Potential role of natural compounds as anti-angiogenic agents in cancer.

Shanmugam MK, Warrier S, Kumar AP, Sethi G, Arfuso F.

Curr Vasc Pharmacol. 2017 Jul 12. doi: 10.2174/1570161115666170713094319. [Epub ahead of print]

Abstract

BACKGROUND:

Neovascularization, also known as angiogenesis, is the process of capillary sprouting from pre-existing blood vessels. This physiological process is a hallmark event in normal embryonic development as blood vessels generally supply both oxygen and nutrients to the cells of the body. Any disruption in this process can lead to the development of various chronic diseases, including cancer. In cancer, aberrant angiogenesis plays a prominent role in maintaining sustained tumor growth to malignant phenotypes and promoting metastasis. The leakiness in the tumor microvasculature is attributed to the tumor cells migrating to distal site organs and forming colonies.

METHODS:

In this article, we briefly review the various mediators involved in the angiogenic process and the anti-angiogenic potential of selected natural compounds against various malignancies.

RESULTS:

Several growth factors and their receptors such as vascular endothelial growth factor and receptor (VEGF/VEGFR), basic fibroblast growth factor and receptor (bFGF/FGFR), angiopoietins, and hypoxia inducible factors facilitate the development of angiogenesis and are attractive anti-cancer targets. Natural products represent a rich diversity of compounds for drug discovery and are currently being actively exploited to target tumor angiogenesis.

CONCLUSION:

Agents such as curcumin, artemisinin and its semi-synthetic derivatives, EGCG, pentacyclic triterpenoids, resveratrol, emodin, celastrol, thymoquinone and tocotrienols all have shown prominent anti-angiogenic effects in the preclinical models of tumor angiogenesis. Several semi-synthetic derivatives and novel nano-formulations of natural compounds have also exhibited excellent anti-angiogenic activity by increasing bioavailability and delivering the drugs to the sites of tumor angiogenesis.

Jung H, Chen CO, Blumberg JB, Kwak HK.

Eur J Nutr. 2017 Jul 10. doi: 10.1007/s00394-017-1480-5. [Epub ahead of print]

Abstract

PURPOSE:

Almonds have shown to beneficially modify some cardiovascular risk factors in clinical trials conducted in diverse ethnic populations but this relationship has never been tested in Koreans. Thus, we tested the impact of almonds consumed as a snack within the context of a typical Korean diet on cardiovascular risk factors.

METHODS:

We conducted a randomized, crossover trial in a free-living setting with a 2-week run-in period, two 4-week intervention phases, and a 2-week washout period between interventions. Eighty four overweight/obese participants (11 M/73 F; 52.4 ± 0.6 year; 25.4 ± 0.22 kg/m²) consumed either 56 g of almonds or isocaloric cookies daily for 4 weeks.

RESULTS:

Mean % daily energy intake at baseline was 64.8, 21.3, and 14.9% from carbohydrate, fat, and protein, respectively. The addition of 56 g of almonds daily decreased carbohydrate energy to 55.0%, increased fat to 32.0%, and maintained protein at 14.7%. Consuming the almonds increased intake of MUFA by 192.3%, PUFA by 84.5%, vitamin E by 102.7%, and dietary fiber by 11.8% and decreased % energy from carbohydrate by 14.1%. Total caloric intake was increased by the almonds, but body weight, waist circumference, and body composition were not affected. Almonds in overweight and obese Korean adults decreased TC, LDL-C, and non-HDL-C by 5.5, 4.6, and 6.4%, respectively, compared to the cookie control (P ≤ 0.05). Almonds increased plasma α-tocopherol by 8.5% (P ≤ 0.05) from the baseline and tended to increase its value as compared to cookies (P = 0.055). Neither the almonds nor cookies altered plasma protein carbonyls, MDA or oxLDL. Of serum inflammatory markers, IL-10 was decreased by almond intake (P ≤ 0.05), and ICAM-1, IL-1β, and IL-6 tended to be lower with almonds, compared to the cookies.

