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Cancer

Multiple Myeloma

EBioMedicine. 2017 Apr;18:41-49. doi: 10.1016/j.ebiom.2017.02.011. Epub 2017 Feb 16.
Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic Acid.

Xia J1, Xu H2, Zhang X3, Allamargot C4, Coleman KL2, Nessler R4, Frech I2, Tricot G5, Zhan F6.

Abstract
High-dose chemotherapies to treat multiple myeloma (MM) can be life-threatening due to toxicities to normal cells and there is a need to target only tumor cells and/or lower standard drug dosage without losing efficacy. We show that pharmacologically-dosed ascorbic acid (PAA), in the presence of iron, leads to the formation of highly reactive oxygen species (ROS) resulting in cell death. PAA selectively kills CD138+ MM tumor cells derived from MM and smoldering MM (SMM) but not from monoclonal gammopathy undetermined significance (MGUS) patients. PAA alone or in combination with melphalan inhibits tumor formation in MM xenograft mice. This study shows PAA efficacy on primary cancer cells and cell lines in vitro and in vivo.
Copyright © 2017 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Published by Elsevier B.V. All rights reserved.

KEYWORDS:
Apoptosis-inducing factor 1; Multiple myeloma; Pharmacologically-dosed ascorbic acid
PMID: 28229908

Onco Targets Ther. 2015 Apr 9;8:775-81. doi: 10.2147/OTT.S81022. eCollection 2015.
The clinical activity of arsenic trioxide, ascorbic acid, ifosfamide and prednisone combination therapy in patients with relapsed and refractory multiple myeloma.

Li X1, Sun WJ2.
Abstract
This study aimed to investigate the activity of arsenic trioxide (As2O3) combined with ascorbic acid, ifosfamide, and prednisone chemotherapy in patients with repeatedly relapsed and refractory multiple myeloma (MM). Here, we retrospectively analyzed medical data of 30 MM patients showing progressive disease after receiving at least two previous lines of treatment including an immunomodulatory agent (thalidomide or lenalidomide) and a proteasome inhibitor. There were 19 men and eleven women, aged 54-73 (median 65) years, in this study. The distribution of different isotypes included immunoglobulin G(IgG) (12 patients), IgA (six patients), IgD (three), and light chain (nine patients). All the patients were Durie-Salmon stage III and had relapsed at least three times; the median cycles of prior therapies was 15 (range 10-18). The patients were treated with As2O3, ascorbic acid, and CP (ifosfamide 1 g on day 1, day 3, day 5, and day 7; prednisone 30 mg taken orally for 2 weeks). As2O3 was administered as an intravenous infusion at a dose of 10 mg/d and ascorbic acid at a dose of 2 g/d for 14 days of each 4-week cycle. The results showed that after 2 cycles of therapy, there were five patients that attained partial response, 15 had minimal response, five had no change, and five had progressive disease. The overall response rate was 66.7% (20/30 cases), 50% (10/20 cases), and 40% (2/5 cases), respectively, after 2, 4, and 6 cycles of the therapy. But there were no patients that attained complete remission. The median time of overall survival and progression-free survival were 48 (29-120) and 6 (2-8) months, respectively. The most common treatment-related adverse events included neutropenia, fatigue, anemia, thrombocytopenia, and infection that could be tolerated. The results showed that As2O3 combined with ascorbic acid, ifosfamide, and prednisone chemotherapy may be a choice treatment for repeatedly relapsed and refractory MM patients.
KEYWORDS:
chemotherapy; response
PMID: 25914547

Glioblastoma

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

d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway.

Miao Z1, Yu F2, Ren Y3, Yang J4.

Abstract

d,l-Sulforaphane (SFN), a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM) cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2. Mechanistically, SFN treatment led to increase the intracellular reactive oxygen species (ROS) level in GBM cells. Meanwhile, SFN also suppressed both constitutive and IL-6-induced phosphorylation of STAT3, and the activation of upstream JAK2 and Src tyrosine kinases, dose- and time-dependently. Moreover, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis by blocking the induction of apoptosis-related genes in GBM cells. Taken together, our data suggests that SFN induces apoptosis in GBM cells via ROS-dependent inactivation of STAT3 phosphorylation. These findings motivate further evaluation of SFN as a cancer chemopreventive agent in GBM treatment.

