Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling

Hanif, Farina; Perveen, Kahkashan; Malhi, Saima Mahmood; Jawed, Huma; Simjee, Shabana Usman

doi:10.1016/j.tiv.2018.07.001

Cited by 19 publications

(32 citation statements)

References 33 publications

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“…However, given how many cytotoxic therapies www.nature.com/scientificreports/ in GBM treatment utilize components of the apoptosis pathways, the validity of this finding is plausible 42 . Similar synergy studies in GBM with other apoptosis-dependent therapies have been performed by Hanif and colleagues, who have investigated the drug verapamil 43 as well as a synthetic acetamide 44 in separate combinations with TMZ. They observed similar combination index results to indicate synergy, and noted that when in combination, bcl-2 expression was decreased, which parallels our observations with La 2 O 3 NPs.…”

Section: Scientific Reportssupporting

confidence: 54%

Cytotoxic lanthanum oxide nanoparticles sensitize glioblastoma cells to radiation therapy and temozolomide: an in vitro rationale for translational studies

Jue

McDonald

2020

Sci Rep

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Glioblastoma (GBM) is a malignant brain tumour with a dismal prognosis, despite best treatment by surgical resection, radiation therapy (RT) and chemotherapy with temozolomide (TMZ). Nanoparticle (NP) therapy is an emerging consideration due to the ability of NPs to be formulated and cross the blood brain barrier. Lanthanum oxide (La2O3) NPs are therapeutically advantageous due to the unique chemical properties of lanthanum making it cytotoxic to cancers, and able to enhance existing anti-cancer treatments. However, La2O3 NPs have yet to be thoroughly investigated in brain tumors. We show that these NPs can reach the brain after venous injection, penetrate into GBM cells via endocytosis, dissociate to be cytotoxic, and enhance the therapeutic effects of RT and TMZ. The mechanisms of cell death by La2O3 NPs were found to be multifaceted. Increasing NP concentration was correlated to increased intrinsic and extrinsic apoptosis pathway markers in a radical oxygen species (ROS)-dependent manner, as well as involving direct DNA damage and autophagic pathways within GBM patient-derived cell lines. NP interactions to sensitize GBM to RT and TMZ were shown to involve these pathways by enhancing ROS and apoptotic mechanisms. We therefore demonstrate the therapeutic potential of La2O3 NPs to treat GBM cells in vitro, and encourage translational exploration in the future.

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Section: Scientific Reportssupporting

confidence: 54%

Cytotoxic lanthanum oxide nanoparticles sensitize glioblastoma cells to radiation therapy and temozolomide: an in vitro rationale for translational studies

Jue

McDonald

2020

Sci Rep

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“…Morphology of U87 cells was observed after treatment with Temozolomide and Opuntiol, morphological changes of U87 cells were aligning with all the apoptotic changes as described previously (Hanif et al 2018).…”

Section: Discussionmentioning

confidence: 67%

“…Briefly, U87 possesses distinct morphological features of forming processes, making contact with neighboring cell and have star shape morphology, while under apoptotic condition it was observed that cells have lost their adherence and contact with neighboring cell and became rounded in appearance (Hanif et al, 2018). DNA fragmentation which is another important hallmarks of apoptosis was also evaluated using terminal dUTP nick-end-labeling (TUNEL) assay kit and it further confirmed the presence of apoptosis in treated cells.…”

Section: Discussionmentioning

confidence: 94%

“…In spite of advance treatment approaches and research in the field of oncology, glioblastoma still remains a deadly tumor with 14-15 months survival rate due to its aggressive nature and recurrence properties. Over the years investigations has been done to find out bioactive molecules which can halt the progression of tumor and improve the prognosis but unfortunately still with only limited success (Hanif et al, 2018). Role of dysregulated apoptotic cell machinery is well established in cancer progression and therefore is an attractive target in cancer therapy (Koff et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…time is also approximately 14 to 15 months post diagnosis which makes it a serious public health issue (Hanif et al, 2018;Moneim et al, 2018). Therefore, there is a dire need to identify new therapeutic compounds or drugs which can target the disease and improve the prognosis.…”

Section: Opuntiol Inhibits Growth and Induces Apoptosis In Human Glioblastoma Cells By Upregulating Active Caspase 3 Expressionmentioning

confidence: 99%

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Opuntiol Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells by Upregulating Active Caspase 3 Expression

Ashfaque

Hanif

Simjee

et al. 2021

Asian Pac J Cancer Prev

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Background: Glioblastoma Multiforme (GBM) is a deadly tumor with poor prognosis. Resistance to apoptosis considered as an important factor in treatment failure. Therefore, identification of new compounds that facilitates apoptosis is crucial. Natural Anti-inflammatory compounds have emerged as potential anti-cancer agents and should be explored for their apoptotic activity against GBM. Therefore, the present study aims to evaluate growth inhibitory and apoptotic activity of a natural anti-inflammatory compound "Opuntiol" against GBM cell line U87. Methods: MTT assay was performed to determine the effect of Temozolomide and Opuntiol on growth inhibition of U87 cell. While, TUNEL assay was used to assess their apoptotic activity. To further assess apoptosis, nuclear condensation and nuclear area factor (NAF) was evaluated through DAPI staining. Whereas, active caspase-3 protein expression determined using immunocytochemistry. Results: Significant growth inhibition was observed in U87 cells treated with Temozolomide (IC50 380 µM) and Opuntiol (IC 50 357 µM). Temozolomide (p<0.001) and Opuntiol (p<0.001) significantly improved rate of apoptosis when compared to control group. A significant decrease in NAF was also observed in Temozolomide (p < 0.05) and Opuntiol (p < 0.05) treated cells. There was a significant increase in active caspase-3 expression when observed in Temozolomide (p<0.001) and Opuntiol (p<0.05) treated groups as compared to control. Conclusion: In conclusion our findings suggests, Opuntiol repress cell viability and possess strong apoptotic activity against GBM cell line U-87. However, further mechanistic studies will be required to confirm whether it can be develop as a potential drug against GBM.

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Synthesis and Biological Evaluation of a Library of Sulfonamide Analogs of Memantine to Target Glioblastoma

Philo,

Caudle,

Moussa

et al. 2023

ChemMedChem

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A library of 34 lipophilic sulfonamides based upon the memantine core has been synthesized to identify potential drug candidates to cross the blood‐brain barrier and target glioblastoma. The library was screened for in vitro activity against 4 mammalian cell lines, including U‐87 (glioblastoma). Additional synthetic variation of the active compounds has validated the importance of specific regions of the pharmacophore, with the sulfonamide functionality and S‐aryl unit displaying the most significant impact. In silico investigations suggest the active compounds might target DDR1 or RET proteins. The investigation has resulted in several compounds that warrant further development for lead optimization.

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Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling

Cited by 19 publications

References 33 publications

Cytotoxic lanthanum oxide nanoparticles sensitize glioblastoma cells to radiation therapy and temozolomide: an in vitro rationale for translational studies

Cytotoxic lanthanum oxide nanoparticles sensitize glioblastoma cells to radiation therapy and temozolomide: an in vitro rationale for translational studies

Opuntiol Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells by Upregulating Active Caspase 3 Expression

Synthesis and Biological Evaluation of a Library of Sulfonamide Analogs of Memantine to Target Glioblastoma

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