Anticancer drugs and their impact on chemobrain development: an in vitro investigation

Authors

  • Maria Barbosa-Azevedo Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313 Porto, Portugal
  • Maria Cardoso Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313 Porto, Portugal
  • Félix Carvalho Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313 Porto, Portugal
  • Vera M. Costa Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313 Porto, Portugal https://orcid.org/0000-0002-0471-2756

DOI:

https://doi.org/10.48797/sl.2024.241

Keywords:

Poster

Abstract

Background: Cancer incidence has been increasing worldwide, over the past few years. “Chemobrain” refers to alterations in cognitive function after cancer treatment, including memory deficits and reduced attention capacity [1]. The blood-brain barrier restricts the entry of certain anticancer drugs into the brain. However, "chemobrain" can also arise from factors extending far beyond direct drug exposure to the brain [1]. Objective: This work aims to access how neurons are affected by different anticancer drugs, such as doxorubicin (DOX), methotrexate (MTX) and sunitinib (SUN), all known to cause clinical cognitive deficits. Methods: Differentiated human neuroblastoma cells (SH-SY5Y) were exposed for 24h or 48h to clinically relevant concentrations of DOX (0.1-10 µM), SUN (1-10 µM) and MTX (5 and 10 µM). Two classical cytotoxicity assays (neutral red uptake and MTT reduction) were performed at the end of the exposure times. In a different paradigm, autophagy inhibitors [3-methyladenine (3-MA) or chloroquine (CLQ)] were used to determine their effects on SUN cytotoxicity. Results: DOX led to concentration-dependent cytotoxicity, which was amplified in the longest exposure time in both assays. On the other hand, MTX caused significant toxicity at 5 µM and 10 µM, which was time-dependent but not concentration-dependent in the MTT reduction assay. In the NR uptake assay, toxicity was seen only on the longest incubation time. Regarding SUN, both assays revealed a time- and concentration-dependent cytotoxicity. For SUN, cells appeared with yellow inclusions and autophagy modulators were used. As for autophagy inhibitors, results were dissimilar, since for SUN 10 µM, 3-MA was partially protective, whereas CLQ significantly increased SUN’s cytotoxicity in both assays at 24h. Conclusions: These findings highlight DOX’s, MTX’s and SUN’s cytotoxicity in neurons, with DOX and SUN being equally potent. Additionally, autophagy inhibitors suggest dysregulation of autophagy as a possible mechanism underlying SUN´s neurotoxicity. Nonetheless, further research is needed.

References

1. Dias-Carvalho, A., Ferreira, M., Ferreira, R., Bastos, M. de, Sá, S. I., Capela, J. P., Carvalho, F., & Costa, V. M. Four decades of chemotherapy-induced cognitive dysfunction: Comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events. Arch. Toxicol. (2021), 96, 11–78.

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Published

2024-05-01

How to Cite

Barbosa-Azevedo, M., Cardoso, M., Carvalho, F., & Costa, V. M. (2024). Anticancer drugs and their impact on chemobrain development: an in vitro investigation. Scientific Letters, 1(Sup 1). https://doi.org/10.48797/sl.2024.241

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