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Article

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma

1
Laboratorio de Cronobiología, Universidad Nacional de Quilmes-CONICET, Bernal 1876, Buenos Aires, Argentina
2
Laboratorio de Oncología Molecular, Universidad Nacional de Quilmes-CONICET, Bernal 1876, Buenos Aires, Argentina
3
Departamento de Física Médica, Comisión Nacional de Energía Atómica, Bariloche 8400, Río Negro, Argentina
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Annabelle Ballesta and Joana Bicker
Pharmaceutics 2021, 13(7), 1091; https://doi.org/10.3390/pharmaceutics13071091
Received: 14 June 2021 / Revised: 10 July 2021 / Accepted: 13 July 2021 / Published: 16 July 2021
(This article belongs to the Special Issue Chronotherapy and Chronomodulated Drug Delivery)
The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human glioblastoma cells and tumor-bearing nude mice. Methods. Wild-type LN229 and BMAL1-deficient (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels. The effects of 1A-116 on proliferation, apoptosis, and migration were then assessed upon applying the drug at different circadian times. Finally, 1A-116 was administered to tumor-bearing mice at two different circadian times. Results. In LN229 cells, circadian oscillations were found for BMAL1, PER1, and TIAM1 (mRNA and protein), and for the effects of 1A-116 on proliferation, apoptosis, and migration, which were abolished in LN229E1 cells. Increased survival time was observed in tumor-bearing mice when treated with 1A-116 at the end of the light period (zeitgeber time 12, ZT12) compared either to animals treated at the beginning (ZT3) or with vehicle. Conclusions. These results unveil the circadian modulation in the efficacy of 1A-116, likely through RAC1 pathway rhythmicity, suggesting that a chronopharmacological approach is a feasible strategy to improve glioblastoma treatment. View Full-Text
Keywords: chronopharmacology; Rho GTPase; glioma; brain tumor chronopharmacology; Rho GTPase; glioma; brain tumor
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MDPI and ACS Style

Trebucq, L.L.; Cardama, G.A.; Lorenzano Menna, P.; Golombek, D.A.; Chiesa, J.J.; Marpegan, L. Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma. Pharmaceutics 2021, 13, 1091. https://doi.org/10.3390/pharmaceutics13071091

AMA Style

Trebucq LL, Cardama GA, Lorenzano Menna P, Golombek DA, Chiesa JJ, Marpegan L. Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma. Pharmaceutics. 2021; 13(7):1091. https://doi.org/10.3390/pharmaceutics13071091

Chicago/Turabian Style

Trebucq, Laura Lucía, Georgina Alexandra Cardama, Pablo Lorenzano Menna, Diego Andrés Golombek, Juan José Chiesa, and Luciano Marpegan. 2021. "Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma" Pharmaceutics 13, no. 7: 1091. https://doi.org/10.3390/pharmaceutics13071091

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