PMID: 28054986   PMCID: PMC5297707

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

The Effect of Ascorbic Acid over the Etoposide- and Temozolomide-Mediated Cytotoxicity in Glioblastoma Cell Culture: A Molecular Study.

Göktürk D1, Kelebek HCeylan SYilmaz DM.

Abstract

Glioblastoma (GBM) is one of the lethal central nervous system tumors. One of the widely used chemical agents for treatment of glioblastoma is temozolomide. It is an orally administered, DNA alkylating agent. DNA alkylation triggers the death of tumor cells. However, some tumor cells are able to repair this type of DNA damage, thus lower the therapeutic effect of temozolomide. Laboratory and clinical studies indicate that temozolomide\’s anticancer effects might be strengthened when combined with other chemotherapeutic agents, like etoposide, or antioxidant agents, like ascorbic acid. In this study we aimed to evaluate the cytotoxic and oxidative stress effects of ascorbic acid (1000 µM), temozolomide (100 µM) and etoposide (25 µM) agents alone, in dual and triple combinations in the glioblastoma U87 MG cell culture.

MATERIAL AND METHODS:

The cytotoxic and oxidative stress effects were investigated by the MTT and LC MS/MS analysis methods.

RESULTS:

Cytotoxicity test results showed that etoposide, temozolomide, \”etoposide + ascorbic acid\”, \”temozolomide + ascorbic acid\”, \”temozolomide + etoposide\” and \”temozolomide + etoposide + ascorbic acid\” combinations have antiproliferative effects. The maximum antiproliferation response was observed in the \”temozolomide + etoposide + ascorbic acid\” added group. Similarly LC MS/MS analyses showed that minimum oxidative DNA damage was occured in the \”temozolomide + etoposide + ascorbic acid\” added group.

CONCLUSION:

The results indicate that ascorbic acid decreases the cytotoxic and genotoxic effect of etoposide and etoposide-temozolomide combination, but it has no meaningful impact on the temozolomide\’s toxicity.

PMID: 28191621

Pancreatic Cancer

Cancer Res. 2015 Aug 15;75(16):3314-26. doi: 10.1158/0008-5472.CAN-14-1707. Epub 2015 Jun 16.

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.

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

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

©2015 American Association for Cancer Research.

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

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.

Milk Thistle & Cancer

Milk thistle is a popular herb used most commonly for helping with liver diseases.  In a 2009 research study, an extract from Milk Thistle, called Silibinin, was found to have significant anti-tumor actions against many types of cancers, including of the skin, breast, lung, colon, bladder, prostate and kidney. 

Milk Thistle Extract & Prevention and Natural Treatment of Hepatocellular Carcinoma

A 2011 study to appear in the medical journal Current Pharmaceutical Biotechnology, noted how milk thistle extract can reduce the free radical damage and insulin resistance of liver cells in existing liver disease (eg: liver cirrhosis, non-alcoholic fatty liver, steatohepatitis).  Patients with these liver diseases have an increased risk of developing primary Hepatocellular Cancer (HCC).  Milk thistle extract has been shown to reduce tumor proliferation, angiogenesis (the development of blood vessels to cancer cells), and also reduce insulin resistance, in addition to known benefits of milk thistle (regenerating healthy liver cells, and reducing liver inflammation overall).  It also has anti-atherosclerotic benefits as well.  Milk thistle extract has shown to prevent the development of HCC in laboratory research.  The study concludes in saying that milk thistle extract can also be using alongside other cancer treatments (as an “adjuvant” cancer treatment) to improve the effectiveness of standard cancer treatments.

References

Silibinin – A Promising New Treatment for Cancer. 

Anticancer Agents Med Chem. 2009 Dec 16. Cheung CW, Gibbons N, Johnson DW, Nicol DL

Silymarin in the Prevention and Treatment of Liver Diseases and Primary Liver Cancer. Curr Pharm Biotechnol. 2011 April 5. [Epub ahead of print] Feher J, Lengyel G.

Cancer Prevention

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

NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting “stemness”.

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