Antitumor Activity of Curcumin in Glioblastoma.

Current standard-of-care treatment for glioblastoma, the most common malignant primary central nervous system (CNS) tumor, consists of surgical resection followed by adjuvant chemotherapy and radiation (Stupp protocol), providing an overall median survival of 15 months. With additional treatment using tumor-treating fields (Optune® therapy, Novocure Ltd., Haifa, Israel), survival can be extended up to 20 months. In spite of significant progress in our understanding of the molecular pathogenesis, the prognosis for patients with malignant gliomas remains poor and additional treatment modalities are critically needed. Curcumin is a bright yellow pigment found in the rhizome of the widely utilized spice, turmeric (Curcuma longa). It has long been used in South Asian traditional medicines and has been demonstrated to have in vitro antioxidant, anti-inflammatory, and antiproliferative effects. Curcumin has been demonstrated to induce multiple cytotoxic effects in tumor cells including cell cycle arrest, apoptosis, autophagy, changes in gene expression, and disruption of molecular signaling. Additionally, curcumin has been shown to potentiate the effect of radiation on cancer cells, while exhibiting a protective effect on normal tissue. Curcumin's positive safety profile and widespread availability make it a promising compound for future clinical trials for high-grade gliomas.

Understanding the Mechanisms of Diet and Outcomes in Colon, Prostate, and Breast Cancer; Malignant Gliomas; and Cancer Patients on Immunotherapy.

Cancer patients often ask which foods would be best to consume to improve outcomes. This is a difficult question to answer as there are no case-controlled, prospective studies that control for confounding factors. Therefore, a literature review utilizing PubMed was conducted with the goal to find evidence-based support for certain diets in specific cancer patients-specifically, we reviewed data for colon cancer, prostate cancer, breast cancer, malignant gliomas, and cancer patients on immunotherapy. Improved outcomes in colon cancer and patients on immunotherapy were found with high-fiber diets. Improved outcomes in malignant gliomas were found with ketogenic diets. Improved outcomes in prostate cancer and breast cancer were found with plant-based diets. However, the data are not conclusive for breast cancer. Additionally, the increased intake of omega-3 fatty acids were also associated with better outcomes for prostate cancer. While current research, especially in humans, is minimal, the studies discussed in this review provide the groundwork for future research to further investigate the role of dietary intervention in improving cancer outcomes.

"Simple Methods to Derive Primary Malignant Glioma Cell Lines and Assay of Cellular Damage for Preclinical Studies".

Primary malignant glioma cell lines are being used for initial screening of anticancer agents. We utilized a simple mechanical disaggregation method for deriving cell lines from tumor tissues; and a Coverslip Culture-Acridine Orange Staining method to study cellular damage. Cell lines could be grown for up to three passages within three weeks after surgery. Cell proliferation, total cellular damage, and MTT assay were studied as parameters of cytotoxic response. Frequencies of damaged cells varied in different cell lines; and increased after cytotoxic treatments under clinically relevant conditions. These methods could contribute to preclinical evaluation of treatment response before commencement of radio-chemotherapy.

Expression of PFKFB3 in brain glioma tissues and its effect on malignant biological behaviors of H4 cells / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: Toevaluatetheexpressionof6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3(PFKFB3) in malignant glioma tissues and the effects of inhibitor of PFKFB3(PFK15) on the proliferation, migration, invasion, clone formation and tumorigenesis of H4 cells. Methods: Malignant brain glioma tissues and corresponding paratumor tissues from 31 patients, who were hospitalized in Department of Neurosurgery,Ankang Hospital of Traditional Chinese Medicine during February 1, 2015 to January 31, 2016 for operative treatment, were collected for this study. Immunohistochemistry and western blotting assays were applied to detect the expression of PFKFB3 in collected tissues. PFKFB3 in H4 cells were blocked by PFK15 (1.25, 2.5, 5.0 μmol/L). The effect of PFK15 on proliferation, migration, clone formation and tumorigenesis of H4 cells were determined by MTT assay, EdU incorporation assay, wound healing assay, Transwell assay, colone formation assay and in vivo xenograft bearing nude mice model respectively. Results: Positive expression rate of PFKFB3 was significantly higher in malignant glioma tissues compared with normal adjacent tissues[(80.60±8.98)% vs (41.57±10.16)%, P<0.05]. The results of MTT assay and EdU incorporation assay indicated that PEK15 significantly inhibited the proliferation of H4 cells in a concentration dependent manner. The migration, invasion and clone formation activity of H4 cells were significantly reduced by treatment with PFK15 (all P<0.05). In tumor bearing nude mice, the tumor volume of mice treated with PFK15 was significantly smaller than that of mice from control group ([254.15±154.25] vs [801.52±224.25] mm3, P<0.05). Conclusion: PFKFB3 was highly expressed in malignant glioma tissues. Blocking of PFKFB3 by PFK15 significantly reduced the malignant biological behaviors and tumorigenesis of H4 cells in vitro and in vivo, which may serve as a promising target for the treatment of malignant gliomas.

Analysis of physical characteristics of Tumor Treating Fields for human glioblastoma.

