radio-protective effect | Botanical Oncology

Cancer: Hepatocellular carcinoma, colorectal, liver

Action: Radio-protective, ameliorated myelosuppression, MDR

Radio-protective

The radio-protective effect of paeoniflorin (PF), a main bioactive component in the traditional Chinese herb peony, on irradiated thymocytes and the possible mechanisms of protection have been investigated. Ionizing radiation can induce DNA damage and cell death by generating reactive oxygen species (ROS).

It was found 60Co γ-ray irradiation increased cell death and DNA fragmentation in a dose-dependent manner while increasing intracellular ROS. Pre-treatment of thymocytes with PF (50–200 µg/ml) reversed this tendency and attenuated irradiation-induced ROS generation. Hydroxyl-scavenging action of PF in vitro was detected through electron spin resonance assay. Several anti-apoptotic characteristics of PF, including the ability to diminish cytosolic Ca2+ concentration, inhibit caspase-3 activation, and up-regulate Bcl-2 and down-regulate Bax in 4 Gy-irradiated thymocytes, were determined.

Extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 kinase, were activated by 4 Gy irradiation, with their activation partly blocked by pre-treatment of cells with PF. The presence of ERK inhibitor PD98059, JNK inhibitor SP600125 and p38 inhibitor SB203580 decreased cell death in 4 Gy-irradiated thymocytes. These results suggest PF protects thymocytes against irradiation-induced cell damage by scavenging ROS and attenuating the activation of the mitogen-activated protein kinases (Li et al., 2007).

Liver Cancer

Prostaglandin E2 (PGE2) has been shown to play an important role in tumor development and progression. PGE2 mediates its biological activity by binding any one of four prostanoid receptors (EP1 through EP4). Paeoniflorin, a monoterpene glycoside, significantly inhibited the proliferation of HepG2 and SMMC-7721 cells stimulated by butaprost at multiple time points (24, 48, and 72 hours). Paeoniflorin induced apoptosis in HepG2 and SMMC-7721 cells, which was quantified by annexin-V and propidium iodide staining. Our results indicate that the expression of the EP2 receptor and Bcl-2 was significantly increased, whereas that of Bax and cleaved caspase-3 was decreased in HepG2 and SMMC-7721 cells.

Paeoniflorin, which may be a promising agent in the treatment of liver cancer, induced apoptosis in hepatocellular carcinoma cells by down-regulating EP2 expression and also increased the Bax-to-Bcl-2 ratio, thus up-regulating the activation of caspase-3 (Hu et al., 2013).

Colorectal Cancer

Results showed that positive cells of Proliferating Cell Nuclear Antigen (PCNA) in paeoniflorin (PF) and docetaxel-treated group was decreased to 30% and 15% respectively, compared with control group of tumors. But apoptosis cells in docetaxel treated groups studied by TUNEL is increased to 40 ± 1.2% and 30 ± 1.5% respectively, compared with 24 ± 2.3% in negative control. Furthermore, the efficiency of tumor-bearing mice treated by PF was superior to docetaxel in vivo. Overall, PF may be an effective chemo-preventive agent against colorectal cancer HT29 (Wang et al., 2012).

Ameliorates Myelosuppression

The administration of paeoniflorin and albiflorin (CPA) extracted from Paeonia radix, significantly ameliorated myelosuppression in all cases. For the X-ray irradiated mice and the chemotherapy treated mice and rabbits, high dosages of CPA resulted in the recovery of, respectively, 94.4%, 95.3% and 97.7% of hemoglobin content; 67.7%, 92.0% and 94.3% of platelet numbers; 26.8%, 137.1% and 107.3% of white blood cell counts; as well as a reversal in the reduction of peripheral differential white blood cell counts.

There was also a recovery of 50.9%, 146.1% and 92.3%, respectively, in the animals' relative spleen weight. Additionally, a recovery of 35.7% and 87.2% respectively in the number of bone marrow nucleated cells was observed in the radio- and chemo -therapy-treated mice. Bone marrow white blood cell counts also resumed to normal levels (Xu et al., 2011).

