Cyclooxygenase (COX) Inhibition by Acetyl Salicylic Acid (ASA) Enhances Antitumor Effects of Nitric Oxide in Glioblastoma In Vitro

Guenzle, Jessica; Garrelfs, Nicklas W C; Goeldner, Jonathan M; Weyerbrock, Astrid

doi:10.1007/s12035-019-1513-6

Cited by 17 publications

(11 citation statements)

References 46 publications

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“…Cell viability was determined by MTT Assay. 5 x 10 4 cells were grown in 96 well plates with complete RPMI and treated with 10-250 µM JR-AB2-011 for up to 72 h. MTT Assay was performed as described before [53]. Absorbance at 570 nm was measured (Tecan, Männedorf, Switzerland).…”

Section: Viability Assaymentioning

confidence: 99%

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Guenzle

Akasaka

Joechle

et al. 2020

IJMS

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Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.

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Section: Viability Assaymentioning

confidence: 99%

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Guenzle

Akasaka

Joechle

et al. 2020

IJMS

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“…Despite inconsistent findings in the literature, the use of aspirin is associated with a reduced risk of glioma [ 30 , 31 ]. The results of cell studies also implicate the apoptotic and combinatory effects of aspirin on glioma cells [ 32 , 33 ]. To extend our understanding of the effects of aspirin on glioma apoptosis, the molecular bases of crosstalk between anti-apoptotic and pro-apoptotic Bcl-2 family proteins and underlying apoptotic programs were investigated.…”

Section: Introductionmentioning

confidence: 99%

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

Chang

Pan

et al. 2020

IJMS

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Clinically, high cyclooxygenase-2 expression in malignant glioma correlates well with poor prognosis and the use of aspirin is associated with a reduced risk of glioma. To extend the current understanding of the apoptotic potential of aspirin in most cell types, this study provides evidence showing that aspirin induced glioma cell apoptosis and inhibited tumor growth, in vitro and in vivo. We found that the human H4 glioma cell-killing effects of aspirin involved mitochondria-mediated apoptosis accompanied by endoplasmic reticulum (ER) stress, Noxa upregulation, Mcl-1 downregulation, Bax mitochondrial distribution and oligomerization, and caspase 3/caspase 8/caspase 9 activation. Genetic silencing of Noxa or Bax attenuated aspirin-induced viability loss and apoptosis, while silencing Mcl-1 augmented the effects of aspirin. Data from genetic and pharmacological studies revealed that the axis of ER stress comprised an apoptotic cascade leading to Noxa upregulation and apoptosis. The apoptotic programs and mediators triggered by aspirin in H4 cells were duplicated in human U87 glioma cell line as well as in tumor-bearing BALB/c nude mice. The involvement of ER stress in indomethacin-induced Mcl-1 downregulation was reported in our previous study on glioma cells. Therefore, the aforementioned phenomena indicate that ER stress may be a valuable target for intervention in glioma apoptosis.

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“…Among the candidate genes, cyclooxygenase 2 (COX-2) overexpression is positively associated with the pathological grade and negatively correlated with the glioma survival rate [13]. Despite conflicting results in clinical practice, COX inhibition induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is still a therapeutic option for glioma treatment, either as a monotherapy or combinatory therapy [14][15][16]. Accumulating evidence indicates that COX-dependent and COX-independent mechanisms underlie the anti-neoplastic action of NSAIDs and that ER stress is an off-target of the latter [17,18].…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

Chang

et al. 2020

IJMS

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The dormancy of cellular apoptotic machinery has been highlighted as a crucial factor in therapeutic resistance, recurrence, and poor prognosis in patients with malignancy, such as malignant glioma. Increasing evidence indicates that nonsteroidal anti-inflammatory drugs (NSAIDs) confer chemopreventive effects, and indomethacin has been shown to have a novel chemotherapeutic application targeting glioma cells. To extend these findings, herein, we studied the underlying mechanisms of apoptosis activation caused by indomethacin in human H4 and U87 glioma cells. We found that the glioma cell-killing effects of indomethacin involved both death receptor- and mitochondria-mediated apoptotic cascades. Indomethacin-induced glioma cell apoptosis was accompanied by a series of biochemical changes, including reactive oxygen species generation, endoplasmic reticulum (ER) stress, apoptosis signal-regulating kinase-1 (Ask1) activation, p38 hyperphosphorylation, protein phosphatase 2A (PP2A) activation, Akt dephosphorylation, Mcl-1 and FLICE-inhibiting protein (FLIP) downregulation, Bax mitochondrial distribution, and caspases 3/caspase 8/caspase 9 activation. Data on pharmacological inhibition related to oxidative stress, ER stress, free Ca2+, and p38 revealed that the axis of oxidative stress/ER stress/Ask1/p38/PP2A/Akt comprised an apoptotic cascade leading to Mcl-1/FLIP downregulation and glioma apoptosis. Since indomethacin is an emerging choice in chemotherapy and its antineoplastic effects have been demonstrated in glioma tumor-bearing models, the findings further strengthen the argument for turning on the aforementioned axis in order to activate the apoptotic machinery of glioma cells.

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Cyclooxygenase (COX) Inhibition by Acetyl Salicylic Acid (ASA) Enhances Antitumor Effects of Nitric Oxide in Glioblastoma In Vitro

Cited by 17 publications

References 46 publications

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

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