Int J Mol Sci. 2017 Jan 4;18(1). pii: E72. doi: 10.3390/ijms18010072.

Miao Z1, Yu F2, Ren Y3, Yang J4.

Abstract

PMID: 28054986   PMCID: PMC5297707

Turk Neurosurg. 2017 Jan 19. doi: 10.5137/1019-5149.JTN.19111-16.1. [Epub ahead of print]

Göktürk D1, Kelebek H, Ceylan S, Yilmaz DM.

Abstract

PMID: 28191621

Du J1, Cieslak JA 3rd2, Welsh JL1, Sibenaller ZA2, Allen BG3, Wagner BA2, Kalen AL2, Doskey CM2, Strother RK2,Button AM4, Mott SL4, Smith B4, Tsai S5, Mezhir J3, Goswami PC6, Spitz DR6, Buettner GR6, Cullen JJ7.

Abstract

PMID: 26081808 PMCID: PMC4537815

Breast Cancer

Sci Pharm. 2017 Jul 3;85(3). pii: E27. doi: 10.3390/scipharm85030027.

Regressions of Breast Carcinoma Syngraft Following Treatment with Piperine in Combination with Thymoquinone.

Talib WH1.
Author information
Abstract
Thymoquinone (TQ) and piperine, the active ingredients in cumin (Nigella sativa) and black pepper (Piper longum), respectively, exhibit various bioactivities including anticancer effects. The aim of the present study is to investigate the antineoplastic activity of a combination of TQ and piperine against breast cancer implanted in mice. The antiproliferative effects of TQ, piperine, and a combination of both agents were tested against mouse epithelial breast cancer cell line (EMT6/P) using MTT assay. The isobolographic method was used to calculate the combination index (CI). Degree of angiogenesis inhibition was detected by measuring vascular endothelial growth factor (VEGF) levels in tissue culture for all treatments. EMT6/P cells were inoculated in Balb/C mice and the antitumor effect of TQ, piperine, and their combination was assessed. Changes in tumor size were calculated for all treatments. Tumor histology was examined using the hematoxylin/eosin staining protocol. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) colorimetric assay and caspase-3 activity assays were used to detect apoptosis. Serum levels of interferon (INF)-γ, interleukin (IL)-4, IL-2, and IL-10 were measured using ELISA and treatment toxicity was evaluated by measuring serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and creatinine. A clear synergistic antiproliferative interaction between TQ and piperine was observed with CI value of 0.788. The combination therapy resulted in significant reduction in tumor size with percentage cure of 60% and percentage death of 0%. High degrees of apoptosis and geographical necrosis were induced in tumors treated with the combination therapy. Combination therapy caused significant decrease in VEGF expression and increased serum INF-γ levels. Normal serum levels of AST, ALT, and creatinine were observed in tumor-bearing mice treated with the combination therapy. The combination of TQ and piperine acts synergistically to target breast cancer in vitro and in vivo. This novel combination exerts its effect by angiogenesis inhibition, apoptosis induction, and shifting the immune response toward T helper1 response. This combination therapy deserves further investigation (including measurement of hypoxia-inducible factor (HIF)1α to be used in clinical studies.
KEYWORDS:
Nigella sativa; anticancer; breast cancer; combination therapy; natural products
PMID: 28671634

 

Curr Drug Targets. 2017 Jun 11. doi: 10.2174/1389450118666170612095959. [Epub ahead of print]
Insights into the targeting potential of thymoquinone for therapeutic intervention against triple-negative breast cancer.

Barkat MA1, Abul H2, Ahmad J3, Khan MA4, Beg S5, Ahmad FJ6.
Abstract
BACKGROUND:
Thymoquinone (TQ) is a bioactive phytoconstituent obtained from Nigella sativa (black seeds). It has promising potential in cancer prevention.
OBJECTIVE:
Previous studies have shown that TQ can modulate signaling pathways responsible for cancer progression, thus enhances the efficacy and improve safety profile of clinically used anticancer drugs.
METHOD:
TQ acts on cell cycle and inhibits progression from G1 to S phase by targeting various proteins (cyclin D1, cyclin E, and p27). It also exhibits histone deacetylase (HDAC) inhibitory effects, targets p21 and Maspin, and induces pro-apoptotic gene, Bax and downregulates anti-apoptotic gene Bcl-2. Breast cancer (BC) is reported as one of the most common malignancies in women.
RESULTS:
Despite the research and advancement, it remains one of the most common causes of cancer related deaths among women. Recent advancements in molecular screening of BC led to identification of clinically challenging condition of triple negative breast cancer (TNBC). TNBC is characterized by absence of targetable receptors viz. estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expressions. It is also characterized by reduced or absence of phosphatase and tensin homolog (PTEN) expression, a tumor suppressor gene having diverse functions including regulation of apoptosis, cell cycle, and metastasis.
CONCLUSION:
Since TQ has been reported to up-regulate several growth factors such as vascular endothelial growth factor (VEGF), EGF and PTEN expression, the present review article discusses the targeting potential of TQ for therapeutic intervention against such types of breast cancer.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

