Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer

Rodríguez-Hernández, Ángeles; Cruz‐Ojeda, Patricia de la; López-Grueso, Ma José; Navarro-Villarán, Elena; Requejo-Aguilar, Raquel; Castejón-Vega, Beatriz; Negrete, María; Gallego, Paloma; Vega-Ochoa, Álvaro; Víctor, Víctor M.; Cordero, Mario D.; Campo, J.A. Del; Bárcena, José Antonio; Padilla, C. Alicia; Muntané, Jordi

doi:10.1016/j.redox.2020.101510

Cited by 46 publications

(33 citation statements)

References 176 publications

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“…Lastly, c-MET expression was also evaluated by IHC as increased c-MET aids in tumor progression and proliferation. c-MET is one of many HIF-1α transcriptional targets, as well as GLUT1 (glucose transporter 1), BNIP3 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 3) and erythropoietin [ 19 ]. Untreated mice had significantly higher c-MET expression (0.24 ± 0.06) compared to both the OKN-007 treated mice (0.12 ± 0.07; p value of 0.0334) and LDN-193189 treated mice (0.09 ± 0.03; p value of 0.0084) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Radiotherapy is routinely used to treat DIPG, but unfortunately is palliative in nature. Prior studies have not demonstrated any survival benefit with the use of adjuvant chemotherapy versus radiation therapy alone [ 19 , 21 ]. The ineffective response to chemotherapeutic agents alone is likely due to the intact BBB seen in DIPG [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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OKlahoma Nitrone-007: novel treatment for diffuse intrinsic pontine glioma

et al. 2020

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Background Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem cancer in childhood. This rapidly progressing brainstem glioma holds a very dismal prognosis with median survival of less than 1 year. Despite extensive research, no significant therapeutic advancements have been made to improve overall survival in DIPG patients. Methods Here, we used an orthotopic xenograft pediatric DIPG (HSJD-DIPG-007) mouse model to monitor the effects of anti-cancer agent, OKlahoma Nitrone-007 (OKN-007), as an inhibitor of tumor growth after 28 days of treatment. Using magnetic resonance imaging (MRI), we confirmed the previously described efficacy of LDN-193189, a known activin A receptor, type I (ACVR1) inhibitor, in decreasing tumor burden and found that OKN-007 was equally efficacious. Results After 28 days of treatment, the tumor volumes were significantly decreased in OKN-007 treated mice (p < 0.01). The apparent diffusion coefficient (ADC), as a measure of tissue structural alterations, was significantly decreased in OKN-007 treated tumor-bearing mice (p < 0.0001). Histological analysis also showed a significant decrease in CD34 expression, essential for angiogenesis, of OKN-007 treated mice (p < 0.05) compared to LDN-193189 treated mice. OKN-007-treated mice also significantly decreased protein expression of the human nuclear antigen (HNA) (p < 0.001), ACVR1 (p < 0.0001), and c-MET (p < 0.05), as well as significantly increased expression of cleaved caspase 3 (p < 0.001) and histone H3 K27-trimethylation (p < 0.01), compared to untreated mouse tumors. Conclusions With the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies, and OKN-007 merits further exploration as a therapeutic agent.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

OKlahoma Nitrone-007: novel treatment for diffuse intrinsic pontine glioma

et al. 2020

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“…Lastly, c-MET expression was also evaluated by IHC as increased c-MET aids in tumor progression and proliferation. c-MET is one of many HIF-1α transcriptional targets, as well as GLUT1 (glucose transporter 1), BNIP3 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 3) and erythropoietin (19). Untreated mice had signi cantly higher c-MET expression (0.24 ± 0.06) compared to both the OKN-007 treated mice (0.12 ± 0.07; p value of 0.0334) and LDN-193189 treated mice (0.09 ± 0.03; p value of 0.0084) ( Figure 12).…”

Section: Resultsmentioning

confidence: 99%

“…Radiotherapy is routinely used to treat DIPG, but unfortunately is palliative in nature. Prior studies have not demonstrated any survival bene t with the use of adjuvant chemotherapy versus radiation therapy alone (19,21). The ineffective response to chemotherapeutic agents alone is likely due to the intact BBB seen in DIPG (29).…”

Section: Treatmentmentioning

confidence: 98%

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OKlahoma Nitrone-007: Novel Treatment for Diffuse Intrinsic Pontine Glioma

Thomas

Smith

Saunders

et al. 2020

Preprint

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Background: Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem cancer in childhood. This rapidly progressing brainstem glioma holds a very dismal prognosis with median survival of less than 1 year. Despite extensive research, no significant therapeutic advancements have been made to improve overall survival in DIPG patients. Methods: Here, we used an orthotopic xenograft pediatric DIPG (HSJD-DIPG-007) mouse model to monitor the effects of anti-cancer agent, OKlahoma Nitrone-007 (OKN-007), as an inhibitor of tumor growth after 28 days of treatment. Using magnetic resonance imaging (MRI), we confirmed the previously described efficacy of LDN-193189, a known activin A receptor, type I (ACVR1) inhibitor, in decreasing tumor burden and found that OKN-007 was equally efficacious.Results: After 28 days of treatment, the tumor volumes were significantly decreased in OKN-007 treated mice (p<0.01). The apparent diffusion coefficient (ADC), as a measure of tissue structural alterations, was significantly decreased in OKN-007 treated tumor-bearing mice (p<0.0001). Histological analysis also showed a significant decrease in CD34 expression, essential for angiogenesis, of OKN-007 treated mice (p<0.05) compared to LDN-193189 treated mice. OKN-007-treated mice also significantly decreased protein expression of the human nuclear antigen (HNA) (p<0.001), ACVR1 (p<0.0001), and c-MET (p<0.05), as well as significantly increased expression of cleaved caspase 3 (p<0.001) and histone H3 K27-trimethylation (p<0.01), compared to untreated mouse tumors.Conclusions: With the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies, and OKN-007 merits further exploration as a therapeutic agent.

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