CONCLUSIONS:

Almonds at 56 g/day consumed as a snack favorably modified the Korean diet by increasing MUFA, PUFA, vitamin E, and dietary fiber intake and decreasing % energy intake from carbohydrate. Almonds also enhanced plasma α-tocopherol status and serum TC and LDL-C in overweight and obese Koreans. Thus, including almonds in typical Korean diets as a snack can help healthy overweight/obese individuals improve nutritional status and reduce their risk for CVD.

Selim A, Khalaf MM, Gad AM, Abd El-Raouf OM.

J Biochem Mol Toxicol. 2017 Jul 6. doi: 10.1002/jbt.21957. [Epub ahead of print]

Abstract

Amikacin (AMIK) is an aminoglycoside antibiotic that possesses considerable nephrotoxic adverse effects. This study examined the protective effects of vitamin E (VIT. E) or rosuvastatin (ROSU) against AMIK-induced nephrotoxicity. For this purpose, eight groups of rats were used. Two control groups received saline and vehicle, AMIK group (1.2 g/kg, i.p.), VIT. E group (1000 mg/kg; p.o.), ROSU group (10 mg/kg; p.o.), AMIK + VIT. E group, AMIK + ROSU group, and combination group. The results showed that AMIK significantly increased serum levels of urea and creatinine. Meanwhile, serum levels of total protein and albumin were decreased. The kidney content of malondialdehyde was increased, whereas glutathione content and catalase activity were decreased. Tumor necrosis factor-α and nuclear transcriptional factor levels were increased. Conversely, administration of VIT. E and/or ROSU with AMIK ameliorated such damage and reduced DNA fragmentation, apoptosis, and necrosis. In conclusion, co-administration of VIT. E, ROSU, or their combination alleviated AMIK-induced nephrotoxicity.

Wong SK, Chin KY, Suhaimi FH, Ahmad F, Ima-Nirwana S.

Front Pharmacol. 2017 Jul 5;8:444. doi: 10.3389/fphar.2017.00444. eCollection 2017.

Abstract

A constellation of medical conditions inclusive of central obesity, hyperglycemia, hypertension, and dyslipidemia is known as metabolic syndrome (MetS). The safest option in curtailing the progression of MetS is through maintaining a healthy lifestyle, which by itself, is a long-term commitment entailing much determination. A combination of pharmacological and non-pharmacological approach, as well as lifestyle modification is a more holistic alternative in the management of MetS. Vitamin E has been revealed to possess anti-oxidative, anti-inflammatory, anti-obesity, anti-hyperglycemic, anti-hypertensive and anti-hypercholesterolemic properties. The pathways regulated by vitamin E are critical in the development of MetS and its components. Therefore, we postulate that vitamin E may exert some health benefits on MetS patients. This review intends to summarize the evidence in animal and human studies on the effects of vitamin E and articulate the contrasting potential of tocopherol (TF) and tocotrienol (T3) in preventing the medical conditions associated with MetS. As a conclusion, this review suggests that vitamin E may be a promising agent for attenuating MetS.

Rezaie Agdam H, Razi M, Amniattalab A, Malekinejad H, Molavi M.

Cell J. 2017 Jul-Sep;19(2):292-305. doi: 10.22074/cellj.2016.490. Epub 2017 Feb 22.

Abstract

OBJECTIVE:

Atrazine (ATZ) as a widely used herbicide is considered as a potent endocrine disrupter which adversely affects reproductive systems in both genders. This study aimed to assess the effects of testosterone (T)- and vitamin E (VitE)- alone and their coadministration on testicular function and sperm parameters after exposure to ATZ in rats.