KEYWORDS:
HDAC; TNBC; Thymoquinone; VEGF; apoptosis; black seeds; breast cancer
PMID: 28606050

Prostate Cancer

Medicine (Baltimore). 2017 Feb;96(5):e5944. doi: 10.1097/MD.0000000000005944.
Serum selenium levels and prostate cancer risk: A MOOSE-compliant meta-analysis.

Cui Z1, Liu D, Liu C, Liu G.
Abstract
Some observational studies have shown that elevated serum selenium levels are associated with reduced prostate cancer risk; however, not all published studies support these results. A literature search of PubMed, Embase, Medline, and the Cochrane Library up until September 2016 identified 17 studies suitable for further investigation. A meta-analysis was conducted on these studies to investigate the association between serum selenium levels and subsequent prostate cancer risk. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the overall OR of prostate cancer for the highest versus the lowest levels of serum selenium. We found a pooled OR (95% CI) of 0.76 (0.64, 0.91; P < 0.05). In subgroup analysis, an inverse association between serum selenium levels and prostate cancer risk was found in each of case-control studies, current and former smokers, high-grade cancer cases, advanced cancer cases, and different populations. Such correlations were not found for subgroups containing each of cohort studies, nonsmokers, low-grade cancer cases, and early stage cancer cases. In conclusion, our study suggests an inverse relationship between serum selenium levels and prostate cancer risk. However, further cohort studies and randomized control trials based on non-Western populations are required.
PMID: 28151881 PMCID: PMC5293444

Int J Med Sci. 2015 Jan 1;12(1):63-71. doi: 10.7150/ijms.9982. eCollection 2015.
Berberine inhibits the metastatic ability of prostate cancer cells by suppressing epithelial-to-mesenchymal transition (EMT)-associated genes with predictive and prognostic relevance.

Liu CH1, Tang WC2, Sia P2, Huang CC3, Yang PM2, Wu MH4, Lai IL5, Lee KH2.
Abstract
BACKGROUND:
Over 70% of cancer metastasis from prostate cancer develops bone metastases that are not sensitive to hormonal therapy, radiation therapy, or chemotherapy. The epithelial-to-mesenchymal transition (EMT) genetic program is implicated as a significant contributor to prostate cancer progression. As such, targeting the EMT represents an important therapeutic strategy for preventing or treating prostate cancer metastasis. Berberine is a natural alkaloid with significant antitumor activities against many types of cancer cells. In this study, we investigated the molecular mechanism by which berberine represses the metastatic potential of prostate cancer.
METHODS:
The effects of berberine on cell migration and invasion were determined by transwell migration assay and Matrigel invasion assay. Expressions of EMT-related genes were determined by an EMT PCR Array and a quantitative RT-PCR. The prognostic relevance of berberine’s modulation of EMT-related genes in prostate cancer was evaluated using Kaplan-Meier survival analysis.
RESULTS:
Berberine exerted inhibitory effects on the migratory and invasive abilities of highly metastatic prostate cancer cells. These inhibitory effects of berberine resulted in significant repression of a panel of mesenchymal genes that regulate the developmental EMT. Among EMT-related genes downregulated by berberine, high BMP7, NODAL and Snail gene expressions of metastatic prostate cancer tissues were associated with shorter survival of prostate cancer patients and provide potential therapeutic interventions.
CONCLUSIONS:
We concluded that berberine should be developed as a pharmacological agent for use in combination with other anticancer drug for treating metastatic prostate cancer.
KEYWORDS:
Berberine; EMT; Prostate cancer.
PMID: 25552920 PMCID: PMC4278877

J BUON. 2014 Oct-Dec;19(4):1055-61.
Enhanced cytotoxicity and apoptosis by thymoquinone in combination with zoledronic acid in hormone- and drug-resistant prostate cancer cell lines.

