Apoptosis Induced by Tanshinone IIA and Cryptotanshinone Is Mediated by Distinct JAK/STAT3/5 and SHP1/2 Signaling in Chronic Myeloid Leukemia K562 Cells

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Source:
Jung JH, Kwon T-R, Jeong S-J, et al. Evidence-Based Complementary and Alternative Medicine. Volume 2013 (2013) http://dx.doi.org/10.1155/2013/805639
Abstract
Though tanshinone IIA and cryptotanshinone possess a variety of biological effects such as anti-inflammatory, antioxidative, antimetabolic, and anticancer effects, the precise molecular targets or pathways responsible for anticancer activities of tanshinone IIA and cryptotanshinone in chronic myeloid leukemia (CML) still remain unclear.
In the present study, we investigated the effect of tanshinone IIA and cryptotanshinone on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. We found that both tanshinone IIA and cryptotanshinone induced apoptosis by activation of caspase-9/3 and Sub-G1 accumulation in K562 cells. However, they have the distinct JAK/STAT pathway, in which tanshinone IIA inhibits JAK2/STAT5 signaling, whereas cryptotanshinone targets the JAK2/STAT3.
In addition, tanshinone IIA enhanced the expression of both SHP-1 and -2, while cryptotanshinone regulated the expression of only SHP-1. Both tanshinone IIA and cryptotanshinone attenuated the expression of bcl-xL, survivin, and cyclin D1. Furthermore, tanshinone IIA augmented synergy with imatinib, a CML chemotherapeutic drug, better than cryptotanshinone in K562 cells.
Overall, our findings suggest that the anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct the JAK/STAT3/5 and SHP1/2 signaling, and tanshinone IIA has the potential for combination therapy with imatinib in K562 CML cells.
Introduction
Salvia miltiorrhiza Bunge (Danshen) is a traditional medicinal herb widely used for treating cardiovascular disease in Korea, China, and Japan [1]. To date, over 90 kinds of chemical constituents from S. miltiorrhiza have been reported [2, 3]. Of the phytochemicals, tanshinones are a group of lipophilic abietane diterpene compounds including tanshinone I, tanshinone IIA-B, cryptotanshinone, dihydrotanshinone I, isotanshinone I, and isocryptotanshinone I-II and have been extensively investigated [1, 4–7].
In particular, tanshinone IIA and cryptotanshinone have been presented the potential as anticancer drugs by targeting the multiple signaling pathways [8–18].STAT family is transcriptional factors that play key roles in cytokine signaling [19]. STAT proteins are constitutively activated in cancer cells or tissues and thus have been suggested as attractive molecular target(s) for cancer therapy. In light of these events, numerous groups reported the inhibitory effects of plant polyphenols such as curcumin, resveratrol, piceatannol, and EGCG on STAT activation in various cancer cells [19, 20].
Tanshinone IIA and cryptotanshinone were also shown to have the inhibitory effects on the STAT activation in C6 glioma [21] and DU145 prostate cancer cells [22], respectively. However, there is no report on the molecular mechanisms leading to anticancer activity of tanshinone IIA and cryptotanshinone through the STAT signaling pathway in leukemia cells.
Conclussion
Our findings clearly demonstrate that anticancer activity of tanshinone IIA and cryptotanshinone is mediated by the distinct JAK/STAT3/5 and SHP1/2 signaling in K562 cells. Of note, tanshinone IIA showed more potential for the synergy with imatinib compared with cryptotanshinone as a potent candidate for combination therapy.

