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Cell Cycle Arrest and Apoptosis in Glioblastoma
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10030564

Glioblastoma multiforme (GBM) account for 49% of all primary malignant central nervous system tumorsand stand for the most malignant part of the clinical spectrum. The current established therapy consists of a gross total resection when safely feasible, followed by adjuvant radio-, chemo-, or radiochemotherapy and application of tumor treating fields (TTF). Nevertheless, prognosis is still poor, and overall survival after completion of these therapies averages less than 2 years.

glioblastoma cell cycle arrest apoptosis p53 pathway Rb pathway ion channels

1. Aberrant Cell Cycle Progression and Apoptosis in Glioblastoma multiforme (GBM) 

Dysregulation of a variety of cellular pathways, in particular those involved in the regulation of the cell cycle machinery and apoptosis, is observed in several types of cancer. Subsequently, tumor cells may escape apoptosis or senescence and show excessive proliferation and tumor growth. One can argue that apoptosis and senescence protect against cancer. The most common alterations found in GBM affect p53 [1]; 30% of primary and 65% of secondary GBM express mutated p53 [2]. Both missense and splice site mutations are observed [3]; in the case of the former, several hotspots in the DNA-binding domain—namely, R175, R248, R249, R273, R273, R282, and G245—are most frequently mutated, according to the GBM PanCancer Atlas of The Cancer Genome Atlas (TCGA) [4][5][6]. In addition, methylation of the p53 gene promoter was detected in 21% of primary GBM in one study [7]. Apart from loss or mutation of the p53 gene, further mechanisms that result in p53 inactivation in GBM include impairment of p53 protein stability and suppression of p53 gene expression through amplification of p53 inhibitor genes, such as MDM2 and MDM4 [8][9], genetic deletion and methylation of the p53 inducer ARF [10], genomic loss of ATM, CHEK2 [11], mutation of Parkin [12], overexpression of NFIA, and miR-141-3o [13][14], Bcl2 [15][16], and MIF [17].
According to the TCGA data, prominent alterations in the Rb pathway include homozygous deletions or mutations of genes coding for members of the pocket protein family, in particular of Rb, and gene amplification of cell cycle promoters such as CDKs (CDK4 and 6) and cyclin D1 [18]. Mutation, deletion, or methylation of Rb is observed more frequently in secondary GBM [19].
The P13K/AKT/mTOR pathway is upregulated in GBM cell lines, such as U138 MG [20]. Homozygous deletions or mutations of PTEN, mutations of P13K, as well as amplification of AKT and FOXO genes are documented in the TCGA [18]. PTEN mutations have been associated with poor survival in GBM patients [21].
A higher expression of p38 showed a positive correlation with the WHO grade of malignancy in gliomas, implying also an aberrant activity of the MAPK pathway [22]. Stem cell GBM cells showed self-renewing ability upon phosphorylation of JNK; the systemic administration of small-molecule JNK inhibitors blocks this ability [23].
The NF-kB pathway, which demonstrates anti-apoptotic activity, is upregulated in GBM cells. The NF-kB p65 subunit is overexpressed in gliomas, showing a positive correlation with the WHO malignancy [24]. Inhibition of the NF-kB subunits RelA and c-Rel drives cell cycle arrest and reduction in tumor growth in GBM cells [25]. Significant interactions between NF-kB and p53 cascades in GBM promote cell cycle arrest, apoptosis, neovascularization, impaired EGFR signaling, and neuroinflammation [26] (Figure 1).
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Figure 1. Interactions between pathways of p53 and NF-kB in GBM. Similar stimuli trigger NF-kB and p53 pathways. In turn, several interactions between the aforementioned cascades are observed in multiple levels at their cytoplasmic as well as their nuclear localization, resulting in cell cycle arrest, apoptosis, neuroinflammation, impaired EGFR signaling, and angiogenesis in GBM. The subcellular translocation is performed by karyopherins (nuclear import: KPNA2; nuclear export: CRM1/XPO1).
Mutations in the TERT gene promoter underlie a further escape mechanism from apoptosis in GBM; GBM cells maintain the telomere length in the context of increased telomerase activity, and this in turn leads to excessive proliferation. TERT promoter mutations are frequently observed in IDH-wildtype GBM [27][28]. TERT promoter mutations have been correlated with shorter survival [29].
In vitro and in vivo studies showed an aberrant nucleocytoplasmic transport in patients with GBM or GBM cell lines [30][31]. KPNA2 and CRM1 are upregulated in brain tumors, whereas their expression correlated positively with the WHO malignancy grade [32][31]. KPNA2 expression, in particular, showed an inverse correlation with the patients’ overall and progression-free survival. Increased KPNA2 expression in the UM87 GBM cell line was associated with more malignant behavior via activation of the p53 pathway [30].