Dirican A1, Erten C, Atmaca H, Bozkurt E, Kucukzeybek Y, Varol U, Oktay Tarhan M, Karaca B, Uslu R.
Abstract
PURPOSE:
Thymoquinone (TQ), an active ingredient of black seed oil (Nigella Sativa), has been shown to possess cytotoxic activity against a variety of cancer cell lines. Our purpose was to investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the TQ in hormone- and drug-refractory prostate cancer cells PC-3 and DU-145.
METHODS:
XTT cell proliferation assay was used to assess cytotoxicity; DNA fragmentation and caspase 3/7 activity were also measured.
RESULTS:
The combination of TQ and ZA resulted in a significant synergistic cytotoxic activity and DNA fragmentation when compared to any single agent alone, in a dose- and time-dependent manner. In addition, TQ and ZA combination increased the caspase 3/7 activity in PC-3 cell line, while this activity could not be demonstrated in DU-145 cell line.
CONCLUSION:
TQ and ZA had minimal hematological and non-hematological toxicity profile compared to cytotoxic agents. So, this combination may be an alternative approach for patients who are unable to be treated by conventional treatments because of poor performance status.
PMID: 25536616

Ovarian Cancer

Nutrients. 2018 Jan 15;10(1). pii: E91. doi: 10.3390/nu10010091.
Deoxyschizandrin, Isolated from Schisandra Berries, Induces Cell Cycle Arrest in Ovarian Cancer Cells and Inhibits the Protumoural Activation of Tumour-Associated Macrophages.
Lee K1, Ahn JH2,3, Lee KT4,5, Jang DS6,7, Choi JH8,9.

Abstract
Deoxyschizandrin, a major lignan of Schisandra berries, has been demonstrated to have various biological activities such as antioxidant, hepatoprotective, and antidiabetic effects. However, the anti-cancer effects of deoxyschizandrin are poorly characterized. In the present study, we investigated the anti-cancer effect of deoxyschizandrin on human ovarian cancer cell lines and tumour-associated macrophages (TAMs). Deoxyschizandrin induced G₀/G₁ phase cell cycle arrest and inhibited cyclin E expression in human ovarian cancer cells. Overexpression of cyclin E significantly reversed the deoxyschizandrin-induced cell growth inhibition. Interestingly, increased production of reactive oxygen species and decreased activation of Akt were observed in A2780 cells treated with deoxyschizandrin, and the antioxidant compromised the deoxyschizandrin-induced cell growth inhibition and Akt inactivation. Moreover, deoxyschizandrin-induced cell growth inhibition was markedly suppressed by Akt overexpression. In addition, deoxyschizandrin was found to inhibit the expression of the M2 phenotype markers CD163 and CD209 in TAMs, macrophages stimulated by the ovarian cancer cells. Moreover, expression and production of the tumour-promoting factors MMP-9, RANTES, and VEGF, which are highly enhanced in TAMs, was significantly suppressed by deoxyschizandrin treatment. Taken together, these data suggest that deoxyschizandrin exerts anti-cancer effects by inducing G₀/G₁ cell cycle arrest in ovarian cancer cells and reducing the protumoural phenotype of TAMs. PMID: 29342940 DOI: 10.3390/nu10010091

Nutr Cancer. 2018 Jan;70(1):109-115. doi: 10.1080/01635581.2018.1380203. Epub 2017 Nov 7.
Active Hexose Correlated Compound (AHCC) Inhibits the Proliferation of Ovarian Cancer Cells by Suppressing Signal Transducer and Activator of Transcription 3 (STAT3) Activation.
Choi JY1, Lee S1, Yun SM1, Suh DH1, Kim K1, No JH1, Jeong EH2, Kim YB1.
Author information
Abstract
The purpose of this study was to investigate the antiproliferative effect of active hexose correlated compound (AHCC), derived from basidiomycete mushroom culture, on ovarian cancer cell lines. An in vitro growth inhibition assay was performed using AHCC in ovarian cancer cell lines. Western blotting was performed to investigate the mechanism of the observed antiproliferative effect of AHCC. We identified that ovarian cancer cell viability was significantly reduced through treatment with AHCC compared to that in the control. AHCC inhibited constitutive signal transducer and activator of transcription 3 (STAT3) phosphorylation in ovarian cancer cell lines. In contrast, treatment with pervanadate, a protein tyrosine phosphatase inhibitor, reversed AHCC-induced STAT3 suppression. AHCC treatment induced the expression of SHP-1, a protein tyrosine phosphatase, and suppressed the expression of cyclin D1, Bcl-2, Mcl-1, survivin, and VEGF, which are STAT3-regulated gene products that are associated with cell proliferation or apoptosis. These results suggest that AHCC has an antiproliferative effect on ovarian cancer cell lines, via STAT3 phosphorylation; thus, this compound has the potential to be a complementary and alternative anticancer therapy for the treatment of ovarian cancer.