References:
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2. A.-H. Liu, L. Li, M. Xu, Y.-H. Lin, H.-Z. Guo, and D.-A. Guo, “Simultaneous quantification of six major phenolic acids in the roots of Salvia miltiorrhiza and four related traditional Chinese medicinal preparations by HPLC-DAD method,” Journal of Pharmaceutical and Biomedical Analysis, vol. 41, no. 1, pp. 48–56, 2006.
3. L. Ma, X. Zhang, H. Guo, and Y. Gan, “Determination of four water-soluble compounds in Salvia miltiorrhiza Bunge by high-performance liquid chromatography with a coulometric electrode array system,” Journal of Chromatography B, vol. 833, no. 2, pp. 260–263, 2006.
4. X. Wang, S. L. Morris-Natschke, and K.-H. Lee, “New developments in the chemistry and biology of the bioactive constituents of Tanshen,” Medicinal Research Reviews, vol. 27, no. 1, pp. 133–148, 2007.
5. H.-C. Bi, Z. Zuo, X. Chen et al., “Preclinical factors affecting the pharmacokinetic behaviour of tanshinone IIA, an investigational new drug isolated from Salvia miltiorrhiza for the treatment of ischaemic heart diseases,” Xenobiotica, vol. 38, no. 2, pp. 185–222, 2008.
6. M.-J. Don, C.-C. Shen, W.-J. Syu, Y.-H. Ding, and C.-M. Sun, “Cytotoxic and aromatic constituents from Salvia miltiorrhiza,” Phytochemistry, vol. 67, no. 5, pp. 497–503, 2005.
7. M. Gu, G. Zhang, Z. Su, and F. Ouyang, “Identification of major active constituents in the fingerprint of Salvia miltiorrhiza Bunge developed by high-speed counter-current chromatography,” Journal of Chromatography A, vol. 1041, no. 1-2, pp. 239–243, 2004.
8. W. Chen, L. Liu, Y. Luo et al., “Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase-independent cell death in tumor cells,” Cancer Prevention Research, vol. 5, pp. 778–787, 2012.
9. W. Chen, Y. Lu, G. Chen, and S. Huang, “Molecular evidence of cryptotanshinone for treatment and prevention of human cancer,” Anti-cancer Agents in Medicinal Chemistry. In press.
10. Y. Ge, R. Cheng, Y. Zhou et al., “Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E,” Molecular and Cellular Biochemistry, vol. 368, pp. 17–25, 2012.
11. J.-H. Kim, S.-J. Jeong, T.-R. Kwon et al., “Cryptotanshinone enhances TNF-?-induced apoptosis in chronic myeloid leukemia KBM-5 cells,” Apoptosis, vol. 16, no. 7, pp. 696–707, 2011.
12. H. J. Lee, D. B. Jung, E. J. Sohn et al., “Inhibition of hypoxia inducible factor alpha and astrocyte-elevated gene-1 mediates cryptotanshinone exerted antitumor activity in hypoxic PC-3 cells,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 390957, 13 pages, 2012.
13. C.-Y. Cheng and C.-C. Su, “Tanshinone IIA may inhibit the growth of small cell lung cancer H146 cells by up-regulating the Bax/Bcl-2 ratio and decreasing mitochondrial membrane potential,” Molecular Medicine Reports, vol. 3, no. 4, pp. 645–650, 2010.
14. C.-C. Su, “Tanshinone IIA potentiates the efficacy of 5-FU in Colo205 colon cancer cells in vivo through downregulation of P-gp and LC3-II,” Experimental and Therapeutic Medicine, vol. 3, no. 3, pp. 555–559, 2012.
15. S.-H. Won, H.-J. Lee, S.-J. Jeong et al., “Tanshinone IIa induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway,” Biological and Pharmaceutical Bulletin, vol. 33, no. 11, pp. 1828–1834, 2010.
16. S.-H. Won, H.-J. Lee, S.-J. Jeong, J. Lü, and S.-H. Kim, “Activation of p53 signaling and inhibition of androgen receptor mediate tanshinone IIA induced G1 arrest in LNCaP prostate cancer cells,” Phytotherapy Research, vol. 26, no. 5, pp. 669–674, 2012.
17. S. Xu and P. Liu, “Tanshinone II-A: new perspectives for old remedies,” Expert Opinion on Therapeutic Patents, vol. 23, pp. 149–153, 2013.
18. S. M. Yun, S. J. Jeong, J. H. Kim et al., “Activation of C-Jun N-terminal kinase mediates tanshinone IIA-induced apoptosis in KBM-5 chronic myeloid leukemia cells,” Biological & Pharmaceutical Bulletin, vol. 36, pp. 208–214, 2013.
19. R. Buettner, L. B. Mora, and R. Jove, “Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention,” Clinical Cancer Research, vol. 8, no. 4, pp. 945–954, 2002.
20. J. Vera, K. Rateitschak, F. Lange, C. Kossow, O. Wolkenhauer, and R. Jaster, “Systems biology of JAK-STAT signalling in human malignancies,” Progress in Biophysics and Molecular Biology, vol. 106, no. 2, pp. 426–434, 2011.
21. C. Tang, H.-L. Xue, H.-B. Huang, and X.-G. Wang, “Tanshinone IIA inhibits constitutive STAT3 activation, suppresses proliferation, and induces apoptosis in rat C6 glioma cells,” Neuroscience Letters, vol. 470, no. 2, pp. 126–129, 2010.

Prescriptions of Traditional Chinese Medicine Are Specific to Cancer Types and Adjustable to Temperature Changes

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Chiu P-H, Hsieh H-Y, Wang S-C (2012) Prescriptions of Traditional Chinese Medicine Are Specific to Cancer Types and Adjustable to Temperature Changes. PLoS ONE 7(2): e31648. doi:10.1371/journal.pone.0031648

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Figure 1. Zipf distributions of TCM formulas and herbs to cancers.

The percentage weight of a formula or herb in a prescription is calculated. The weights are averaged over individual cancers, and then over the 30 cancer types. Formulas and herbs are ranked according to the averaged weights. (A) Weights averaged over the 30 cancers are plotted against their ranks. Note of the log scale of the axes. Lines are linear regressions to their top 50 formulas and/or herbs. The slopes of the lines give the Zipf exponents. (B) Weights over individual cancers are plotted against their ranks. Lines are linear regression fits to their top 20 formulas and herbs.

Targeted cancer therapies, with specific molecular targets, ameliorate the side effect issue of radiation and chemotherapy and also point to the development of personalized medicine. Combination of drugs targeting multiple pathways of carcinogenesis is potentially more fruitful. Traditional Chinese medicine (TCM) has been tailoring herbal mixtures for individualized healthcare for two thousand years. A systematic study of the patterns of TCM formulas and herbs prescribed to cancers is valuable. We analysed a total of 187,230 TCM prescriptions to 30 types of cancer in Taiwan in 2007, a year’s worth of collection from the National Health Insurance reimbursement database (Taiwan).
We found that a TCM cancer prescription consists on average of two formulas and four herbs. We show that the percentage weights of TCM formulas and herbs in a TCM prescription follow Zipf’s law with an exponent around 0.6. TCM prescriptions to benign neoplasms have a larger Zipf’s exponent than those to malignant cancers. Furthermore, we show that TCM prescriptions, via weighted combination of formulas and herbs, are specific to not only the malignancy of neoplasms but also the sites of origins of malignant cancers. From the effects of formulas and natures of herbs that were heavily prescribed to cancers, that cancers are a ‘warm and stagnant’ syndrome in TCM can be proposed, suggesting anti-inflammatory regimens for better prevention and treatment of cancers. We show that TCM incorporated relevant formulas to the prescriptions to cancer patients with a secondary morbidity.
We compared TCM prescriptions made in different seasons and identified temperatures as the environmental factor that correlates with changes in TCM prescriptions in Taiwan. Lung cancer patients were among the patients whose prescriptions were adjusted when temperatures drop. The findings of our study provide insight to TCM cancer treatment, helping dialogue between modern western medicine and TCM for better cancer care.

