Interfering with mitochondrial dynamics sensitizes glioblastoma multiforme to temozolomide chemotherapy

Wang, Nan; Huang, Renxuan; Yang, Kunmeng; He, Yichun; Gao, Yufei; Dong, Delu

doi:10.1111/jcmm.17147

Cited by 14 publications

(6 citation statements)

References 64 publications

(67 reference statements)

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“…Mitochondria plays an important role both in regulating cell bioenergy production and in therapeutic resistance. [22,23] Responsible for producing 95% of total cellular ATP through oxidative phosphorylation (OXPHOS) as well as for controlling cell death and survival, mitochondria are critical for cellular function. [23] Cellular bioenergy production comes from glycolysis and mitochondrial OXPHOS essential for cell survival.…”

Section: Introductionmentioning

confidence: 99%

Novel DZ‐SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma

Wang

Chu

et al. 2022

Advanced Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. A novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (DZ), and HMG-CoA inhibitor simvastatin (SIM), is developed and its efficacy in PDAC is assessed. PDAC cell specific targeting of DZ-SIM is measured by determining the fluorescence in cells and animals. Mitochondrial bioenergetics and functions are measured by Seahorse and flow cytometry, respectively. Apoptosis is assessed by DNA fragmentation, annexin V/propidium iodide staining, and TUNEL. Markers of cell invasion, epithelial-to-mesenchymal transition, and cancer stemness are measured. The effect of DZ-SIM on survival, tumor growth, and metastasis is measured in the Kras þ/LSLG12D ;Trp53 þ/LSLR172H ;Pdx-1 −Cre transgenic mice and in syngeneic and subcutaneous PDAC models. NIR fluorescence imaging shows specific localization of DZ-SIM to cancer, but not to normal cells and tissues. DZ-SIM significantly inhibits tumor growth and re-sensitizes therapeutically resistant PDAC cells to conventional therapies. DZ-SIM kills cancer cells through unique pathways involving decreasing mitochondrial bioenergetics, including oxygen consumption and ATP production, and increasing ROS production. Mitochondrial depletion prevents the effect of DZ-SIM. Administration of DZ-SIM in three PDAC animal models results in a marked increase in survival and a decrease in tumor growth and metastasis.

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Section: Introductionmentioning

confidence: 99%

Novel DZ‐SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma

Wang

Chu

et al. 2022

Advanced Therapeutics

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“…In the present study, we found that VEGFR2 inhibition elevated mitochondrial biogenesis and increased OXPHOS respiration, resulting in suppressing cell proliferation and promoting cell apoptosis. There is an earlier report showing that temozolomide treatment increased mitochondria size and OXPHOS levels in glioblastomas and resulted in temozolomide resistance, and that the interruption of mitochondria fusion process downregulated OXPHOS level and sensitized GBM cells to temozolomide [37]. Thus, the impact of elevated OXPHOS levels for glioblastoma treatment may be complex.…”

Section: Discussionmentioning

confidence: 99%

VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis

Guo,

Zhang,

Han

et al. 2024

J Transl Med

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Background Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. Methods VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. Results VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. Conclusions VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

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“…A similar trend was also observed for the expression of CD44 and CD133 in BCSCs (two well-established markers of stemness) after treatment with AZD5363. Some studies reported a possible direct correlation between increased mitochondrial fusion and the chemo-resistance of tumor cells (Wang et al, 2022 ). In our study, the IC 50 value of doxorubicin, a common chemo drug used against TNBC, was significantly lower when combined with AZD5363 on BCSCs.…”

Section: Discussionmentioning

confidence: 99%

Targeting mitochondrial dynamics by AZD5363 in triple-negative breast cancer MDA-MB-231 cell–derived spheres

Dong

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Breast cancer stem cells (BCSCs) have been suggested to contribute to chemotherapeutic resistance and disease relapse in breast cancer. Thus, BCSCs represent a promising target in developing novel breast cancer treatment strategies. Mitochondrial dynamics in BCSCs were recently highlighted as an available approach for targeting BCSCs. In this study, a three-dimensional (3D) cultured breast cancer stem cell spheres model was constructed. Mitochondrial dynamics and functions were analyzed by flow cytometry and confocal microscopy. We have demonstrated that the protein levels of FIS 1 and Mitofusin 1 were significantly increased in BCSCs. Moreover, Capivasertib (AZD5363) administration could suppress Mitofusin1 expression in BCSCs. Our use of MitoTracker Orange and annexin V double-staining assay suggested that AZD5363 could induce apoptosis in BCSCs. The sensitivity of stem cell spheres to doxorubicin was investigated by CCK8 assay, and our results indicated that AZD5363 could re-sensitize BCSCs to Doxo. Flow cytometry analysis identified doxo-induced CD44 and CD133 expression in BCSCs could be suppressed by AZD5363. In combination with AZD536, doxo-induced apoptosis in the BCSCs was significantly increased. In conclusion, our study explored, for the first time, that AZD5363 could target mitochondrial dynamics in 3D cultured stem cell spheres (BCSCs) by regulating Mitofusin.

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Interfering with mitochondrial dynamics sensitizes glioblastoma multiforme to temozolomide chemotherapy

Cited by 14 publications

References 64 publications

Novel DZ‐SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma

Novel DZ‐SIM Conjugate Targets Cancer Mitochondria and Prolongs Survival in Pancreatic Ductal Adenocarcinoma

VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis

Targeting mitochondrial dynamics by AZD5363 in triple-negative breast cancer MDA-MB-231 cell–derived spheres

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