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Updated: Aug 1, 2026
Method for Novel Anti-Cancer Drug Development using Tumor Explants of Surgical Specimens
Published on: July 29, 2011
Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma
S I Omoruyi1,2, O E Ekpo1, D M Semenya3
1Department of Medical Bioscience, Faculty of Natural Sciences, University of the Western Cape, Bellville, Cape Town, 7530, South Africa.
Abstract:
Glioblastoma remains the most malignant of all primary adult brain tumours with poor patient survival and limited treatment options. This study adopts a drug repurposing approach by investigating the anti-cancer activity of a derivative of the antipsychotic drug phenothiazine (DS00329) in malignant U251 and U87 glioblastoma cells. Results from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays showed that DS00329 inhibited short-term glioblastoma cell viability and long-term survival while sparing non-cancerous cells. Western blot analysis with an antibody to γH2AX showed that DS00329 induced DNA damage and flow cytometry and western blotting confirmed that it triggered a G1 cell cycle arrest which correlated with decreased levels in Cyclin A, Cyclin B, Cyclin D1 and cyclin dependent kinase 2 and an increase in levels of the cyclin dependent kinase inhibitor p21. DS00329 treated glioblastoma cells exhibited morphological and molecular markers typical of apoptotic cells such as membrane blebbing and cell shrinkage and an increase in levels of cleaved PARP. Flow cytometry with annexin V-FITC/propidium iodide staining confirmed that DS00329 induced apoptotic cell death in glioblastoma cells. We also show that DS00329 treatment of glioblastoma cells led to an increase in the autophagosome marker LC3-II and autophagy inhibition studies using bafilomycin A1 and wortmannin, showed that DS00329-induced-autophagy was a pro-death mechanism. Furthermore, DS00329 treatment of glioblastoma cells inhibited the phosphatidylinositol 3'-kinase/Akt cell survival pathway. Our findings suggest that DS00329 may be an effective treatment for glioblastoma and provide a rationale for further exploration and validation of the use of phenothiazines and their derivatives in the treatment of glioblastoma.
Insights
A phenothiazine derivative, DS00329, effectively targets glioblastoma cells by inducing DNA damage, cell cycle arrest, and apoptosis. This repurposed drug shows promise for treating aggressive brain tumors while sparing healthy cells.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma is an aggressive brain tumor with limited treatment options and poor patient survival.
- Drug repurposing offers a strategy to identify novel therapeutic agents for glioblastoma.
Purpose of the Study:
- To investigate the anti-cancer activity of DS00329, a phenothiazine derivative, against malignant glioblastoma cells.
- To elucidate the mechanisms underlying DS00329's effects on glioblastoma cell viability, cell cycle, apoptosis, and survival pathways.
Main Methods:
- MTT and clonogenic assays were used to assess glioblastoma cell viability and survival.
- Western blotting and flow cytometry were employed to analyze DNA damage, cell cycle arrest, apoptosis, and autophagy markers.
- Inhibition studies with bafilomycin A1 and wortmannin were conducted to investigate the role of autophagy.
Main Results:
- DS00329 significantly inhibited glioblastoma cell viability and long-term survival while sparing non-cancerous cells.
- DS00329 induced DNA damage, G1 cell cycle arrest, and apoptosis, evidenced by increased cleaved PARP and annexin V/propidium iodide staining.
- DS00329 triggered a pro-death autophagic response and inhibited the phosphatidylinositol 3'-kinase/Akt survival pathway.
Conclusions:
- DS00329 exhibits potent anti-cancer activity against glioblastoma cells through multiple mechanisms, including DNA damage, cell cycle arrest, apoptosis, and autophagy.
- DS00329 demonstrates potential as an effective therapeutic agent for glioblastoma.
- Phenothiazines and their derivatives warrant further investigation for glioblastoma treatment.