Discussion

Environmental changes induce physiological responses. Therapies that take into account interactions between the environment and the individual are conceived to be more productive. Among changes in the three meteorological variables, only drop in temperatures was found to correlate temporally with the changes in prescription. Taiwan summer is both hottest and dampest while Taiwan winter is coldest but not necessarily driest. If prescriptions were adjusted to drop in temperatures in winter, it would be expected that they be adjusted to rise in temperatures and humidities in summer too. One explanation is that most Taiwan households are equipped with air-conditioners. Indoor conditions in summer are therefore not as hot and humid as the records show. On the other hand, Taiwan winter is cold both indoor and outdoor as typical Taiwan households are not equipped with heaters. Lungs could be affected as they take in cold airs. The digestive and female reproductive systems might need to adjust as the body needs more energy and blood in cold days. Our analysis of the TCM prescriptions to cancers in Taiwan therefore identifies the relevant environmental factor, organs and patients for better care.

TCM theories hold that imbalance or disharmony in the interactions among the functional elements in the body or in the interaction between the body and the environment lead to disease. TCM is allopathic like modern western medicine. It is therefore interesting to learn, from the prescription data, what cancers are in TCM perspective. Peptic and tranquilizing formulas are relatively few in the repertoire of reimbursable TCM formulas, ranking, respectively, 11th and 16th in the 21 TCM categories. However, in TCM prescriptions to cancer patients with stomach and sleep secondary disorders, the percentage weights of peptic and tranquilizing formulas were among the top three along with tonifying and mediating formulas. A sensible mapping between ICD-9 and TCM therapeutic categories seems to be established, helping dialogue between the two medicines. Furthermore, in the prescriptions to single, primary malignant cancers without comorbidities, mediating formulas rose to 2nd heaviest from their 7th position in the TCM categories, in contrast to tonifying formulas, which, although the heaviest, are the most common. Tonifying formulas, unlike mediating, are thus probably not peculiar in cancer treatment. According to TCM theories, mediating formulas are for the so-called Shao Yang syndromes which are neither exterior nor interior, and neither cold nor warm. The indeterministic nature of the TCM syndrome in regard to malignant cancers may be recapitulating the transformability and/or metastasizing of the disease.

Likewise, comparing TCM natures’ weights in the cancer prescriptions with the natures’ relative frequencies in the arsenal of the reimbursable herbs (warm, cold, neutral, mild-cold, cool, mild-warm, hot, in the order of their frequencies, we found predominance of cold or mild-cold TCM natures to neoplasms. The same comparison leads to pungent-bitter TCM herbs in the TCM cancer prescriptions. Since, in TCM theories, cold herbs antagonize warm syndromes and pungent herbs move and disperse, the analysis may suggest that TCM views neoplasms as a warm and stagnant syndrome. As warmth and swelling are two of the features of inflammation, anti-inflammatory regimens such as exercise and toxin-free diets/environment may help prevent cancers. Indeed, the chemopreventive effect of non-steroidal anti-inflammatory drugs on colorectal and probably other cancers has been recognized and clinical trials for the evaluation of risks and benefits have been underway.

The ICD-9 codes in the study share a common denominator, that is, they are cancers with the same hallmarks at the cellular level. They differ otherwise, originating from different anatomical organs of different physiological functions. The design of the study helps address the issue of tissue-specificity of TCM prescriptions. Provided that the TCM treatments of cancers were efficacious, the result supports tissue-specificity of TCM prescriptions via weighted combinations of formulas and herbs. In western pharmaceutics, a targeted therapy drug which was approved for a cancer was later approved for other indications. The knowledge of TCM combinations may help inspire further indication expansion of targeted cancer drugs.

In linguistics, less specific words have higher frequencies. Use of low (high) specificity words, although appealing to speakers (hearers), incurs decoding (memory) cost of the hearers (speakers). A trade-off in the efforts between both parties was shown to lead to Zipf’s distribution of words. Abundances of expressed genes in human normal and cancer tissues were found to be Zipf-distributed. In the chemical world, a recent study shows that the distributions of such features as rigid segments, ring systems and circular substructures of small, organic molecules follow power law. The Zipf distribution of the weights of the TCM formulas and herbs may therefore suggest TCM treatment as a dialect, with herbs as words and formulas as phrases, in the communications to the human body. Note that Zipf distributions are considered a necessary but not sufficient condition for a language as ‘words’ in random texts were also found to exhibit Zipf distributions. The Zipf-like distribution however may have implications in the dosage optimization of targeted cancer drug cocktails.

Modern western medicine is the major treatment modality in Taiwan. TCM patients might have received prior western cancer therapy or be under concomitant therapies. The information is not available in the dataset, nor is the information about prognosis of the TCM treatment. Interpretation can become diverse. For example, the most prescribed tonifying formulas and sweet herbs in TCM prescriptions could be aiming at fatigue, which is the most common side effect of radiation and chemotherapy. Despite the limitations, the systematic and exploratory analysis of the current study sheds light on TCM treatment of cancer, providing a fertile ground for the development of an integrated cancer management.

The synergistic effects of traditional Chinese herbs and radiotherapy for cancer treatment

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9traditional-chinese-Medicine

radiotherapy

JIA LL, MA SM, HOU X et al. Oncol Lett. 2013 May; 5(5): 1439–1447. Published online 2013 March 12. doi: 10.3892/ol.2013.1245 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678704/

Abstract

Traditional Chinese medicine (TCM) has been demonstrated to have potent cytotoxic activity against certain malignant tumors. Ionizing radiation (IR) is one of the most effective methods used in the clinical treatment of cancer. The drawback of a single formula is that it limits the treatment efficacy for cancer, while comprehensive strategies require additional theoretical support. However, a combination of different antitumor treatment modalities is advantageous in restricting the non-specific toxicity often observed with an extremely high dose of a single regimen. The induction of apoptotic cell death is a significant process in tumor cells following radiotherapy or chemotherapy, and resistance to these treatments has been linked to a low propensity for apoptosis. Autophagy is a response of cancer cells to IR or chemotherapy, and involves the prominent formation of autophagic vacuoles in the cytoplasm. In this review, the synergistic effects of TCM and radiotherapy are summarized and the underlying mechanisms are illustrated, providing new therapeutic strategies for cancer.

