Mitoxantrone is More Toxic than Doxorubicin in SH-SY5Y Human Cells: A "Chemobrain' In Vitro Study

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Almeida, D (Author) Other; Pinho, R (Author) Other; Correia, V (Author) Other; Soares, J (Author) Other; Maria de Lourdes Bastos (Author) FFUP; Felix Carvalho (Author) FFUP; Capela, JP (Author) Other; Costa, VM (Author) Other

Journal

Title: Pharmaceuticals

Vol. 11

Final page: 41

ISSN: 1424-8247

Publisher: MDPI

Indexing

ISI Web of Knowledge - 1 Citation

Scopus - 1 Citation

Other information

Authenticus ID: P-00P-NJA

DOI: 10.3390/ph11020041

Abstract (EN): The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro neurotoxicity of two commonly used chemotherapeutic drugs, DOX and MTX, and study their underlying mechanisms in the SH-SY5Y human neuronal cell model. Undifferentiated human SH-SY5Y cells were exposed to DOX or MTX (0.13, 0.2 and 0.5 M) for 48 h and two cytotoxicity assays were performed, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction and the neutral red (NR) incorporation assays. Phase contrast microphotographs, Hoechst, and acridine orange/ethidium bromide stains were performed. Mitochondrial membrane potential was also assessed. Moreover, putative protective drugs, namely the antioxidants N-acetyl-l-cysteine (NAC; 1 mM) and 100 M tiron, the inhibitor of caspase-3/7, Ac-DEVD-CHO (100 M), and a protein synthesis inhibitor, cycloheximide (CHX; 10 nM), were tested to prevent DOX- or MTX-induced toxicity. The MTT reduction assay was also done in differentiated SH-SY5Y cells following exposure to 0.2 M DOX or MTX. MTX was more toxic than DOX in both cytotoxicity assays and according to the morphological analyses. MTX also evoked a higher number of apoptotic nuclei than DOX. Both drugs, at the 0.13 M concentration, caused mitochondrial membrane potential depolarization after a 48-h exposure. Regarding the putative neuroprotectors, 1 mM NAC was not able to prevent the cytotoxicity caused by either drug. Notwithstanding, 100 M tiron was capable of partially reverting MTX-induced cytotoxicity in the NR uptake assay. One hundred M Ac-DEVD-CHO and 10 nM cycloheximide (CHX) also partially prevented the toxicity induced by DOX in the NR uptake assay. MTX was more toxic than DOX in differentiated SH-SY5Y cells, while MTX had similar toxicity in differentiated and undifferentiated SH-SY5Y cells. In fact, MTX was the most neurotoxic drug tested and the mechanisms involved seem dissimilar among drugs. Thus, its toxicity mechanisms need to be further investigated as to determine the putative neurotoxicity for multiple sclerosis and cancer patients.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 20