancer cells. The researchers concluded “… DHA and EPA inhibited the proliferation of [lung cancer] cells and induced cell apoptosis and autophagy, which may provide new safe and effective options for the treatment of lung cancer in the future” (Yao 2014).
Derived from magnolia trees, honokiol is a bioactive phytochemical shown to initiate apoptosis and inhibit growth of several cancer cell lines; it possesses anti-angiogenic and anti-carcinogenic properties (Bai 2003; Yang 2002). Honokiol also appears to hamper migration of NSCLC cancer cells; one study identified COX-2 inhibition as a mechanism possibly responsible for this effect (Singh 2013). In an animal model of lung cancer, honokiol alone conferred antitumor activity, which was enhanced when combined with cisplatin. The scientists who conducted the study postulated that the effects of honokiol were attributable to induction of apoptosis and inhibition of angiogenesis (Jiang 2008).
The maitake mushroom contains polysaccharides called beta-glucans (particularly, beta-1,6 glucan), which have been shown to possess potent immunomodulating and anticancer properties (Kodama 2002). A few clinical trials have studied the impact of maitake extracts on various immunologic and cytologic (relating to the properties of cells) outcomes in cancer patients including one in breast cancer patients and another in patients with various types of cancer (Deng 2009; Kodama 2002). In the latter study, maitake extract and whole maitake powder were given to 36 patients with stage II – IV cancers, including 8 lung cancer patients, whom had discontinued chemotherapy due to side effects. Following treatment with maitake, cancer regression or symptomatic improvement was observed in 5 of the 8 lung cancer patients (Kodama 2002).
Some additional ingredients have a sound mechanistic basis for potential benefit in the context of lung cancer. Reishi mushroom (Ganoderma lucidum) may support host antitumor immunity, and since it is generally well-tolerated and nontoxic, may be a worthwhile adjunct to conventional cancer treatment (Jin 2012). Arabinoxylan, a non-starch component of dietary fiber in whole grains, may also favorably modulate anticancer immunity (Lattimer 2010; Ghoneum 2011). It has been shown to sensitize cancer cells to chemotherapeutic agents and enhance apoptosis (Ghoneum 2005; Gollapudi 2008). Mistletoe preparations (eg, Iscador) have been shown to reduce side effects of chemotherapy in NSCLC patients (Piao 2004; Bar-Sela 2013). Although more studies are needed to determine whether mistletoe preparations confer a survival benefit in lung cancer patients, several studies have identified mechanisms suggestive of enhanced immunity (Gardin 2009; Huber 2011; Matthes 2010). Intravenous vitamin C is sometimes used as an anticancer therapy in integrative medical clinics. Some research suggests that this approach may mitigate inflammatory responses in cancer patients and decrease levels of tumor markers, and several cases of cancer remission after intravenous vitamin C treatment have been reported (Mikirova 2012; Fritz 2014). A systematic review published in 2014 concluded that available data suggest potentially important antitumor activity of intravenous vitamin C as well as a good safety profile. One area that makes it difficult to draw firm conclusions about the benefit of intravenous vitamin C in cancer patients is the lack of consistency across trials with regard to methodology, and especially, dosing, which ranges from 1 g to more than 200 g two to three times weekly (Fritz 2014). More studies are needed to clarify these discrepancies and determine the best approach to intravenous vitamin C therapy in the context of cancer.
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