Keywords: traditional Chinese medicine, apoptosis, autophagy, radiosensitization, cancer treatment

Contents

1. Introduction

2. Application of TCM in cancer

3. TCM and radiotherapy

4. TCM, radiosensitivity and apoptosis

5. TCM, radiosensitivity and autophagy

6. Prospects

1.?Introduction

Ionizing radiation (IR) is widely used in cancer therapy and can induce cell cycle arrest, DNA repair and repair, and/or apoptosis, leading to different biological consequences depending on the cell type. Traditional Chinese medicine (TCM) is often considered to be an alternative or complementary medicine in cancer treatment; it is able to suppress tumor growth and angiogenesis, as well as inhibit invasion and metastasis.

TCMs may also function as a radiosensitizers during the radiotherapy of cancer.

Apoptosis, or type I programmed cell death, is a major response of cancer cells to various therapies including IR and TCM.

Apoptosis is controlled by extrinsic or intrinsic inducers, which often act as targets of TCM to trigger cell death during radiotherapy. Autophagy (type II programmed cell death), a protein degradation system involving the autophagic/lysosomal compartment, is another response of cancer cells to various therapies. The process of autophagy is initiated by the sequestration of a portion of the cytoplasm to form the autophagosome. Subsequently, the autophagosome fuses with the lysosome and the contents of the autophagosome are lyzed. Activation of autophagy in the tumor cells may improve the outcome of radiotherapy. The roles of TCM in radiation-induced cell death determine the application of TCM in cancer treatment.

2.?Application of TCM in cancer

TCM has been used for thousands of years. The majority of Chinese herbal formulae comprise several herbal components and have been used to treat various chronic diseases, mainly by immunomodulation or by altering inducible cell death. Although TCM has assigned anticancer activities, the underlying mechanisms are not well understood. Certain herbs are able to inhibit the migration and invasion of cancer cells in vitro, while others trigger apoptosis in cancer cells. The herbs used in TCMs for treating human cancer are summarized in Table I.

Summary of reported effects on human cancer following TCM administration.

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TCM, traditional Chinese medicine; GSPP, gekko sulfated polysaccharide-protein complex; DATS, diallyl trisulfide; ERK, extracellular signal-related kinase; ASPK, aspartate kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; AKT, v-akt murine thymoma viral oncogene homolog 1; mTOR, mammalian target of rapamycin; P70S6K, ribosomal protein S6 kinase, 70kDa, polypeptide 1; Rac-1, Ras-related C3 botilinum toxin substrate 1; VASP, vasodilator-stimulated phosphoprotein; MMP2, matrix metallopeptidase 2; MMP9, matrix metallopeptidase 9; NF-?B, nuclear factor of ? light polypeptide gene enhancer in B-cells; Bcl-2, B-cell CLL/lymphoma 2; Bax, Bcl-2-associated X protein; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor.

3.?TCM and radiotherapy

A series of studies concerning the radioprotective and radiosensitizing functions of TCM have been conducted over a long time period. In the 20th century, scientists focused on testing the radioprotective effects of TCM in experimental animals. A series of bioactive components were isolated from TCMs and the mechanisms of radioprotection were studied. Improving the function of the hematopoietic and immune systems may be characteristic of such TCM herbs.

Kuei-Pi-Tang is a type of TCM that has been suggested to have therapeutic effects on hemato-deficient diseases and radiation-related injuries. Kuei-Pi-Tang has been demonstrated to increase the recovery of cellular immunocompetence, particularly when administered at a concentration of 20 mg/20 g body weight following ?-ray irradiation.

Additionally, Ren-Shen-Yang-Rong-Tang, Zaizhang-I (ZZ-I) and Juzen-Taiho-Toh (TJ-48) have demonstrated effects on the hematopoietic recovery from radiation-related injury in mice, by stimulating hematopoietic stem cells and by improving the hematopoietic inductive microenvironment (HIM). The results demonstrated that these TCM herbs significantly promoted the recovery of the colony-forming unit-spleen (CFU-S) and the colony-forming unit-granulocyte/macrophage (CFU-GM).

Furthermore, Gynostemma pentaphyllum (Gp) has been shown to assist in the recovery of decreased leukocyte counts, GOT, GPT and IgG serum levels, and the proliferation of splenocytes stimulated by PHA, LPS and Con A in ?-ray-irradiated mice.

Moreover, Dang-Gui-Shao-Yao-San (DGSYS), administered to previously X-irradiated mice increased the number of CFU-S in the mice that survived the irradiation, as well as significantly ameliorating leukopenia, thrombocytopenia and the depression of hematocrits following irradiation.

In addition, certain TCMs have been demonstrated to increase immunocompetence in ?-ray-irradiated mice; Ganoderma lucidum (GI) and Krestin (PSK) increased the splenic weight and leukocyte count following ?-ray irradiation.

Furthermore, Si-Wu-Tang was observed to protect the jejunal crypts, increase the formation of endogenous spleen colonies and reduce the frequency of radiation-induced apoptosis when administered prior to irradiation; while extracts of Danggui and Baishaoyao have been revealed to have potentially significant radioprotective effects.

Throughout the 21st century, numerous scientists have begun to administer TCM herbs as an adjunct to radiotherapy/chemotherapy for certain types of cancer. We discuss examples of such herbs used in radiotherapy. TCM has been shown to exhibit radiomodifying effects on tumors and normal tissues by in vitro and in vivo studies. A number of these agents are able to enhance the therapeutic gain of radiotherapy by acting as radiosensitizers to the tumor cells and/or as radioprotectors to normal cells. Botanical agents are comprised of multiple phytochemical compounds that may work individually or synergistically to not only improve the outcomes of radiotherapy, but also to induce a variety of anticancer effects. It is important to evaluate these botanical agents for their efficacy, tumor specificity and safety profiles during radiotherapy.