PMID: 29111786 DOI: 10.1080/01635581.2018.1380203

 

Liver Cancer, Hepatocellular Carcinoma

Vitamin C enhances epigenetic modifications induced by 5-azacytidine and cell cycle arrest in the hepatocellular carcinoma cell lines HLE and Huh7
Sahar Olsadat Sajadian†, Chaturvedula Tripura†, Fazel Sahraneshin Samani, Marc Ruoss, Steven Dooley, Hossein Baharvand and Andreas K. NusslerEmail author
Clinical Epigenetics The official journal of the Clinical Epigenetics Society20168:46
DOI: 10.1186/s13148-016-0213-6© Sajadian et al. 2016
Received: 15 December 2015Accepted: 20 April 2016Published: 30 April 2016
Abstract

Background
5-Azacytidine (5-AZA), a DNA methyl transferase inhibitor, is a clinically used epigenetic drug for cancer therapy. Recently, we have shown that 5-AZA upregulates ten-eleven translocation (TET) protein expression in hepatocellular carcinoma (HCC) cells, which induce active demethylation. Vitamin C facilitates TET activity and enhances active demethylation. The aim of this study is to investigate whether vitamin C is able to enhance the effect of 5-AZA on active demethylation and to evaluate its consequence in HCC cell lines.

Methods
HCC cell lines (Huh7 and HLE) were treated with 5-AZA and vitamin C. After 48 h of treatment, viability (resazurin conversion), toxicity (lactose dehydrogenase (LDH) release), and proliferation ((proliferating cell nuclear antigen (PCNA)) of single- and combined-treated cells were assessed. The effect of the treatment on 5-hydroxymethylcytosine (5hmC) intensity (immunofluorescence (IF) staining), TET, Snail, GADD45B, and P21 mRNA (real-time PCR) and protein expression (Western blot) were investigated.

Results
Our results indicated that vitamin C enhances the anti-proliferative and apoptotic effect of 5-AZA in HCC cell lines. By further analyzing the events leading to cell cycle arrest, we have shown for the first time in HCC that the combination of 5-AZA and vitamin C leads to an enhanced downregulation of Snail expression, a key transcription factor governing epithelial-mesenchymal transition (EMT) process, and cell cycle arrest.

Conclusions
We conclude that when combined with 5-AZA, vitamin C enhances TET activity in HCC cells, leading to induction of active demethylation. An increase in P21 expression as a consequence of downregulation of Snail accompanied by the induction of GADD45B expression is the main mechanism leading to cell cycle arrest in HCCs.

Oncotarget. 2017 Mar 28;8(13):20667-20678. doi: 10.18632/oncotarget.15400.

Bonuccelli G1, De Francesco EM1,2, de Boer R1, Tanowitz HB3, Lisanti MP4.

Abstract

Here, we assembled a broad molecular “tool-kit” to interrogate the role of metabolic heterogeneity in the propagation of cancer stem-like cells (CSCs). First, we subjected MCF7 cells to “metabolic fractionation” by flow cytometry, using fluorescent mitochondrial probes to detect PCG1α activity, as well ROS and hydrogen-peroxide (H2O2) production; NADH levels were also monitored by auto-fluorescence. Then, the various cell populations were functionally assessed for “stem cell activity”, using the mammosphere assay (3D-spheroids). Our results indicate that a sub-population of MCF7 cells, with increased PGC1α activity, high mitochondrial ROS/H2O2 production and high NADH levels, all form mammospheres with a higher efficiency. Thus, it appears that mitochondrial oxidative stress and the anti-oxidant response both contribute to the promotion of mitochondrial biogenesis and oxidative metabolism in CSCs. Further validation was provided by using specific inhibitors to target metabolic processes (the NAD+ salvage pathway, glycolysis, mitochondrial protein synthesis and OXPHOS), significantly reducing CSC propagation. As a consequence, we have now identified a variety of clinically-approved drugs (stiripentol), natural products (caffeic acid phenyl ester (CAPE), ascorbic acid, silibinin) and experimental pharmaceuticals (actinonin, FK866, 2-DG), that can be used to effectively inhibit CSC activity. We discuss the use of CAPE (derived from honey-bee propolis) and Vitamin C, as potential natural therapeutic modalities. In this context, Vitamin C was ~10 times more potent than 2-DG for the targeting of CSCs. Similarly, stiripentol was between 50 to 100 times more potent than 2-DG.

KEYWORDS: NADH; cancer stem-like cells; metabolic cell fractionation; metabolic heterogeneity; mitochondria

PMID: 28223550  PMCID:PMC5400535