2. Principles of GBM Molecular Targeting

2.1. Current Therapy in GBM and Cell Cycle Control

The current therapy of patients with GBM consists of maximal safe tumor resection followed by adjuvant radiation and chemotherapy. Different types of radiation and chemotherapy are used for newly diagnosed vs. recurrent GBM and for disparate tumor biology. Additional application of alternating electrical (“tumor treating”, TTF) fields appear as a safe and promising additional therapy [33].
Radiation induces a variety of DNA lesions, such as damaged bases and DNA strand breaks. Approximately 1000 single and 40 double strand breaks are produced per Gy per cell [34]. The radiation-induced DNA damage is monitored by the kinases ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related protein (ATR), which in turn initiate the DNA damage response, as previously described [35]. As a consequence, the tumor cells initially undergo cell cycle arrest, and in case of a serious unrepairable DNA damage, cell death via mitotic catastrophe and apoptosis [34]. The effect of radiation therapy depends on the total dose, the number of fractions applied [36], as well as the quality of radiation [37]. The initiation of the mitotic catastrophe occurs not immediately after radiation but rather after accumulation of sufficient genetic damage, reflecting the delayed clinical and imaging response of GBM to radiation.
Combined treatment with temozolomide and “tumor treating” (TTF) prolonged the overall and progression-free survival of patients with newly diagnosed GBM (EF-14 trial) [33]. TTF force dipole alignment and dielectrophoresis of proteins involved in spindle formation and mitosis, such as septin 2, 6, and 7, a/b tubulin, and microtubules of spindles [38]. The impaired formation of microtubules induces cytoplasmic blebbing, mitotic failure, and abnormal chromosome segregation, with subsequent disruption of mitosis and cell death via apoptosis [39].
The cytotoxicity of the alkylating agent temozolomide is mediated among others by the addition of methyl groups at O6 sites on guanines in genomic DNA, which in turn causes base mispairing [40]. In more detail, their toxic product O6-methylguanine is then paired with thymine instead of cytosine during DNA replication. The mismatched O6-methylguanine to thymine base pair is sensed by DNA repair pathways involving the repair proteins MLH1, MSH2, MSH6, and PMS2, which place the tumor cells initially into cell cycle arrest and eventually cause cell death. However, approximately 60% of patients with GBM show resistance to temozolomide, since a nuclear enzyme, named O6-methylguanine-DNA methyltransferase (MGMT), removes alkyl groups from the O6-position of O6-methylguanine and returns the cell into the regular cell cycle mode. The methylation status of the MGMT promoter, which silences MGMT expression, has been identified as being a beneficial prognostic predictor in patients undergoing TMZ chemotherapy [41].
Nitrosoureas are anticancer agents used in the therapy of recurrent GBM but also for newly diagnosed GBM with MGMT promoter hypermethylation [42][43]. Lomustine or CCNU, a well-known nitrosourea, transfers its chloroethyl group to the O6 sites of guanine on DNA. This causes interstrand and intrastrand cross-linking of DNA, which inactivates DNA synthesis and leads to cell death. Similar to temozolomide, O6-methylguanine DNA methyltransferase (MGMT) also reverts the product of CCNU—namely, the of O6-chloroethylguanine, removing its alkyl group, restricting the meaningful use of CCNU in patients with methylated MGMT [44].