The goji berry, Lycium barbarum, is well-recognized in TCM for its various therapeutic properties based on its antioxidant and immunomodulating effects. A previous study demonstrated the antioxidant activity of the goji berry in the skin; 5% goji berry juice provided significant protection against lipid peroxidation induced by UVA radiation. Two known inducible endogenous skin antioxidants, haem oxygenase-1 and metallothionein, were found to be involved in the photoimmune protection. Therefore, goji berry juice has the potential to provide additional photoprotection for susceptible humans.

Studies have also demonstrated that TCM herbs are able to protect hematopoietic organs against radiation-induced damage. For example, panaxatriol (PT) has been observed to relieve myelosuppression induced by radiation injury. The ability of the agent to regulate the expression of the hematopoietic growth factor GM-CSF and to promote the maturation of bone marrow cells may be responsible for a number of these beneficial effects.

Additionally, the effects of the main ingredients of Bu-Zhong-Yi-Qi-Tang on jejunal crypt survival, endogenous spleen colony formation and apoptosis in jejunal crypt cells were investigated in mice irradiated with high and low doses of ?-rays.

IR is capable of inducing DNA damage and cell death by generating reactive oxygen species (ROS). Pre-treatment of thymocytes with paeoniflorin (PF) has been demonstrated to reverse this tendency and to attenuate irradiation-induced ROS generation. Several antiapoptotic characteristics of PF, including the ability to diminish cytosolic Ca2+ concentration, inhibit caspase-3 activation, upregulate Bcl-2 and downregulate Bax in 4-Gy-irradiated thymocytes, have been identified. PF was also observed to block extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase, which were activated by 4-Gy irradiation.

Furthermore, in human dermal fibroblasts, berberine (BBR) was able to decrease UV-induced MMP-1 expression and reverse UV-induced reduction of type I procollagen in a dose-dependent manner.

Additionally, an isoflavone extract from soybean cake decreased UVB-induced HaCaT cell death and the phosphorylation of p38, JNK and ERK1/2 in vitro. In the in vivo studies, topical application of isoflavone extract prior to UVB irritation decreased the epidermal thickness and the expression levels of COX-2 and PCNA, and increased the catalase concentration.

Moreover, the Chinese herbal preparation, Yangyin Humo Decoction (YHD), was able to alleviate the oral mucomembranous reaction to radiation applied to patients with head-neck tumors.

In addition, aloe polysaccharides (AP) have demonstrated radioprotective effects by blocking the upregulation of pro-apoptotic p53, Bax and Bad, and the downregulation of Bcl-2, in normal human cells in vitro and in mice in vivo.

4.?TCM, radiosensitivity and apoptosis

Apoptosis is one of the processes of programmed cell death (PCD) that occurs in multicellular organisms, where biochemical events lead to characteristic cell changes and death. In addition to the significance of apoptosis as a biological phenomenon, defective apoptotic processes have been implicated in numerous types of diseases. Excessive apoptosis causes atrophy, as in the case of ischemic damage; whereas an insufficient level of apoptosis results in uncontrolled cell proliferation, such as in cancer. TCMs act in cancer via various effects and pathways (Tables II, III and andIV)IV)

Summary of reported actions of TCM in apoptosis through Fas/FasL.

TCMCancerEffectPathwayReference

Licorice Prostate Induces autophagy mTOR (85)
Alisol B <Gastrc/td> Induces autophagy CaMKK-AMPK-mTOR (86)
Osthole Breast Inhibits proliferation; induces autophagy AKT/mTOR (34)
SYUNZ-16 Hepatoma Inhibits growth autophagy PKB/AKT; AKT/FOXO (35)
Casticin Leukemia Autophagy PI3K/AKT (36)
AECM Breast Autophagy AKT (37)
Antroquinonol Hepatoma G1 arrest; autophagy AMPK; mTOR (38)

TCM, traditional Chinese medicine; KLT, Kang-Lai-Te; Fas, TNF receptor superfamily; FasL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand; JNK, c-Jun N-terminal kinase.

Summary of reported actions of TCM in apoptosis through the mTOR pathway.

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TCM, traditional Chinese medicine; AECM, aqueous extract of Cordyceps militaris; AKT, v-akt murine thymoma viral oncogene homolog 1; mTOR, mammalian target of rapamycin; PKB, protein kinase B; FOXO, forkhead box; PI3K, phosphoinositide-3-kinase.

Summary of reported actions of TCM in apoptosis through the Bcl-2 family.

table5

TCM, traditional Chinese medicine; ApoG2, apogossypolone; As2O3, arsenic trioxide; GA3, gambogic acid 3; GA, gambogic acid; ON-III, 2?,4?-dihydroxy-6?-methoxy-3?,5?-dimethylchalcone; PSI, Paris Saponin I; DHA, dihydroartemisinin; CPBF, Cordyceps pruinosa butanol fraction; ART, artesunate; Bcl-2, B-cell CLL/lymphoma 2; Bcl-xL, apoptosis regulator Bcl-X; Bax, Bcl-2-associated X protein; Bid, BH3-interacting domain death agonist; AIF, apoptosis inducing factor; Bim, Bcl-2-like 11; ROS, c-ros oncogene.

Radiosensitive cells have been demonstrated to correlate with a good outcome following radiotherapy. An increased understanding of the molecular processes underlying cellular sensitivity to IR has led to the identification of novel targets for intervention. A combination of a monoclonal antibody (TRA-8) to the human death receptor (DR5) and IR enhanced radiosensitivity in the human radioresistant larynx squamous carcinoma cell line, providing an effective treatment strategy for patients with radioresistant cancers. Additionally, wortmannin combined with X-rays inhibited DNA-dependent protein kinase (DNA-PK), resulting in the inhibition of double-strand break (dsb) repair in the fast component. This effect enhanced the induction of apoptosis during the radiosensitization of bladder tumors.

