Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Annovazzi, Laura; Mellai, Marta; Schiffer, Davide

doi:10.3390/cancers9060057

Cited by 70 publications

(54 citation statements)

References 109 publications

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“…Similar to the PI3K signalling cascade, the MEK/ERK pathway is considered to enhance survival and confer resistance against radio-and chemotherapy 19,20 , although this seems to be not universally accepted 21,22 . ERK has been implicated in several cellular aspects of GB behaviour, again frequently overlapping with the previously identified roles of the PI3K signalling cascade: The MEK/ERK pathway enhances migration and invasion of GB cells in response to treatment 23 , and increases DNA damage repair both through non-homologous end joining repair as well as homologous recombinational repair pathways 24 . The role of ERK in maintenance of stemness is rather controversial.…”

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confidence: 63%

The limitations of targeting MEK signalling in Glioblastoma therapy

Selvasaravanan

Wiederspohn

Hadzalic

et al. 2020

Sci Rep

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Glioblastoma (GB) is a highly aggressive, difficult to treat brain tumour. Successful treatment, consisting of maximal safe tumour de-bulking, followed by radiotherapy and treatment with the alkylating agent Temozolomide (TMZ), can extend patient survival to approximately 15 months. Combination treatments based on the inhibition of the PI3K pathway, which is the most frequently activated signalling cascade in GB, have so far only shown limited therapeutic success. Here, we use the clinically approved MEK inhibitor Trametinib to investigate its potential use in managing GB. Trametinib has a strong anti-proliferative effect on established GB cell lines, stem cell-like cells and their differentiated progeny and while it does not enhance anti-proliferative and cell death-inducing properties of the standard treatment, i.e. exposure to radiation or TMZ, neither does MEK inhibition block their effectiveness. However, upon MEK inhibition some cell populations appear to favour cellsubstrate interactions in a sprouting assay and become more invasive in the Chorioallantoic Membrane assay, which assesses cell penetration into an organic membrane. While this increased invasion can be modulated by additional inhibition of the PI3K signalling cascade, there is no apparent benefit of blocking MEK compared to targeting PI3K. Glioblastoma (GB), formerly Glioblastoma multiforme, is the most common primary brain tumour in adults and-due to its aggressive and highly infiltrative nature-among the most lethal malignancies per se 1. The current standard therapy involves maximum safe surgical resection followed by radio-and chemotherapy with the alkylating agent Temozolomide (TMZ) 2 which leads to a mean patient survival of only 15 months 3. Although GB only rarely metastasised outside the neuraxis, upon clinical presentation it will almost invariably have infiltrated the surrounding brain tissue, impeding full surgical resection and resulting in tumour recurrence 4. GB exhibits a rather low mutational burden 5 , with the most consistent alterations found in the PI3K signalling cascade, which is activated in ~88% of all GBs 6,7. Despite intensive efforts to translate modulation of this signalling pathway into a clinical setting, so far, only two mTOR (a downstream modulator of PI3K signalling) inhibitors, Everolimus and Temsirolimus, have been approved for clinical use 8. This might be, at least in part, due to the complexity of the PI3K pathway, while frequently reduced to a "survival pathway" in the context of cancer research, this network has several distinct and somehow competing functions 9,10. In our hands, inhibition of PI3K signalling in differentiated GB cells (DGBCs) only weakly reduces their proliferation and has little effect on their resistance to apoptosis; however, it strongly reduces their motility. In contrast the motility of the corresponding stem cell-like cells (SCs) was not affected, but the increased resistance of SCs compared to DGBCs with regard to apoptosis induction, seems to be mediated, at least in part, by PI...

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confidence: 63%

The limitations of targeting MEK signalling in Glioblastoma therapy

Selvasaravanan

Wiederspohn

Hadzalic

et al. 2020

Sci Rep

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“…MGMT is a repair enzyme that removes the methyl group from the O 6 -position of guanine, thereby preventing further mismatches and preventing MMR activation. Hypermethylation of the promoter region of MGMT is found in 30-60% of all GB patients [18]. MGMT, however, is a highly debated predictive biomarker for therapy response, as the MGMT status does not universally correlate with TMZ responsiveness [19].…”

Section: Introductionmentioning

confidence: 99%

Considering the Experimental Use of Temozolomide in Glioblastoma Research

Herbener¹,

Burster

Goreth³

et al. 2020

Biomedicines

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Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus—ultimately—cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge.

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“…DNA is the prime target of a large number of chemotherapeutic drugs which activate DNA damage response, leading to inhibiting cell proliferation and inducing cell death [ 10 ]. DNA damage is important in determining the efficacy of these therapies.…”

Section: Discussionmentioning

confidence: 99%

A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway

et al. 2018

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Through cell-based screening models, we have identified a new compound IMB5043, a thiophenylated pyridazinone, which exerted cytotoxicity against cancer cells. In the present study, we evaluated its antitumor efficacy and the possible mechanism. By MTT assay, IMB5043 inhibited the proliferation of various human cancer cells lines, especially hepatocarcinoma SMMC-7721 cells. IMB5043 blocked cell cycle with G2/M arrest, induced cell apoptosis, and inhibited the migration and invasion of SMMC-7721 cells. As verified by comet assay and γ-H2AX foci formation, IMB5043 caused DNA damage and activated ATM, Chk2 and p53 through phosphorylation. As shown by Gene microarray analysis, the differentially expressed genes in SMMC-7721 cells treated with IMB5043 were highly related to cell death and apoptosis. IMB5043 suppressed the growth of hepatocarcinoma SMMC-7721 xenograft in athymic mice. By histopathological examination, no lesions were found in bone marrow and various organs of the treated mice. Our findings reveal that IMB5043 as an active compound consisting of both pyridazinone and thiophene moieties exerts antitumor efficacy through activation of ATM-Chk2 pathway. IMB5043 may serve as a promising leading compound for the development of antitumor drugs.

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Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma

Cited by 70 publications

References 109 publications

The limitations of targeting MEK signalling in Glioblastoma therapy

The limitations of targeting MEK signalling in Glioblastoma therapy

Considering the Experimental Use of Temozolomide in Glioblastoma Research

A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway

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