2.2. Targeting the Cell Cycle Machinery in GBM

Since GBM cells show uncontrolled cell cycle progression due to alterations of the p53 and Rb pathway, many studies have focused on restoring these functions [45]. Mutations of p53 and Rb are the most common sources of impairments, but direct targeting of p53 and Rb mutations is challenging. However, alternative ways of pathways’ modulations, such as inhibition of natural p53 and Rb deactivators, such as MDM2 or CDKIs, may be both feasible and promising [46][47][48][49][50][51]. Nutlin-3 is a MDM2 inhibitor that targets the MDM2–p53 interaction, inhibiting GBM cell growth via upregulation of apoptosis and senescence [49]. A second generation nutlin analogue called RG7388 is currently under evaluation in conjunction with radiation in the context of the NOA-20 trial (NCT03158389, https://clinicaltrials.gov/ct2/show/NCT03158389, accessed on 30 December 2021). Piperidinones, such as AMG232, are further MDM2–p53 interaction inhibitors, which are tested in a phase I clinical trial in primary and recurrent GBM (NCT03107780) (https://clinicaltrials.gov/ct2/show/NCT03107780, accessed on 30 December 2021). Alternative ways of restoring p53 functions are direct blocking of MDM2 expression via siRNA [52] or restoration of p53 expression via a p53 activator, such as RITA [53]. Similarly, targeting the Rb pathway and CDKs or cyclins drives GBM cells to cell cycle arrest in GBM models [54][55]. CDK4 and CDK6 inhibitors, which showed promising activity in various type of cancers [56], are currently under evaluation in the NCT02345824 ongoing GBM trial (https://clinicaltrials.gov/ct2/show/NCT02345824, accessed on 30 December 2021). TG02, a novel CDK9 inhibitor, is being studied in the clinical trials NCT02942264 and NCT03224104 for recurrent and newly diagnosed GBM, respectively (https://clinicaltrials.gov/ct2/show/NCT02942264; https://clinicaltrials.gov/ct2/show/NCT03224104, accessed on 30 December 2021) [57].
A variety of natural substances have been identified as being physiological regulators of the cell cycle via p53 and Rb [58]. Compared with synthetic anticancer agents, they demonstrate a diminished drug toxicity and higher permeability through the BBB [58]. The family of natural compounds comprise among others plant derivatives, curcuminoids, coumarins, alkaloids, carotenoids, flavonoids, marine peptides, and natural steroids [59][60]. The biochemical structures of the studied natural compounds but also the remaining therapeutic agents mentioned are shown in the Table 1. Curcumin upregulates CDKN2A/p16 in DBTRG glial cells, which in turn inhibits phosphorylation of Rb, which leads to a G1/S cell cycle arrest [61]. An increased BAX/BCL2 ratio is also caused by curcumin, inducing apoptosis in a p53-dependent manner via intrinsic mitochondrial pathways [62]. In addition, curcumin is reported to modulate the JAK/STAT, MAPK, p13k/Akt, and NF-kB pathways in favor of cell cycle arrest [60]. Flavonoids such as alkylaminophenol [63] and tectorigenin [64] are metabolites of plants, which promote a p53-, Rb-, and CDK-mediated cell cycle arrest and apoptosis [64][63]. An additional plant compound, named moschamine, activates the intrinsic pathway of apoptosis via dysregulation of the mitochondrial membrane potential, whereas the combined exposure of GBM cell lines to moschamine and temozolomide promotes a stronger cell cycle arrest compared with sole temozolomide exposure [65].
Table 1. Biochemical structures of potential therapeutic agents in GBM.
Table
Therapeutic Agents Biochemical Structure
Nutlin-3 Biomedicines 10 00564 i001
RITA Biomedicines 10 00564 i002
Ribociclib Biomedicines 10 00564 i003
TG02 Biomedicines 10 00564 i004
Curcumin Biomedicines 10 00564 i005
Moschamine Biomedicines 10 00564 i006
Flavonoids Biomedicines 10 00564 i007
JQ1 Biomedicines 10 00564 i008
UM-002 Biomedicines 10 00564 i009
Thiabenzole Biomedicines 10 00564 i010
Flubendazole Biomedicines 10 00564 i011
5-ALA Biomedicines 10 00564 i012
Haloperidol Biomedicines 10 00564 i013
Selinexor Biomedicines 10 00564 i014
The bromodomain and extraterminal (BET) family proteins are epigenetic regulators of gene transcription by binding via their two tandem bromodomains to lysine-acetylated histones. Since BET proteins regulate the transcription of specific oncogenes as well as cell cycle related genes [66][67][68] they have been investigated as potential therapeutic targets in various cancers [69]. BET inhibitors such as JQ1 [70] induce apoptosis in glioma stem cells by modulating P13K/AKT. A novel BET inhibitor, UM-002, reduced the cell proliferation in patient-derived xenograft GBM cell lines GBM22 and GBM39 [68]. MicroRNAs are non-coding RNAs that regulate gene expression of cell cycle regulatory pathways [71]. Downregulation of microRNA-21 induces in GBM cell lines a G0/G1 cell cycle arrest and increased apoptosis and inhibits chemotherapeutic resistance to doxorubicin [72].