MDR

Studies have shown that NF-κB activation may play an essential role in the development of chemotherapy resistance in carcinoma cells. Paeonißorin, a principal bioactive component of the root of Paeonia lactißora, has been reported to exhibit various pharmacological effects. In the present study, Fanh et al. (2012) reported for the first time that paeoniflorin at non-toxic concentrations may effectively modulate multi-drug resistance (MDR) of the human gastric cancer cell line SGC7901/vincristine (VCR) via the inhibition of NF-κB activation and, at least partly, by subsequently down-regulating its target genes MDR1, BCL-XL and BCL-2.

References

Fang S, Zhu W, Zhang Y, Shu Y, Liu P. (2012). Paeoniflorin modulates Multi-drug resistance of a human gastric cancer cell line via the inhibition of NF- κB activation. Mol Med Rep, 5(2):351-6. doi: 10.3892/mmr.2011.652.

Hu S, Sun W, Wei W, et al. (2013). Involvement of the prostaglandin E receptor EP2 in paeoniflorin-induced human hepatoma cell apoptosis. Anti-cancer Drugs, 24(2):140-9. doi: 10.1097/CAD.0b013e32835a4dac.

Li CR, Zhou Z, Zhu D, et al. (2007). Protective effect of paeoniflorin on irradiation-induced cell damage involved in modulation of reactive oxygen species and the mitogen-activated protein kinases. The International Journal of Biochemistry & Cell Biology, 39(2):426–438

Wang H, Zhou H, Wang CX, et al. (2012). Paeoniflorin inhibits growth of human colorectal carcinoma HT 29 cells in vitro and in vivo. Food Chem Toxicol, 50(5):1560-7. doi: 10.1016/j.fct.2012.01.035.

Xu W, Zhou L, Ma X, et al. (2011). Therapeutic effects of combination of paeoniflorin and albiflorin from Paeonia radix on radiation and chemotherapy-induced myelosuppression in mice and rabbits. Asian Pac J Cancer Prev, 12(8):2031-7.

Cancer: Prostate, breast, endometrial

Action: Anti-estrogenic effects, radio-protective effect, pneumonitis, cachexia-inhibiting

Prostate Cancer, Breast Cancer

Isoflavones have been investigated in detail for their role in the prevention and therapy of prostate cancer. This is primarily because of the overwhelming data connecting high dietary isoflavone intake with reduced risk of developing prostate cancer. A number of investigations have evaluated the mechanism(s) of anti-cancer action of isoflavones such as genistein, daidzein, biochanin A, equol, etc., in various prostate cancer models, both in vitro and in vivo.

Nuclear receptors are considered to be a central goal for maximizing treatment opportunities in breast cancer. Among natural ligands for estrogen receptors (ER and ERβ), which are members of the nuclear receptors super-family, are found isoflavones. These natural compounds have a similar structure to the main female hormone 17β-estradiol. A rich source of isoflavones is soy and its products. Three isoflavones of the aglycone form (genistein, daidzein, glycitein) are predominantly found in soybean and red clover. Other important isoflavones are biochanin A and formononetin (Bialešová et al., 2013).

Breast Cancer

Soy isoflavones do not function as an estrogen, but rather exhibit anti-estrogenic properties. However, their metabolism differs between humans and animals and therefore the outcomes of animal studies may not be applicable to humans. The majority of breast cancer cases are hormone-receptor-positive; therefore, soy isoflavones should be considered a potential anti-cancer therapeutic agent (Douglas et al., 2013).

Anti-cancer Effects

Use of soy isoflavone mixture has been advocated as an alternative, wherein daidzein can negate harmful effects of genistein. Recent research indicates the novel role of genistein and other isoflavones in the potentiation of radiation therapy, epigenetic regulation of key tumor suppressors and oncogenes, and the modulation of miRNAs, epithelial-to-mesenchymal transition, and cancer stem cells, which has renewed the interest of cancer researchers in this class of anti-cancer compounds (Ahmad et al. 2013).