Moreover, increased levels of heat shock protein (Hsp) 27 and 70 have been identified to be closely correlated with tumorigenesis, metastasis, resistance to anticancer therapeutics and thus a poor prognosis in a wide range of tumors. Silencing of Hsp27 and Hsp70 has both enhanced radiation sensitivity and amplified irradiation-induced apoptosis.

Certain agents have demonstrated their ability to inhibit antiapoptotic proteins of the Bcl-2 and caspase families on exposure to radiation, thus enhancing the radiation sensitivity. Exploration of the clinical applications of these agents as radiosensitizers for tumor therapy is merited.

Simultaneous inhibition of STAT3 and ErbB2 has been demonstrated to induce U251 cell apoptosis, which was primarily associated with the mitochondrial apoptotic pathway and radiosensitizing activity in human glioma.

The HDAC inhibitor, valproic acid (VPA), which enhances IR-induced mitochondrial localizations of Bax and Bcl-xL, was observed to upregulate the mitochondrial membrane potential and be involved in the release of cytochrome c only in wild-type p53 cell lines. It was also found to enhance the radiotherapy response in colorectal cancer, particularly in tumors with the wild-type p53 genotype.

p53-upregulated modulator of apoptosis (PUMA), is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member that directly binds and antagonizes all known antiapoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase.

Additionally, Ser46 phosphorylation of p53 has been demonstrated to induce coincident caspase-7 and PARP cleavage in response to IR. Furthermore, mutation of p53 (Ser46) to alanine attenuated IR-induced apoptotic signaling, and ought, therefore, to be a target for radiosensitization.

Moreover, inhibition of Bcl-xL expression has been observed to result in potent antitumor activity and radiosensitization in human prostatic carcinoma.

Certain TCM herbs act as radioprotective or radiosensitizing agents via apoptotic pathways. Treatment with a combination of arsenic trioxide and irradiation has been shown to enhance the apoptotic effects in U937 cells through increased mitotic arrest and ROS generation accompanied by a decrease in Bcl-2 and Bcl-xL levels, and upregulation of caspase-3 levels.

In addition, a water-soluble ginseng (Panax root) extract was observed to provide greater protection against radiation-induced DNA damage than isolated ginsenoside fractions (saponins). The underlying radioprotective mechanism of ginseng may be linked, directly or indirectly, to its antioxidative capability by the free radicals responsible for DNA damage. Ginseng is considered to be a promising radioprotector in therapeutic or preventive protocols that is able to attenuate the deleterious effects of radiation in human normal tissue, particularly in cancer patients undergoing radiotherapy.

5.?TCM, radiosensitivity and autophagy

Autophagy, also known as type II programmed cell death or autophagocytosis, is a catabolic process involving the degradation of cellular components through the lysosomal machinery. It is a tightly regulated process that occurs naturally in cell growth, development and homeostasis, and assists in maintaining a balance between the synthesis, degradation and subsequent recycling of cellular products. It is a key mechanism by which a starving cell reallocates nutrients from unnecessary processes to more essential processes. It is unknown whether the autophagic activity in dying cells itself causes death or whether it simply occurs as a process alongside it. A cell may either die or survive, and these two outcomes are dependent on environmental factors. It is unclear whether the increase in autophagosomes indicates an increase in
autophagic activity or a decrease in autophagosome-lysosome fusion.

Many signal pathways participate in the process of autophagy. Mammalian target of rapamycin (mTOR) senses nutrient, metabolic and hormonal signals and is involved in numerous regulatory events associated with energy metabolism, including the nuclear localization of nutrient-regulated transcription factors. mTOR is abundantly expressed when nutrients are plentiful and it suppresses autophagy. Phosphoinositide-3-kinase I (PI3KI)/AKT is an upstream regulator of mTOR and p70S6 kinase is the downstream effector of mTOR, PI3KI/AKT-mTOR-p70S6 kinase signaling represses the process of autophagy. Additionally, Beclin 1 represents an important component of the autophagic machinery; it interacts with proteins that positively regulate autophagy, such as Vps34, UVRAG and Ambra1, as well as with antiapoptotic proteins such as Bcl-2 (via its BH3-like domain) to negatively regulate autophagy.

Beclin 1 acts as a part of the class III PI3K (PI3KIII) Vps34 complex that induces autophagy.

The Bcl-2 families are also regulators of autophagy; Bcl-xL, which normally protects cells from autophagy by inhibiting the Beclin-1/Vps34 complex, is essential for autophagy.

Bax and Bak, which act as a gateway for caspase-mediated cell death, also function as downregulators of autophagy.

Several regulators of the apoptotic pathway, such as PI3K/Akt signaling, p53 and Bcl-2 family members, also function as modulators of autophagy. Taking Bcl-2 as an example, Beclin 1 is capable of binding to PI3KIII as well as to Bcl-2, and the Bcl 2-Beclin complex inhibits the process of autophagy, while the dissociation of Beclin 1 from its Bcl-2 inhibitor is essential for its autophagic activity. DAPK is able to phosphorylate Beclin 1 at Thr119, which is located at a crucial position within its BH3 domain, and thus promote the dissociation of Beclin 1 from Bcl-xL and the induction of autophagy.

Therfore, there may be a ‘molecular switch’ between apoptosis and autophagy that has these pathways in common. The theory that TCM plays an active role in cancer treatment by inducing autophagy has been studied. The medicinal mushroom, Ganoderma lucidum, is one of the most esteemed natural products that has been used as a TCM. G. lucidum triterpene extract (GLT) has been demonstrated to suppress the phosphorylation of p38 MAPK, and to induce autophagy and Beclin 1 expression in colon cancer cells.

In addition, pheophorbide-a (Pa) is an active component isolated from a Chinese herb and Pa-based photodynamic therapy (Pa-PDT) has demonstrated antitumor effects by activating mitochondria-mediated apoptosis and ERK-mediated autophagy in MDA-MB-231.

