Effects of rhubarb extract on radiation induced lung toxicity via decreasing transforming growth factor-beta-1 and interleukin-6 in lung cancer patients treated with radiotherapy

Department of Radiation Oncology, Qilu Hospital, Medical school, Shandong University, Jinan, Shandong Province 250012, China.
Lung Cancer (Impact Factor: 3.96). 02/2008; 59(2):219-26. DOI: 10.1016/j.lungcan.2007.08.007
Source: PubMed


Radiation induced lung toxicity (RILT) is the main adverse effect in the radiation therapy of lung cancer. However, the optimal management of RILT has not been defined. In this paper, we investigated the effects of rhubarb extract on RILT, pulmonary function (PF), transforming growth factor-beta-1 (TGF-beta1), and interleukin-6 (IL-6) in lung cancer patients treated with radiotherapy.
We conducted a randomized, double-blind, placebo-controlled trial. Eighty consecutive patients were randomly enrolled into two groups: trial group and control group. The trial group received three-dimensional conformal radiation therapy (3D-CRT) plus rhubarb (at a dose of 20 mg kg(-1) once a day) for 6 weeks. The control group received 3D-CRT plus a placebo containing starch for 6 weeks. Plasma TGF-beta1 and serum IL-6 were measured in all patients before, every 2 weeks during, and at 6 weeks after the completion of the treatment. RILT and PF were evaluated at 6 weeks and 6 months after the end of the treatment, respectively. The differences of TGF-beta1, IL-6, RILT, and PF between the two groups were analysed.
The incidence of RILT in the trial group was significantly lower than that in the control group at 6 weeks and 6 months after treatment (32.4% versus 56.7% at week 6, and 27.0% versus 52.8% at month 6, both P<0.05). The plasma TGF-beta1 levels in the trial group were significantly lower than that in the control group during and after the treatment (P<0.05 or 0.01, respectively). The serum IL-6 levels in the trial group were significantly lower than that in the control group during the treatment (all P<0.01). The forced vital capacity (FVC), forced expiratory volume at 1s (FEV1) at 6 weeks and the diffusion capacity for carbon monoxide (DLCO) at 6 months in the trial group were significantly improved compared to the control group (P<0.05 or 0.01, respectively).
The rhubarb extract significantly attenuated RILT and improved PF, probably by decreasing the level of TGF-beta1 and IL-6. These results may be of value for the prophylaxis of RILT, but the exact mechanisms underlying these prophylactic effects remain to be further explored.

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    • "Total rhubarb anthraquinones (TRAs), active therapeutic components that have been isolated from rhubarb roots (Rheum palmatum L. or Rheum tanguticum Maxim.), have been widely used in traditional Chinese medicine for centuries. Recent studies have demonstrated many pharmacological properties of rhubarb extracts , such as purgative (Peigen et al., 1984; Xu et al., 2011), anti-inflammatory (Cuellar et al., 2001; Gao et al., 2011), liver protection (Zhao et al., 2009), and attenuation of radiation-induced lung toxicity (Yu et al., 2008). Despite its therapeutic value, potential side effects of rhubarb extracts have been shown in experimental studies. "
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    ABSTRACT: Aloe-emodin (AE; 1,8-dihydroxy-3-hydroxymethyl-9,10-anthracenedione) is one of the primary active compounds in total rhubarb anthraquinones (TRAs), which induce nephrotoxicity in rats. However, it is still not known whether AE has a similar effect on human kidney cells. In this study, 3-(4,5,-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that AE decreases the viability of HK-2 cells (a human proximal tubular epithelial cell line) in a dose- and time-dependent manner. AE induced G2/M arrest of cell cycle in HK-2 cells, which was detected with propidium iodide (PI) staining. This apoptosis was further investigated by Hoechst staining, transmission electron microscopy (TEM), DNA fragmentation, and Annexin V/PI staining. Apoptosis of the cells was associated with caspase 3 activation, which was detected by Western blot analysis and a caspase activity assay. In addition, changes in the endoplasmic reticulum (ER) ultrastructure as observed by TEM showed the effects of AE on ER. Treatment with AE also resulted in an increase in eukaryotic initiation factor-2α (eIF-2α) phosphorylation, X-box binding protein 1 (XBP1) mRNA splicing, c-Jun N-terminal kinase (JNK) phosphorylation, glucose-regulated protein (GRP) 78 and CAAT/enhancer-binding protein-homologous protein (CHOP) accumulation. These results suggest that AE induces ER stress in HK-2 cells, which is involved in AE-induced apoptosis. In conclusion, AE induces apoptosis in HK-2 cells, and the ER stress is involved in AE-induced apoptosis in vitro. The implications of the toxic effects of AE for clinical use are unclear and these findings should be taken into account in the risk assessment for human exposure.
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    • "Rheum undulatum L. (RL), a well-known traditional Chinese medicine, has been widely used for thousands of years in China for the treatment of many diseases (He et al, 2009). In particular, the root of the species is widely used as a purgative and anti-inflammatory agent in East Asia (Chang et al, 1996; Kuo et al, 2001; Yu et al, 2008). It has been also reported that RL is used traditionally in Korea for the treatment of dental disease (Kim et al, 2010). "
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    • "The rhubarb extract from Rheum officinale significantly attenuated radiation induced lung toxicity and improved pulmonary function (Yu et al., 2008). Polygonum multiflorum water extract exerts a preventive effect against cognitive deficits in Alzheimer's disease (Um et al., 2006). "
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