**4. Antioxidants and gliomas relationship**

Gliomas are a class of primary central nervous system tumors and they originated from glial cells [1]. Glial progenitor cells have different subtypes: astrocyte, oligodendrocyte, and ependyma. In general, the classification of gliomas is based on these cell types [4]. The most detailed classification belongs to WHO. WHO suggests that four different grades (I–II–III–IV) are described for gliomas according to morphological and histological features [1]. Besides these features, some molecular and genetic features (epidermal growth factor upregulation, isocitrate dehydrogenase 1/2 mutations, p53 mutations, etc.) also alter the grading [2].

Tumor grade and class are major factors to determine the therapy options. Surgery, chemotherapy, and radiotherapy are preferred to treat the gliomas. After surgery, chemotherapy or radiotherapy is applied. For the glioma treatment, the most frequently encountered problems are the blood-brain barrier and drug resistance [31]. The blood-brain barrier is a control mechanism in relation to the transition of ions, molecules, and cells between the blood and brain. If a drug does not pass through the blood-brain barrier, it cannot reach the brain cells [32].

The second problem is drug resistance [33]. Temozolomide is the most common chemotherapeutic agent for gliomas. It is an alkylating agent [34]. In case of elevated levels of O6 -metil guanine DNA methyltransferase expression, temozolomide meets with resistance [35]. On the other hand, increased levels of antioxidant response system SLC7A11 triggered the drug resistance [31].

Over the past decades, antioxidant supplementation becomes a necessity for cancer treatment. Basically, antioxidants use to eliminate the elevated levels of ROS, but cancer in question nothing is understandable. For this reason, researchers have carried out some studies. Understanding the beneficial or harmful roles of antioxidants in cancer treatment is essential. Further to that understanding of ROS effects in terms of cancer progression is really important. ROS is a reason for cancer progression, but in course of cancer development increased levels of ROS might be a cell-death option. Moreover, increased levels of ROS alter the cell signaling in cancer cell in consequence of acting as secondary messengers [17]. For instance, Akt overexpression is frequently showed in gliomas, and protein kinase C (PKC) activation stimulates some molecules like Akt, MAPK.All these molecules are under the control by cellular redox state [36]. As a result of these features, ROS antioxidants can be provided new approaches in order to treat glioma. It is still an unknown and questionable area for the researchers.

against agents. They found that the most effective agent was nobiletin on four different cell

Antioxidant Supplementation during Glioma Therapy: Friend or Foe?

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In 2001, Naidu et al. studied the effects of ascorbyl stearate (Asc-S) on human glioblastoma multiforme cells. They used different doses of Asc-S on T98G human glioblastoma cell lines for 24 h. They showed that Asc-S inhibited insulin-like growth factor-dependent cell proliferation in a dose-dependent manner. Asc-S modulated IGF-R expression, in consequence of

In 2007, Rooprai et al. studied on IPSB-18 human astrocytoma cells. They treated cells with selenite and found that selenite was altered the expressions of matrix metalloproteinases and their inhibitors. It was also decreased the epidermal growth factor (EGFR) expression. This

In 2013, Pozsgai et al. studied on quercetin effects on glioblastoma standard treatment. They found that combination treatment provided significant reduction in cell viability in U251 and DBTRG-05MG glioblastoma multiforme cell lines. They also showed that quercetin alone, or in a combination with IR triggered the apoptosis [29]. In 2016, Lou et al. found that quercetin nanoparticles stimulated the autophagy and apoptosis by activating AKT/erk/caspase 3 sig-

In 2017, increasing cell proliferation of glioblastoma multiforme cell lines with low doses of

The combination of berbamine and paclitaxel were decreased the cell proliferation on U87

Higher levels of ascorbate led the DNA strand breakages by creating genotoxic and metabolic

In 1981, Newell et al. used a mixture of vitamins C and B12 in high dose on rats with glioma. They observed no difference in survival time between experimental and control groups [49]. In 1989, Wang et al. showed that retinoids (retinal, retinoic acid, retinyl acetate, and retinyl palmitate) and carotenoids (beta-carotene, lycopene, and crocetin) inhibited the tumor growth

A study regarding naringenin using was carried out on rats by Sabarinathan et al. [30]. With supplementation of naringenin in glioma induced rats the status of lipid peroxidation was decreased, on the contrary antioxidant status increased. Besides this, naringenin also modu-

(CBD) effects on tumor growth in xenograft glioblastoma multiforme model. THC and CBD loaded on microparticles and delivered locally. At the end of the study they found that THC

and CBD stimulated apoptosis and induced cell proliferation and angiogenesis [51].


stress on glioma cells, but it also caused the development of radioresistance [48].

this situation programmed cell death was triggered on T98G cells by Asc-S [43].

lines and it was decreased the MMP-2 and -9 secretions [42].

was suggested that selenite had anti-metastatic effects [44].

selenomethionine was showed by Harmanci et al. [46].

naling pathway [45].

*4.1.2. Animal studies*

glioblastoma multiforme cells [47].

in C6 glioma cells inoculated rats [50].

late the glial-tumor cell proliferation [30].

In 2013, Perez de la Ossa et al. examined that Δ<sup>9</sup>

Accumulating data suggest two different approaches regarding antioxidant consumption. One is that antioxidants make tumor cells resistance against chemotherapy or radiotherapy and the survival rates are decreased. On the other hand, the second is that antioxidants protect the normal cells from oxidative damage and they are decreased side effects of therapy and provide better survival [8, 37, 38]. The next part of this chapter is related to evidence regarding these two opinions.