Moreover, as mTOR plays a central role in the autophagy pathway, TCMs that are able to induce tumor cell death through mTOR may potentially induce autophagy (Table V). Other TCMs mentioned in Table IV may also potentially participate in the regulation of autophagy. Furthermore, flavokawain B, a novel chalcone from Alpinia pricei Hayata with potent anticancer activity, significantly inhibits the growth of colon cancer cells, thus providing novel insights into the molecular mechanisms underlying its apopototic activity. Flavokawain B provokes G2/M accumulation in addition to autophagy, and it also acts through ROS generation and GADD153 upregulation to regulate the expression of Bcl-2 family members, thereby inducing mitochondrial dysfunction and apoptosis in HCT116 cells.

Furthermore, licorice, a common Chinese medicinal herb with antitumor activity, is able to induce autophagy by downregulating Bcl-2 and inhibiting the mTOR pathway.

Summary of reported actions of TCM in tumors through the mTOR pathway, by inducing or potentially inducing autophagy.

Screen Shot 2013-07-09 at 8.58.34 AM

TCM, traditional Chinese medicine; AECM, aquenous extract of Cordyceps militaris; mTOR, mammalian target of rapamycin; CaMKK, calcium/calmodulin-dependent protein kinase kinase; AMPK, AMP-activated protein kinase; AKT, v-akt murine thymoma viral oncogene homolog 1; PKB, protein kinase B; FOXO, forkhead box; PI3K, phosphoinositide-3-kinase.

Previously, it was considered that cell death induced by IR is apoptotic, while autophagy is an alternative cell death pathway that is induced by mTOR inhibitors and upregulated when apoptosis is defective. The novel response of cancer cells to IR or chemotherapy has been demonstrated to increase the resistance of cancer cells to various apoptotic stimuli. Upregulation of autophagy by inhibitors of caspase-3 and mTOR enhanced radiotherapy responses in a mouse model of lung cancer. Combined Bcl-2/mTOR inhibition was observed to lead to enhanced radiosensitivity via induction of apoptosis and autophagy in vitro and in a lung cancer xenograft model; this is a potential therapeutic strategy for enhancing radiation therapy in patients with non-small cell lung cancer. Bromodeoxyuridine (BrdU) was found to enhance and modify radiation-induced cell death by accelerating the increase in the Bax/Bcl-2 ratio in non-irradiated cells, subsequently increasing radiation-induced apoptosis and/or autophagy depending on the radiation dosage.

Moreover, the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin (BCG/CWS) is an effective antitumor immunotherapy agent; BCG/CWS plus IR-induced autophagy and cell death were predominantly mediated by the generation of ROS. This suggests that BCG/CWS in combination with IR is a promising therapeutic strategy for enhancing radiation therapy in colon cancer cells through the induction of autophagy.

However, once a tumor has formed, autophagy inhibition may be a therapeutic target for radiosensitization and chemosensitization. At present, the relationship between cancer and deregulated autophagy appears to be complex and must be disentangled by further in-depth study.

Z-VAD, a broad-spectrum caspase inhibitor, is a radiosensitizer in breast and lung cancer in vitro and in vivo. Caspase inhibition is proposed to have the potential to enhance the therapeutic ratio of radiation therapy in solid tumors. Therefore, clinical trials are required to determine the potential of this combination therapy in cancer patients. In addition, the autophagy inhibitors, 3-methyladenine (3-MA) and bafilomycin A1, may represent a new application of radiosensitization for malignant glioma cells.

Moreover, vitamin D or vitamin D analogs are involved in the radiosensitization of breast tumor cells mediated via autophagy, and also delay and attenuate the proliferative recovery that may be a preclinical indicator of disease recurrence.

Furthermore, DNA-PK plays a key role in the DNA DSB repair induced by IR; inhibition of DNA-PK combined with IR is capable of inducing autophagy and radiosensitizing the malignant glioma cells, and may be promising as a new therapy for radiosensitizing tumors. Additionally, pharmacological inhibition of nuclear factor (NF)-?B has been demonstrated to enhance cell damage and radiosensitization through autophagy in glioma cell lines.

6.?Prospects

Currently, the functions of TCMs in cancer cells and the relative underlying molecular mechanisms are not yet completely understood. The studies described in this review have indicated that TCMs, which are observed to have a radiosensitizing effect through mechanisms involving their apoptotic and autophagic properties, have the potential to be effective systemic radiosensitizers that may be used to amplify radiation-induced toxicity in tumor tissues. TCMs are able to exhibit anticancer roles by apoptosis and autophagy, through mTOR and the Bcl-2 family pathway. Although the molecular mechanisms underlying autophagy are not yet fully understood, modulators of autophagy may have a number of potential benefits; promoters of autophagy may induce autophagy-mediated cell death in types of cancer with a high threshold to apoptosis. Certain TCM herbs may be used as radioprotectors that are able to ameliorate radiation-induced toxicity in normal tissue in cancer patients undergoing radiotherapy. We propose further evaluation of TCM for its radiosensitive and radioprotection potential in a clinical setting.

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Teng-Long-Bu-Zhong-Tang, a Chinese herbal formula, enhances anticancer effects of 5 – Fluorouracil in CT26 colon carcinoma.

8th Monday, 2013  |   Herb or Compound  |  no comments

Source:
Deng S, Hu B, An HM, Du Q, et al. BMC Complement Altern Med. 2013 Jun 8;13(1):128.

