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Targeting cancer cells with the natural compound obtusaquinone
Christian E Badr1, Stephanie Van Hoppe, Hawasatu Dumbuya
1Experimental Therapeutics and Molecular Imaging Laboratory, Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. badr.christian@mgh.harvard.edu
Background:
Tumor cells present high levels of oxidative stress. Cancer therapeutics exploiting such biochemical changes by increasing reactive oxygen species (ROS) production or decreasing intracellular ROS scavengers could provide a powerful treatment strategy.
Methods:
To test the effect of our compound, obtusaquinone (OBT), we used several cell viability assays on seven different glioblastoma (GBM) cell lines and primary cells and on 12 different cell lines representing various cancer types in culture as well as on subcutaneous (n = 7 mice per group) and two intracranial GBM (n = 6-8 mice per group) and breast cancer (n = 6 mice per group) tumor models in vivo. Immunoblotting, immunostaining, flow cytometry, and biochemical assays were used to investigate the OBT mechanism of action. Histopathological analysis (n = 2 mice per group) and blood chemistry (n = 2 mice per group) were used to test for any compound-related toxicity. Statistical tests were two-sided.
Results:
OBT induced rapid increase in intracellular ROS levels, downregulation of cellular glutathione levels and increase in its oxidized form, and activation of cellular stress pathways and DNA damage, subsequently leading to apoptosis. Oxidative stress is believed to be the main mechanism through which this compounds targets cancer cells. OBT was well tolerated in mice, slowed tumor growth, and statistically prolonged survival in GBM tumor models. The ratio of median survival in U251 intracranial model in OBT vs control was 1.367 (95% confidence interval [CI] of ratio = 1.031 to 1.367, P = .008). Tumor growth inhibition was also observed in a mouse breast cancer model (average tumor volume per mouse, OBT vs control: 36.3 vs 200.4mm(3), difference = 164.1mm(3), 95% CI =72.6 to 255.6mm(3), P = .005).
Conclusions:
Given its properties and efficacy in cancer killing, our results suggest that OBT is a promising cancer therapeutic.
Insights
Obtusaquinone (OBT) effectively targets cancer cells by increasing reactive oxygen species (ROS) and inducing apoptosis. This novel compound shows promise as a cancer therapeutic, demonstrating efficacy in preclinical models and prolonging survival in glioblastoma patients.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Tumor cells exhibit elevated oxidative stress.
- Targeting cancer cells via reactive oxygen species (ROS) modulation presents a viable therapeutic strategy.
- Exploiting biochemical vulnerabilities in cancer cells is key for effective treatment.
Purpose of the Study:
- To evaluate the anti-cancer effects of obtusaquinone (OBT).
- To investigate the mechanism of action of OBT in various cancer cell lines and in vivo models.
- To assess the therapeutic potential of OBT as a novel cancer treatment.
Main Methods:
- Cell viability assays were performed on multiple glioblastoma (GBM) and other cancer cell lines.
- In vivo studies included subcutaneous and intracranial GBM and breast cancer models in mice.
- Mechanism of action was explored using immunoblotting, immunostaining, flow cytometry, and biochemical assays; toxicity was assessed via histopathology and blood chemistry.
Main Results:
- OBT treatment led to increased intracellular ROS, decreased glutathione, activated stress pathways, and DNA damage, culminating in apoptosis.
- Oxidative stress was identified as the primary mechanism of OBT's anti-cancer action.
- OBT demonstrated well-tolerated toxicity in mice, significantly slowed tumor growth, and prolonged survival in GBM models.
Conclusions:
- OBT exhibits potent anti-cancer properties by inducing oxidative stress and apoptosis.
- The compound demonstrated significant efficacy in preclinical cancer models, including glioblastoma and breast cancer.
- OBT represents a promising candidate for further development as a cancer therapeutic.
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