Radiation-induced Pneumonitis, Radiation-induced Side-effects

Radiation-induced pneumonitis and fibrosis have restricted radiotherapy for lung cancer. In a preclinical lung tumor model, soy isoflavones showed the potential to enhance radiation damage in tumor nodules and simultaneously protect normal lung from radiation injury. Soy isoflavones given pre- and post-radiation protected the lungs against adverse effects of radiation including skin injury, hair loss, increased breathing rates, inflammation, pneumonitis and fibrosis, providing evidence for a radio-protective effect of soy (Hillman et al., 2013 a).

Radio-sensitizer

Combined soy and radiation caused a significantly stronger inhibition of tumor progression compared to each modality alone in contrast to large invasive tumor nodules seen in control mice. At the same time, soy reduced radiation injury in lung tissue by decreasing pneumonitis, fibrosis and protecting alveolar septa, bronchioles and vessels (Hillman et al., 2013 b).

Endometrial Cancer

Because of their anti-oxidant and anti-mutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have anti-estrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells. The intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins was measured and high consumption of selected proanthocyanidins may reduce endometrial cancer risk (Rossi et al., 2013).

Breast Cancer Protection

The evidence to date from observational epidemiologic studies, suggests that soy food intake, in the amount consumed in Asian populations (about 10 to 20 mg isoflavones per day), may be associated with a reduction of risk of breast cancer development as well as mortality and recurrence among women with breast cancer. The large number of clinical intervention studies on soy that have investigated intermediate biomarkers of breast cancer risk, including circulating estrogen levels, mammographic density, and breast tissue changes (cell proliferation), have not shown clear beneficial or deleterious effects (Wu et al., 2013).

Cachexia-Inhibiting

Isoflavones possess anti-proliferative effects of cachexia-inducing cells (MKN45cl85 and 85As2mLuc) cancer cell lines. Isoflavone treatment on the models induced tumor cytostasis, attenuation of cachexia, and prolonged survival whereas discontinuation of the treatment resulted in progressive tumor growth and weight loss (Yanagihara et al., 2013).

Methylation Effects

There is an inverse correlation between estrogenic marker complement (C)3 and genistein, which suggests an anti-estrogenic effect. Isoflavones induced dose-specific changes in RARβ2 and CCND2 gene methylation, which correlated with genistein levels. Research by Qin & Zhu (2009) provides novel insights into estrogenic and methylation effects of dietary isoflavones.

References

Ahmad A, Biersack B, Li Y, et al. (2013). Perspectives on the Role of Isoflavones in Prostate Cancer. AAPS J, 15(4):991-1000.

Bialešová L, Brtko J, Lenko V, Macejov‡ D. (2013). Nuclear receptors – target molecules for isoflavones in cancer chemoprevention. Gen Physiol Biophys.

Douglas CC, Johnson SA, Arjmandi BH. (2013). Soy and its isoflavones: the truth behind the science in breast cancer. Anti-cancer Agents Med Chem, 13(8):1178-87.

Hillman GG, Singh-Gupta V, Lonardo F, et al [a]. (2013). Radioprotection of Lung Tissue by Soy Isoflavones. J Thorac Oncol.

Hillman GG, Singh-Gupta V, Hoogstra DJ, et al [b]. (2013). Differential effect of soy isoflavones in enhancing high intensity radiotherapy and protecting lung tissue in a preclinical model of lung carcinoma. Radiother Oncol. doi: 10.1016/j.radonc.2013.08.015.

Rossi M, Edefonti V, Parpinel M, et al. (2013). Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case-control study in Italy. Br J Cancer, 109(7):1914-1920. doi: 10.1038/bjc.2013.447.

Wu AH, Lee E, Vigen C. (2013). Soy isoflavones and breast cancer. Am Soc Clin Oncol Educ Book, 2013:102-6. doi: E10.1200/EdBook_AM.2013.33.102.

Yanagihara K, Takigahira M, Mihara K, et al. (2013). Inhibitory effects of isoflavones on tumor growth and cachexia in newly established cachectic mouse models carrying human stomach cancers. Nutr Cancer, 65(4):578-89. doi: 10.1080/01635581.2013.776089.