Tumor Treating Fields (TTFields) therapy is an approved treatment that has known clinical efficacy against recurrent and newly diagnosed glioblastoma. However, the distribution of the electric fields and the corresponding pattern of energy deposition in the brain are poorly understood. To evaluate the physical parameters that may influence TTFields, postacquisition MP-RAGE, T1 and T2 MRI sequences from a responder with a right parietal glioblastoma were anatomically segmented and then solved using finite-element method to determine the distribution of the electric fields and rate of energy deposition at the gross tumor volume (GTV) and other intracranial structures. Electric field-volume histograms (EVH) and specific absorption rate-volume histograms (SARVH) were constructed to numerically evaluate the relative and/or absolute magnitude volumetric differences between models. The electric field parameters EAUC , VE150 , E95% , E50% , and E20% , as well as the SAR parameters SARAUC , VSAR7.5 , SAR95% , SAR50% , and SAR20% , facilitated comparisons between models derived from various conditions. Specifically, TTFields at the GTV were influenced by the dielectric characteristics of the adjacent tissues as well as the GTV itself, particularly the presence or absence of a necrotic core. The thickness of the cerebrospinal fluid on the convexity of the brain and the geometry of the tumor were also relevant factors. Finally, the position of the arrays also influenced the electric field distribution and rate of energy deposition in the GTV. Using EVH and SARVH, a personalized approach for TTFields treatment can be developed when various patient-related and tumor-related factors are incorporated into the planning procedure.

The Chemistry and Biological Activities of Mimosine: A Review.

Mimosine [ß-[N-(3-hydroxy-4-oxypyridyl)]-α-aminopropionic acid] is a non-protein amino acid found in the members of Mimosoideae family. There are a considerable number of reports available on the chemistry, methods for estimation, biosynthesis, regulation, and degradation of this secondary metabolite. On the other hand, over the past years of active research, mimosine has been found to have various biological activities such as anti-cancer, antiinflammation, anti-fibrosis, anti-influenza, anti-virus, herbicidal and insecticidal activities, and others. Mimosine is a leading compound of interest for use in the development of RAC/CDC42-activated kinase 1 (PAK1)-specific inhibitors for the treatment of various diseases/disorders, because PAK1 is not essential for the growth of normal cells. Interestingly, the new roles of mimosine in malignant glioma treatment, regenerative dentistry, and phytoremediation are being emerged. These identified properties indicate an exciting future for this amino acid. The present review is focused on the chemistry and recognized biological activities of mimosine in an attempt to draw a link between these two characteristics. Copyright © 2016 John Wiley & Sons, Ltd.

[Glutamate and malignant gliomas, from epilepsia to biological aggressiveness: therapeutic implications]. / Glutamate et gliomes malins, de l'épilepsie à l'agressivité biologique : implications thérapeutiques.

In this review article, we describe the unrecognized roles of glutamate and glutamate receptors in malignant glioma biology. The neurotransmitter glutamate released from malignant glioma cells in the extracellular matrix is responsible for seizure induction and at higher concentration neuronal cell death. This neuronal cell death will create vacated place for tumor growth. Glutamate also stimulates the growth and the migration of glial tumor cells by means of the activation of glutamate receptors on glioma cells in a paracrine and autocrine manner. The multitude of effects of glutamate in glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters in the adjuvant treatment of malignant gliomas in neurology and neuro-oncology. Using the website www.clinicaltrials.gov/ as a reference - a service developed by the National Library of Medicine for the National Health Institute in USA - we have evoked the few clinical trials completed and currently ongoing with therapies targeting the glutamate receptors.

Effect of High-Dose Tamoxifen on Malignant Gliomas

In vitro studies have shown that the nonsteroidal antiestrogen tamoxifen can suppress deoxyribonucleic acid(DNA) synthesis and cell proliferation in cultured human gliomas. This growth suppression is independent on its antiestrogenic properties. Tamoxifen may act through the inhibition of the enzyme protein kinase C(PKC), which transduces mitogenic signals from the cell surface to the nucleus. In order to evaluate the therapeutic response and side effect of high-dose tamoxifen, we performed a clinical study of 28 patients with malignant gliomas who were treated with high-dose tamoxifen in our hospital between February 1991 and January 1993. An effect was defined as a statistically improved survival times/rates. In patients who were assigned to receive high-dose tamoxifen, it was first administered at standard antiestrogen doses(20mg orally bid/day) to observe for any side effect and if tolerated, the dose was increased weekly to achieve target doses(100mg orally bid/day) over a 1 month period. We compared the survival times/rates between anaplastic astrocytomas and glioblastoma mutiformes. Although the median survival time was slightly longer in anaplastic astrocytomas than that of glioblastoma multiformes, there was no statistical difference of survival curves between two groups at the p=0.05 level. We also examined the survival times/rates of malignant gliomas according to treatment modalities(radiotherapy alone, radiotherapy plus ACNU, and radiotherapy plus tamoxifen). Although the survival rate and time were slightly higher in radiotherapy plus tamoxifen group than those of another treatment groups, we could not find the statistical significance of survival curves between three treatment groups(p>0.05). High-dose oral tamoxifen appeared to be well tolerated in most patients. Five patients developed anorexia following dose escalation of tamoxifen. Another complications were amenorrhea, nausea/vomiting, and constipation. There were no changes in hematological studies that could be attributed to tamoxifen. We think that high-dose tamoxifen cah be administered safely to malignant gliomas patients. Our results were not impressive. We conclude that the definition of the true efficacy of high-dose tamoxifen in patients harboring malignant gliomas is not possible from this limited study, and a further large scale, randomized trial of this agent is necessary.