Reassigning a novel role to already established drugs known to be safe is a potentially promising concept in medical oncology. The benzimidazole carbamate family compounds were initially used for the treatment of anthelminthics, but they have shown additional anticancer behavior [73][74]. Hu et al. analyzed the effect of thiabenzole on GBM cell lines (P3, U251, LN229, A172, and U118MG). Thiabenzole was found to induce a G2/M arrest in GBM cell lines via downregulation of mini-chromosome maintenance protein 2 [75]. Flubendazole induces apoptosis via increasing the expression of proapoptotic proteins; in addition, cell cycle arrest is being promoted through downregulation of cyclin B1 and upregulation of p53 and CDKIs, such as p21 in GBM cells [76][77]. Recently, antipsychotic drugs have emerged as potential anticancer agents, whereas 12 candidate substances have been identified [78][79]. Treatment with haloperidol, in particular, has been reported to promote G2/M cell cycle arrest in the U87 GBM cell line [80].
5-Aminolevulinic acid (5-ALA), which induces accumulation of the protoporphyrin IX in GBM cells, is well known as the main diagnostic agent that differentiates the tumor-infiltrated tissue from adjacent healthy brain parenchyma during fluorescence-guided brain surgery [81]. Recently 5-ALA has been assigned a new role either in the context of photodynamic therapy [82] or as a direct cytotoxic agent for GBM [83]. Jalili-Nik et al. report a reduction in Bcl-2 and an increase in Bax and p53 expression, and therefore an increase in apoptotic cells, in the U87MG GBM cell line after in vitro application of 5-ALA [83].
Trans- and intracellular shuttling is a fundamental process enabling crucial cell functions, such as the regulation of cell cycle [30][84]. Transmembrane ion channels regulate the responses of the cells to external stimuli, whereas karyopherins translocate macromolecules through the nuclear envelope. Various ion channels, such as Kv10.1, NaV1.6, VDAC2, or CLIC1 are dysregulated in GBM [85][86][72]; higher expressions of TRM3, P2RX4, or CLIC1 are linked to poorer survival [86][72][87]. Since dysregulated ion channels drive tumorigenesis and cell proliferation of GBM cells, their inhibition leads to senescence or apoptosis. Inhibition of the ether-a-go-go-related gene encodes the pore-subunit of K+ channel Kv11.1 via siRNA-mediated apoptosis in GBM cell lines [88]. In vitro suppression of the Ca2+-activated K+ channel BK via its inhibitor, called iberiotoxin, induced S phase arrest and apoptosis [89].
Karyopherins are essential in cell cycle control, as they translocate relevant transcription factors, such as E2F1 and tumor suppressors, as well as oncogenes, through the nuclear envelope [90]. SiRNA-mediated silencing of the most well-characterized importin, karyopherin a2, in U87MG GBM cell line was found to induce cell cycle arrest and apoptosis in a p53-dependent manner [30]. Inhibition of the importin XPO1 or CRM1 via selinexor has reduced proliferation and prolonged survival in GBM animal models [91]. A phase 2 study on efficacy, safety, and intratumoral pharmacokinetics of selinexor monotherapy in recurrent GBM (KING Trial) [92] concluded that there was a clinically relevant response in patients with GBM to a 80 mg weekly dose of selinexor in terms of prolonged progression-free survival [92]. The follow-up study NCT04421378 analyses the effect of selinexor in combination with standard of care therapy for newly diagnosed or recurrent GBM (https://clinicaltrials.gov/ct2/show/NCT04421378, accessed on 30 December 2021). A graphic presentation of the target points of the aforementioned therapeutic agents is given in Figure 2.
Biomedicines 10 00564 g004 550
Figure 2. Molecular targeting of GBM therapeutic agents. The current figure depicts the molecular targets of potential therapeutic agents for GBM within the pathways of apoptosis and cell cycle (arrow: upregulation; line: downregulation).

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Konstantinos Gousias
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