MATERIALS AND METHODS:

In this experimental study, the rats (n=30) are assigned into the following 5 groups: control-sham group (n=6) receiving corn oil, ATZ group (n=6) receiving 200 mg/kg ATZ alone, ATZ+VitE group (n=6) receiving 150 mg/kg ATZ+VitE, ATZ+T group (n=6) receiving 400 µg/kg ATZ+T, and ATZ+VitE+T group (n=6) receiving ATZ+VitE+T for 48 consecutive days. Total antioxidant capacity (TAC), total thiol molecules (TTM), and malondialdehyde (MDA) were analyzed. Serum levels of T, luteinizing hormone (LH), and inhibin-B (IN-B) were also determined. Histological examination and sperm analysis were performed. The data were analyzed using Graph-Pad Prism software version 2.01.

RESULTS:

Co-administration of VitE and T significantly (P<0.05) increased ATZ-decreased TAC and TTM levels and reduced ATZ-increased MDA content. T and VitE significantly (P<0.05) increased serum levels of ATZ-reduced T (1.94 ± 0.96), IN-B (122.10 ± 24.33) and LH (0.40 ± 0.10). The T+VitE animals showed a reduction in apoptotic cells and an increase in Leydig cells steroidogenesis. Co-administration of T and VitE significantly (P<0.05) reduced the ATZ-induced DNA disintegrity and chromatin de-condensation. VitE and T protected germinal cells RNA and protein contents against ATZ-induced damages.

CONCLUSION:

T and VitE in simultaneous form of administration were able to normalize the ATZ-induced derangements through promoting antioxidant capacity and endocrine function.

Saoudi M, Ncir M, Ben Ali M, Grati M, Jamoussi K, Allouche N, El Feki A.

Gen Physiol Biophys. 2017 Jul;36(3):331-342. doi: 10.4149/gpb_2016057.

Abstract

In the present study, we evaluated the antioxidant potential of Artemisia campestris essential oil (ACEO) and the possible protective effects against deltamethrin induced hepatic toxic effects. The ACEO showed radical scavenging activity with IC50 = 47.66 ± 2.51 µg/ml, ferric reducing antioxidant power (FRAP) potential (EC50 = 5.36 ± 0.77 µg/ml), superoxide scavenging activity (IC50 = 0.175 ± 0.007 µg/ml) and ˙OH scavenging activity (IC50 = 0.034 ± 0.007 µg/ml). The obtained results of phenolic profile demonstrated that phenolic compounds are the major contributor to the antioxidant activity of ACEO. GC-MS analysis revealed the presence of 61 components in which monoterpene hydrocarbons constitute the major fraction (38.85%). In in vivo study, deltamethrin exposure caused an increase of serum AST, ALT and ALP activities, hepatic malondialdehyde (MDA) (measured as TBARS) and conjugated dienes markers of lipid peroxidation (LPO), while antioxidant enzyme activities (SOD, CAT and GPx) decreased significantly. Furthermore, it induces DNA damage as indicated by DNA fragmentation accompanied with severe histological changes in the liver tissues. The treatment with vitamin E or ACEO significantly improved the hepatic toxicity induced by deltamethrin. It can be concluded that vitamin E and ACEO are able to improve the hepatic oxidative damage induced by deltamethrin. Therefore, ACEO is an important product in reducing the toxic effects of deltamethrin.

Dong Y, Liu Y, Shu Y, Chen X, Hu J, Zheng R, Ma D, Yang C, Guan X.

Medicine (Baltimore). 2017 Jul;96(27):e7470. doi: 10.1097/MD.0000000000007470.

Abstract

BACKGROUND:

The effect of low serum vitamin E levels on the risk of colorectal cancer (CRC) remains inconclusive. This meta-analysis aims to synthesize relevant studies to evaluate the association between serum vitamin E and the risk of CRC based on case-control studies.

METHODS:

Potentially relevant studies were selected by searching PubMed, EMBASE, and China National Knowledge Infrastructure databases according to inclusion and exclusion criteria. The association between serum vitamin E levels and CRC was estimated by the weighted mean difference (WMD) and 95% confidence interval (CI) using a random-effects model. Heterogeneity was evaluated using Q test and I statistic. Subgroup analysis was conducted to explore sources of heterogeneity. Sensitivity analysis was performed to reveal stability and reliability.