Colorectal cancer remains one of the leading causes of cancer death worldwide. Traditional Chinese Medicine (TCM) has played a positive role in colorectal cancer treatment. There is a great need to establish effective herbal formula for colorectal cancer treatment. Based on TCM principles and clinical practices, we have established an eight herbs composed formula for colorectal cancer treatment, which is Teng-Long-Bu-Zhong-Tang (TLBZT). We have demonstrated the anticancer effects of TLBZT against colorectal carcinoma in vitro. In present study, we evaluated the anticancer potential of TLBZT, used alone or in combination with low dose of 5-Fluorouracil (5-Fu), in CT26 colon carcinoma in vivo.
CT26 colon carcinoma was established in BALB/c mice and treated with TLBZT, 5-Fu, or TLBZT plus 5-Fu. The tumor volumes were observed. Apoptosis was detected by TUNEL assay. Caspases activities were detected by colorimetric assay. Cell senescence was indentified by senescence beta-galactosidase staining. Gene expression and angiogenesis was observed by immunohistochemistry or western blot.
TLBZT significantly inhibited CT26 colon carcinoma growth. TLBZT elicited apoptosis in CT26 colon carcinoma, accompanied by Caspase-3, 8, and 9 activation and PARP cleavage, and downregulation of XIAP and Survivin. TLBZT also induced cell senescence in CT26 colon carcinoma, with concomitant upregulation of p16 and p21 and downregulation of RB phosphorylation. In addition, angiogenesis and VEGF expression in CT26 colon carcinoma was significantly inhibited by TLBZT treatment. Furthermore, TLBZT significantly enhanced anticancer effects of 5-Fu in CT26 colon carcinoma.
TLBZT exhibited significantly anticancer effect, and enhanced the effects of 5-Fu in CT26 colon carcinoma, which may correlate with induction of apoptosis and cell senescence, and angiogenesis inhibition. The present study provides new insight into TCM approaches for colon cancer treatment that are worth of further study.
Teng-Long-Bu-Zhong-Tang
Actinidia chinensis (Teng-Li-Geng) 30 g, Solanum nigrum (Long-Kui) 15 g, Duchesnea indica (She-Mei) 15 g, Atractylodes macrocephala Koidz (Bai-Zhu) 9 g, Poria cocos (Fu-Ling) 15 g, Coix seed (Yi-Yi-Ren) 30 g, Mistletoe (Hu-Ji-Sheng) 15 g, and Scutellaria barbata (Ban-Zhi-Lian) 30 g

High Red Blood Cell Folate Levels Linked to Silenced Tumor-Suppressor

19th Wednesday, 2013  |   Others  |  no comments

series-image_1-11 http://www.sciencedaily.com/releases/2010/12/101222173103.htm People with higher levels of folate in their red blood cells were more likely to have two tumor-suppressing genes shut down by methylation, a chemical off switch for genes, researchers report in the December issue of Cancer Prevention Research. DNA hypermethylation, notes co-author Jean-Pierre Issa, M.D., professor in MD Anderson’s Department of Leukemia, is found in a variety of cancers and diseases of aging, such as heart disease. Methyl groups attach to genes at sites called CpG islands and protrude like tags or book marks from the promoter region, preventing gene expression. Our new finding is that having high levels of folate in the blood, as observed in a sensitive measure of red blood cell (RBC) folate, is related to higher levels of DNA methylation. Folate is a naturally occurring B-vitamin that plays a role in DNA creation, repair and function as well as red blood cell production. Pregnant women who have a folate deficiency are at elevated risk of giving birth to a child with neural tube defects, which are caused by the failure of the spinal cord or brain to fully close during development. Folate is found in leafy vegetables, fruits, dried beans cialis 120 mg and peas. Since 1998 its synthetic version, folic acid, has been added to breads cereals, flours, pastas, rice and other grain products under order from the U.S. Food and Drug Administration. This has driven down the rate of neural tube defects in the United States, according to the U.S. Centers for Disease Control and Prevention. Folate also is taken as a dietary supplement. The recommended daily requirement is 400 micrograms for adult men and women and an additional 400 for women capable of becoming pregnant. Folate’s effect on cancer, once thought to be mainly preventive, has become less clear in recent years, with scientists finding cancer-promoting aspects of folate intake in colorectal, prostate and other cancers. The research team analyzed the cialisdosage-storeonline.com association between folate blood levels and dietary and lifestyle factors on DNA methylation in normal colorectal tissue. They enrolled 781 patients from a parent clinical trial that compared folate to aspirin in the prevention of precancerous colorectal polyps. They gathered demographic, lifestyle and dietary information and compared methylation of two tumor-suppressing genes between the first colonoscopy and one three years later. The genes, ER? and SFRP1, are expressed in normal colorectal tissue but silenced by methylation in colon cancer. The two genes also have been found to be methylated in breast, prostate and lung tumours. Age was strongly associated with increased methylation — a finding that confirmed longstanding research. Methylation levels also varied between the rectum and right colon and among different ethnic groups for each gene. Neither folate nor aspirin treatment were significantly associated with methylation levels. However, RBC folate was associated with methylation of both genes with significant differences emerging between the top quarter of patients with the highest RBC folate count and the bottom quarter with the lowest. RBC folate levels closely reflect long-term folate intake. These differences were not trivial, they were the equivalent of 10 years of extra aging for those with high RBC folate counts. Today it’s worrisome that taking extra folate over the long term might lead to more DNA methylation, which then might lead to extra diseases including potentially an increased chance of developing cancer and other diseases of ageing. The data for folate supplementation right now are very ambiguous and I personally think people taking folate should think twice about it,” Issa said. “Also, these findings, added to other data, should trigger a rethinking of the U.S. position that everyone should be taking extra folate. Reference Kristin Wallace, Maria V. Grau, A. Joan Levine, Lanlan Shen, Randala Hamdan, Xinli Chen, Jiang Gui, Robert W. Haile, Elizabeth L. Barry, Dennis Ahnen, Gail Mckeown-Eyssen, John A. Baron and Jean Pierre J. Issa. Association between Folate Levels and CpG Island Hypermethylation in Normal Colorectal Mucosa. Cancer Prevention Research, December 2010 3:1552-1564 DOI: 10.1158/1940-6207.CAPR-