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

Abstract

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.

The Role of Purine Metabolism-Related Genes PPAT and IMPDH1 in the Carcinogenesis of Intrahepatic Cholangiocarcinoma Based on Metabonomic and Bioinformatic Analyses

“…Guanine nucleotides are building blocks of DNA and RNA and are also used by the guanine binding protein family (gproteins) for a large number of cellular functions, such as cytoskeletal rearrangement, membrane transport, protein synthesis, and signal transduction [20]. Te biosynthetic pathway of GTP is important for the progression of many tumors, such as glioblastoma [21], small cell lung cancer subgroup [22], solid and serous malignancies, and clear cell renal cell carcinoma [23]. GTP is a well-known biological metabolite in the context of cancer.…”

Major roles of the circadian clock in cancer

“…Some researchers have proposed that 1A-116 in GBM treatment, at the end of light (ZT12) administration rather than the beginning of light (ZT3) administration, prolongs survival time in mice 196 . This finding is contrary to the conclusion that at ZT2, the time of administration in CRC, anti-angiogenesis drugs have a more potent anti-tumor effect.…”

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

“…The effectiveness of 1A‐116 could be further optimized by finding the optimized time for the administration. The higher efficacy of 1A‐116 was observed at low BMAL1 expression in glioblastoma cells and a differential OS was found when applying 1A‐116 at Zeitgeber times 12 (ZT 12) to glioma‐bearing nude mice 112 . The time‐dependent pharmacological application of 1A‐116 is a feasible strategy to improve OS.…”

“…Currently, experimental research performed serum shock procedures to synchronize cells in vitro 107 . In vivo, animals were kept at an inverse 12 h light/12 h dark cycle, facilitating adaptation to the environmental cycle of day and night 21,112 . Besides, the different TME between in vivo and in vitro are worthy of attention.…”

“…In vivo, animals were kept at an inverse 12 h light/12 h dark cycle, facilitating adaptation to the environmental cycle of day and night. 21 , 112 Besides, the different TME between in vivo and in vitro are worthy of attention. The circadian clock of laboratory animals may differ significantly from those of humans.…”