RESULTS:

A total of 10 papers with 11 studies, including 6431 subjects with 520 CRC patients and 5981 controls, were included in this present meta-analysis. The results indicated that compared with healthy controls, patients with CRC showed lower concentrations of serum vitamin E (WMD = -2.994 μmol/L, 95% CI = -4.395 to -1.593). Ethnicity subgroup analysis indicated that the serum vitamin E levels were lower in European (WMD = -1.82 μmol/L, 95% CI = -3.00 to -0.65), but not in Asian. Control-source subgroup analysis revealed that a significant association was observed in subgroup with hospital-based controls (WMD = -3.43 μmol/L, 95% CI = -6.27 to -0.59), but not in those with population-based controls. Sensitivity analysis suggested no significant difference in the pooled estimates, indicating stable results.

CONCLUSIONS:

CRC is associated with a lower concentration of serum vitamin E. However, necessary prospective cohort studies should be conducted to assess the effect of serum vitamin E on the risk of CRC in the future.

Butt H, Mehmood A, Ali M, Tasneem S, Anjum MS, Tarar MN, Khan SN, Riazuddin S.

Life Sci. 2017 Jul 3. pii: S0024-3205(17)30322-3. doi: 10.1016/j.lfs.2017.07.002. [Epub ahead of print]

Abstract

AIMS:

Oxidative microenvironment of burnt skin restricts the outcome of cell based therapies of thermal skin injuries. The aim of this study was to precondition human dermal fibroblasts with an antioxidant such as vitamin E to improve their survival and therapeutic abilities in heat induced oxidative in vitro environment.

MAIN METHODS:

Fibroblasts were treated with 100μM vitamin E for 24h at 37°C followed by heat shock for 10min at 51°C in fresh serum free medium.

KEY FINDINGS:

Preconditioning with vitamin E reduced cell injury as demonstrated by decreased expression of annexin-V, cytochrome p450 (CYP450) mediated oxidative reactions, senescence and release of lactate dehydrogenase (LDH) accomplished by down-regulated expression of pro-apoptotic BAX gene. Vitamin E preconditioned cells exhibited remarkable improvement in cell viability, release of paracrine factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), stromal derived factor-1alpha (SDF-1α) and also showed significantly up-regulated levels of PCNA, VEGF, BCL-XL, FGF7, FGF23, FLNβ and Col7α genes presumably through activation of phosphatidylinositol 3-kinase (PI3-K)/Akt pathway.

SIGNIFICANCE:

The results suggest that pretreatment of fibroblasts with vitamin E prior to transplantation in burnt skin speeds up the wound healing process by improving the antioxidant scavenging responses in oxidative environment of transplanted burn wounds.

Xun C, Mamat M, Guo H, Mamati P, Sheng J, Zhang J, Xu T, Liang W, Cao R, Sheng W.

Exp Ther Med. 2017 Jul;14(1):431-438. doi: 10.3892/etm.2017.4505. Epub 2017 May 23.

