Targeted Anti-Mitochondrial Therapy: The Future of Oncology

Taghizadeh‐Hesary, Farzad; Akbari, Hassan; Bahadori, Moslem; Behnam, Babak

doi:10.3390/genes13101728

Cited by 23 publications

(24 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nrf2 is an important player in the maintenance of mitochondrial homeostasis and structural integrity; under oxidative and inflammatory stress conditions, the protective role of Nrf2 is particularly critical [ 32 ]. The importance of mitochondrial metabolism in cancer survival and progression has recently been studied, suggesting that novel strategies targeting mitochondria could potentially represent the future of oncology [ 33 ]. Therefore, the interference of the Nrf2/PPAR signaling with mitochondrial functions during cancer cell apoptosis may represent a valuable anticancer strategy.…”

Section: Discussionmentioning

confidence: 99%

Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells

Gallorini

Valerio

Bruno

et al. 2023

IJMS

View full text Add to dashboard Cite

The NF-E2-related factor 2 transcription factor (Nrf2) orchestrates the basal and stress-inducible activation of a vast array of antioxidant genes. A high amount of reactive oxygen species (ROS) promotes carcinogenesis in cells with defective redox-sensitive signaling factors such as Nrf2. In breast cancer (BC), emerging evidence indicates that increased Nrf2 activity enhances cell metastatic potential. An interconnection between peroxisome proliferator-activated receptors (PPARs) and Nrf2 pathways in cancer has been shown. In this light, newly synthesized PPARα antagonists, namely IB42, IB44, and IB66, were tested in the BC cell line MCF7 in parallel with GW6471 as the reference compound. Our results show that the most promising compound of this phenylsulfonimide series (IB66) is able to decrease MCF7 proliferation by blocking cells at the G2/M checkpoint. The underlying mechanism has been investigated, disclosing a caspase 3/Akt-dependent apoptotic/pyroptotic pathway induced by the increased generation of oxidative stress. Moreover, the involvement of Nrf2 and COX2 in IB66-treated MCF7 cell response has been highlighted. The reported data lay the groundwork for the development of alternative targeted therapy involving the Nrf2/PPARα molecular axis, able to overcome BC cell chemoresistance and cause better clinical outcomes, promoting other forms of programmed cell death, such as pyroptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells

Gallorini

Valerio

Bruno

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…The DNA damage by photon or X-rays irradiation is mainly through an indirect mechanism (by producing reactive oxygen species (ROS)), while the carbon ion irradiation directly mediates the DNA damage and is less dependent on the ROS. 55 , 56 Glioma cells with high glycolysis generate radio-resistance via ROS generation to X-rays irradiation while CII could not. As glycolytic flux is a consequence of metabolic reprogramming in cancer cells, certain intermediates of glycolysis efficiently scavenge radiation-induced ROS that may lead to resistance to X-rays or photons.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Glycolysis Confers Resistance Against Photon but Not Carbon Ion Irradiation in Human Glioma Cell Lines

Vashishta¹,

Kumar²,

Guha³

et al. 2023

CMAR

View full text Add to dashboard Cite

Purpose Metabolic reprogramming is a key hallmark in various malignancies and poses a challenge in achieving success with various therapies. Enhanced glycolysis is known to confer resistance against photon irradiation while the tumor response to carbon ion irradiation (CII) has not been investigated. This study aimed to investigate the effects of enhanced glycolysis on the response of human glioma cell lines to CII compared to the response to X-rays. Material and Methods Glycolysis was stimulated using Dinitrophenol (DNP), a mild OXPHOS inhibitor, in three human glioma cell lines (U251, U87, and LN229) and assessed by monitoring glucose uptake and utilization as well as expression of regulators of glycolysis (glucose transporter protein type 1(Glut1), hexokinase-II (HKII), and Pyruvate Kinase-2 (PKM2). Radiation (X-rays and CII) induced loss of clonogenic survival growth inhibition and perturbations in cell cycle progression (G 2 +M block), cytogenetic damage (micronuclei formation), apoptosis, necrosis (reflecting interphase death), and cell migration (Scratch assay) were investigated as parameters of radiation response. Results DNP (1 mM) enhanced the expression levels of GLUT1, HKII, and PKM2 by 30–60% and glucose uptake as well as usage by nearly 3 folds in U251 cells suggesting the stimulation of glycolysis. Enhanced glycolysis attenuated the loss of clonogenic survival with D 10 doses increasing by 20% to 65% in these cell lines, while no significant changes were noted following CII. Concomitantly, dose-dependent growth inhibition, and cytogenetic damage as well as apoptosis and necrosis induced by X-rays were also reduced by elevated glycolysis in U251 and LN229 cells by 20–50%. However, stimulation of glycolysis enhanced the X-ray-induced cell migration, while it had negligible effect on migration following CII. Conclusion Our results suggest that enhanced glycolysis confers resistance against X-ray-induced cell death and migration, while it may not significantly alter the cellular responses to carbon ion irradiation.

