Poly[3-(3, 4-dihydroxyphenyl) glyceric acid] from Comfrey exerts anti-cancer efficacy against human prostate cancer via targeting androgen receptor, cell cycle arrest and apoptosis

The major obstacles in human prostate cancer (PCA) treatment are the development of resistance to androgen ablation therapy leading to hormone-refractory state and the toxicity associated with chemotherapeutic drugs. Thus, the identification of additional non-toxic agents that are effective against both androgen-dependent and androgen-independent PCA is needed. In the present study, we investigated the efficacy of a novel phytochemical poly[3-(3, 4-dihydroxyphenyl)glyceric acid] (p-DGA) from Caucasian species of comfrey (Symphytum caucasicum) and its synthetic derivative syn-2, 3-dihydroxy-3-(3, 4-dihydroxyphenyl) propionic acid (m-DGA) against PCA LNCaP and 22Rv1 cells. We found that both p-DGA and m-DGA suppressed the growth and induced death in PCA cells, with comparatively lesser cytotoxicity towards non-neoplastic human prostate epithelial cells. Furthermore, we also found that both p-DGA and m-DGA caused G(1) arrest in PCA cells through modulating the expression of cell cycle regulators, especially an increase in CDKIs (p21 and p27). In addition, p-DGA and m-DGA induced apoptotic death by activating caspases, and also strongly decreased AR and PSA expression. Consistent with in vitro results, our in vivo study showed that p-DGA feeding strongly inhibited 22Rv1 tumors growth by 76% and 88% at 2.5 and 5mg/kg body weight doses, respectively, without any toxicity, together with a strong decrease in PSA level in plasma; and a decrease in PCNA, AR and PSA expression but increase in p21/p27 expression and apoptosis in tumor tissues from p-DGA-fed mice. Overall, present study identifies p-DGA as a potent agent against PCA without any toxicity, and supports its clinical application.     

Generation of reactive oxygen species by grape seed extract causes irreparable DNA damage leading to G2/M arrest and apoptosis selectively in head and neck squamous cell carcinoma cells

Head and neck squamous cell carcinoma (HNSCC) accounts for 6% of all malignancies in USA and unfortunately the recurrence of secondary primary tumors and resistance against conventional treatments decrease the overall 5 year survival rate in HNSCC patients. Thus, additional approaches are needed to control HNSCC. Here, for the first time, employing human HNSCC Detroit 562 and FaDu cells as well as normal human epidermal keratinocytes, we investigate grape seed extract (GSE) efficacy and associated mechanism in both cell culture and nude mice xenografts. GSE selectively inhibited the growth and caused cell cycle arrest and apoptotic death in both Detroit 562 and FaDu cells by activating DNA damage checkpoint cascade, including ataxia telangiectasia mutated/ataxia telangiectasia-Rad3-related-checkpoint kinase 1/2-cell division cycle 25C as well as caspases 8, 9 and 3. Consistent with these results, GSE treatment resulted in a strong DNA damage and a decrease in the levels of DNA repair molecules breast cancer gene 1 and Rad51 and DNA repair foci. GSE-caused accumulation of intracellular reactive oxygen species was identified as a major mechanism of its effect for growth inhibition, DNA damage and apoptosis, which was remarkably reversed by antioxidant N-acetylcysteine. GSE feeding to nude mice decreased Detroit 562 and FaDu xenograft tumor growth by 67 and 65% (P < 0.001), respectively. In immunohistochemical analysis, xenografts from GSE-fed groups showed decreased proliferation but increased DNA damage and apoptosis. Together, these findings show that GSE targets both DNA damage and repair and provide mechanistic insights for its efficacy selectively against HNSCC both in cell culture and mouse xenograft, supporting its translational potential against HNSCC.     

Hepatocellular carcinoma review:Current treatment,and evidence-based medicine

Hepatocellular carcinoma(HCC)is the fifth most common tumor worldwide.Multiple treatment options are available for HCC including curative resection,liver transplantation,radiofrequency ablation,trans-arterial chemoembolization,radioembolization and systemic targeted agent like sorafenib.The treatment of HCC depends on the tumor stage,patient performance status and liver function reserve and requires a multidisciplinary approach.In the past few years with significant advances in surgical treatments and locoregional therapies,the short-term survival of HCC has improved but the recurrent disease remains a big problem.The pathogenesis of HCC is a multistep and complex process,wherein angiogenesis plays an important role.For patients with advanced disease,sorafenib is the only approved therapy,but novel systemic molecular targeted agents and their combinations are emerging.This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature.     

Degradation Dynamics of Emamectin Benzoate on Cabbage Under Subtropical Conditions of Punjab, India

Emamectin benzoate (Proclaim 5 SG) was applied to cabbage at 8.5 and 17 g a.i. ha^?1, during the head initiation stage. A high performance liquid chromatography (HPLC) analytical method, for the determination of emamectin benzoate in cabbage, was developed. Average recoveries of emamectin benzoate ranged from 92 % to 96 % at different fortification levels (0.05, 0.25 and 0.50 mg kg^?1). The initial deposits, 0.11 and 0.21 mg kg^?1 of emamectin benzoate at 8.5 and 17 g a.i. ha^?1, dissipated below the determination limit of 0.05 mg kg^?1 in 3 and 5 days, respectively.     

Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model

Herein, using transgenic adenocarcinoma of the mouse prostate (TRAMP) model, we assessed the "stage-specific" efficacy of silibinin feeding against prostate cancer (PCa) initiation, progression, angiogenesis and metastasis, and associated molecular events involved in silibinin effects during these stages. Male TRAMP mice starting at ages 4, 12, 20, and 30 weeks of age were fed with control or 1% silibinin-supplemented diet for 8 to 15 weeks in stage-specific manners. At the end of studies, silibinin-fed mice showed less severe prostatic lesions compared with positive controls. During early stages of prostate tumor development, silibinin mediated its efficacy mostly via antiproliferative mechanisms. Feeding of silibinin to animals burdened with higher stages of prostate tumor significantly decreased tumor grade via antiproliferative effect, and inhibition of angiogenesis as evidenced by decreased expressions of platelet endothelial cell adhesion molecule-1/CD-31, vascular endothelial growth factor, and associated receptor, vascular endothelial growth factor R2, hypoxia-inducible factor-1alpha, and inducible nitric oxide synthase. Metastasis to distant organs was decreased in silibinin-fed mice, which was associated with a decreased expression of matrix metalloproteinases, mesenchymal markers snail-1, and fibronectin in the prostatic tissue and retention of epithelial characteristics. Together, these findings are both novel and highly significant in establishing the dual efficacy of silibinin where it inhibits progression of primary prostatic tumor and also shows protective efficacy against angiogenesis and late stage metastasis. These effects of silibinin could have potential implications to improve the morbidity and survival in PCa patients.