Abstract

In recent years accumulating evidence has indicated that tocotrienol exhibits an oxidation resistance function, decreased cholesterol function, inhibits cancer function and has unique physiological functions, including anti-inflammatory, anti-apoptotic and anti-oxidative properties. The present study investigated the effect of tocotrienols on spinal cord injury (SCI) by evaluating oxidative stress, inflammation and inducible nitric oxide synthase (iNOS) in rats. A rat model of SCI was induced by operation. SCI rats were treated with 120 mg/kg/day tocotrienol once a day for eight consecutive weeks. Functional recovery following SCI was measured by using the Basso Beattie Bresnahan (BBB) locomotor rating scale. Then the volume of spinal cord contusions was measured following induction of SCI in the rats. In SCI rats, serum malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, nuclear factor-κB p65 unit, tumor necrosis factor-α, interleukin (IL)-1β and IL-6 levels were analyzed using respective commercial immunoassay kits. Firstly, iNOS, transforming growth factor (TGF)-β, collagen type IV and fibronectin protein expression levels, in addition to iNOS activity and plasma nitric oxide (NO) production in SCI rats was analyzed using western blot analysis, commercial kits and Griess reagent, respectively. Tocotrienol treatment elevated BBB scores and contused volume in the SCI rats. Tocotrienol protected against SCI with reduced oxidative stress and inflammation, and inhibited iNOS protein expression iNOS activity and plasma NO production in rats. In addition, treatment with tocotrienols suppressed TGF-β, collagen type IV and fibronectin protein expression levels in SCI rats. These results suggest that tocotrienols protect SCI, and suppress oxidative stress, inflammation and iNOS in this model of SCI through TGF-β, collagen type IV and fibronectin signaling pathways.

Abubakar IB, Lim KH, Kam TS, Loh HS.

Phytomedicine. 2017 Jul 1;30:74-84. doi: 10.1016/j.phymed.2017.03.004. Epub 2017 Mar 10.

Abstract

BACKGROUND:

γ-Tocotrienol, a vitamin E isomer possesses pronounced in vitro anticancer activities. However, the in vivo potency has been limited by hardly achievable therapeutic levels owing to inefficient high-dose oral delivery which leads to subsequent metabolic degradation. Jerantinine A, an Aspidosperma alkaloid, originally isolated from Tabernaemontana corymbosa, has proved to possess interesting anticancer activities. However, jerantinine A also induces toxicity to non-cancerous cells.

PURPOSE:

We adopted a combinatorial approach with the joint application of γ-tocotrienol and jerantinine A at lower concentrations in order to minimize toxicity towards non-cancerous cells while improving the potency on brain cancer cells.

METHODS:

The antiproliferative potency of individual γ-tocotrienol and jerantinine A as well as combined in low-concentration was firstly evaluated on U87MG cancer and MRC5 normal cells. Morphological changes, DNA damage patterns, cell cycle arrests and the effects of individual and combined low-concentration compounds on microtubules were then investigated. Finally, the potential roles of caspase enzymes and apoptosis-related proteins in mediating the apoptotic mechanisms were investigated using apoptosis antibody array, ELISA and Western blotting analysis.

RESULTS:

Combinatorial study between γ-tocotrienol at a concentration range (0-24µg/ml) and fixed IC₂₀ concentration of jerantinine A (0.16µg/ml) induced a potent antiproliferative effect on U87MG cells and led to a reduction on the new half maximal inhibitory concentration of γ-tocotrienol (i.e._tIC₅₀=1.29µg/ml) as compared to that of individual γ-tocotrienol (i.e. IC₅₀=3.17µg/ml). A reduction on undesirable toxicity to MRC5 normal cells was also observed. G0/G1 cell cycle arrest was evident on U87MG cells receiving IC₅₀ of individual γ-tocotrienol and combined low-concentration compounds (1.29µg/ml γ-tocotrienol + 0.16µg/ml jerantinine A), whereas, a profound G2/M arrest was evident on cells treated with IC₅₀ of individual jerantinine A. Additionally, individual jerantinine A and combined compounds (except individual γ-tocotrienol) caused a disruption of microtubule networks triggering Fas- and p53-induced apoptosis mediated via the death receptor and mitochondrial pathways.

CONCLUSIONS:

These findings demonstrated that the combined use of lower concentrations of γ-tocotrienol and jerantinine A induced potent cytotoxic effects on U87MG cancer cells resulting in a reduction on the required individual concentrations and thereby minimizing toxicity of jerantinine A towards non-cancerous MRC5 cells as well as probably overcoming the high-dose limiting application of γ-tocotrienol. The multi-targeted mechanisms of action of the combination approach have shown a therapeutic potential against brain cancer in vitro and therefore, further in vivo investigations using a suitable animal model should be the way forward.