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Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma

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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.

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Abbreviations

PTZ:

Phenothiazine

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

γH2AX:

Phosphorylated H2A histone family member X

CDK2:

Cyclin-dependent kinase 2

PARP:

Poly (ADP-ribose) polymerase

FITC:

Fluorescein isothiocyanate (FITC)

LC3:

Microtubule-associated protein light chain 3

FACS:

Fluorescence-activated cell sorting

AVO:

Acidic vesicular organelles

PI3K/Akt:

Phosphatidylinositol 3′ kinase/Akt

MAPK:

Mitogen activated protein kinase

ATM:

Ataxia-telangiectasia mutated

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Acknowledgements

This work was supported by the Cancer Association of South Africa (CANSA), the South Africa National Research Foundation (NRF), the South Africa Medical Research Council (SA MRC), the University of Cape Town, the University of the Western Cape and the University of Benin.

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Authors and Affiliations

  1. Department of Medical Bioscience, Faculty of Natural Sciences, University of the Western Cape, Bellville, Cape Town, 7530, South Africa

    S. I. Omoruyi & O. E. Ekpo

  2. Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa

    S. I. Omoruyi & S. Prince

  3. Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch, Cape Town, 7701, South Africa

    D. M. Semenya & A. Jardine

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  1. S. I. Omoruyi
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Omoruyi, S.I., Ekpo, O.E., Semenya, D.M. et al. Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma. Apoptosis 25, 261–274 (2020). https://doi.org/10.1007/s10495-020-01594-5

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