show abstract

“…Tumour biology in young patients is also a likely contributing factor to the high proportion presenting with advanced disease. Compared to older patients, young adults have better vascular supply and, as such, access to oxygen and glucose, resulting in greater tumourigenesis and larger tumours [ 16 ]. This in turn may result in greater tumour hypoxia, increased hypoxia-inducible factor 1 (HIF-1) and associated epithelial-mesenchymal transition, a pre-requisite for metastasis [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Non-Small Cell Lung Cancer (NSCLC) in Young Adults, Age < 50, Is Associated with Late Stage at Presentation and a Very Poor Prognosis in Patients That Do Not Have a Targeted Therapy Option: A Real-World Study

Hughes

Kapiris

Nevajda

et al. 2022

Cancers

View full text Add to dashboard Cite

(1) Background: Non-small cell lung cancer (NSCLC) in young patients is uncommon. Real-world evidence on the outcomes of these patients is limited. (2) Methods: We conducted a retrospective cohort study of young NSCLC patients, age < 50 years at diagnosis, who were treated between 2011–2020 in South-East-London cancer centres. Clinicopathological characteristics, treatment and outcomes were analysed. (3) Results: Of 248 NSCLC patients, median age was 46 years, 50% (n = 125) female, 58% (n = 145) white, 18% (n = 45) black and 4% (n = 10) Asian ethnicity. Amongst patients with a documented smoking history, 30% (n = 64) were never-smokers. Most patients had adenocarcinoma (77%, n = 191) and presented with metastatic disease (67%, n = 166). Only 31% (n = 76) had treatment with curative intent. In patients who presented or developed metastatic non-squamous NSCLC (n = 179), EGFR mutation status was known in 88% (n = 157) and mutation present in 19% (n = 34), ALK was known in 66% (n = 118) with a translocation in 10% (n = 18), ROS1 status was known in 57% (n = 102) with a translocation in 4% (n = 8), and KRAS status was known in 66% (n = 119) with a mutation in 12% (n = 22). Overall, 76% (n = 152) patients with metastatic NSCLC received first-line systemic anti-cancer therapy. Median overall survival in metastatic NSCLC was 9.0 months (95% CI 6.5–11.6 months), with superior median overall survival in those with a targeted therapy option (28.7 months) compared to those without (6.6 months; p < 0.001). (4) Conclusion: Young patients contribute a significant proportion of those presenting with lung cancer. They present with advanced stage at diagnosis and have a poor prognosis. Identification of a targeted therapy option is associated with improved survival. However, most patients do not have a known genomic driver, which is in part due to limited testing, particularly in the early years of this study period. These findings highlight the particular importance of rapid-turnaround comprehensive genomic profiling in this age group and the need to identify strategies to facilitate earlier diagnosis in young NSCLC patients.

show abstract

Targeted Anti-Mitochondrial Therapy: The Future of Oncology

Cited by 23 publications

References 119 publications

Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells

Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells

Enhanced Glycolysis Confers Resistance Against Photon but Not Carbon Ion Irradiation in Human Glioma Cell Lines

Non-Small Cell Lung Cancer (NSCLC) in Young Adults, Age < 50, Is Associated with Late Stage at Presentation and a Very Poor Prognosis in Patients That Do Not Have a Targeted Therapy Option: A Real-World Study

Contact Info

Product

Resources

About