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EXPERIMENTAL THERAPEUTICS AND PHARMACOLOGY

ABSTRACT: The multifunctional protein - tissue inhibitor of metalloproteinases-1 (TIMP-1) - has been associated with poor prognosis in several types of cancers including glioblastomas. Glioblastomas are the most common and malignant primary brain tumor known for being highly invasive and resistant to therapy. New treatment strategies are continuously being explored and currently vascular endothelial growth factor (VEGF) inhibitors administered in combination with Irinotecan is the most promising second line treatment. TIMP-1 has been associated with decreased response to chemotherapy in breast and colorectal cancer and especially the family of topoisomerase (TOP) inhibitors, such as Irinotecan, has been suggested to be affected by TIMP-1. In the present study, we investigated whether a high TIMP-1 expression in glioblastoma cells played a role in TOP inhibitor resistance. We established two TIMP-1 over-expressing cell lines and evaluated the sensitivity towards the TOP1 inhibitor SN-38 and the TOP2 inhibitor Epirubicin using a viability and a cytotoxicity assay. In addition, we investigated the invasive features of the cells in a brain slice culture model as well as in an orthotopic xenograft model. The results showed that TIMP-1 over-expressing U87MG cell line sub-clones were significantly more resistant than the controls when exposed to SN-38 and Epirubicin. The same tendency was seen for the TIMP-1 over-expressing A172 sub-clones. No significant differences in invasion patterns were observed for TIMP-1 over-expressing sub-clones when compared to controls. In conclusion, the present study suggests that TIMP-1 over-expression reduces the effect of TOP inhibitors in the glioblastoma cell line U87MG. There was no significant effect of TIMP-1 over-expression on tumor cell invasion. The association found between TIMP-1 cellular levels and the effect of TOP inhibitors needs to be validated in clinical patient material.

SUBMITTER: Aaberg-Jessen C

PROVIDER: S-EPMC3823891 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Project description:BackgroundSkeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration.MethodsRelevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase.ResultsTizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer's disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel.ConclusionTizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

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EXPERIMENTAL THERAPEUTICS AND PHARMACOLOGY

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