Glioblastoma Multiforme: Probing Solutions to Systemic Toxicity towards High-Dose Chemotherapy and Inflammatory Influence in Resistance against Temozolomide

Abstract

Temozolomide (TMZ), the first-line chemotherapeutic drug against glioblastoma multiforme (GBM), often fails to provide the desired clinical outcomes due to inflammation-induced resistance amid inefficient drug delivery across the blood-brain barrier (BBB). The current study utilized solid lipid nanoparticles (SLNPs) for targeted delivery of TMZ against GBM. After successful formulation and characterization of SLNPs and conjugation with TMZ (SLNP-TMZ), their in-vitro anti-cancer efficacy and effect on the migratory potential of cancer cells were evaluated using temozolomide-sensitive (U87-S) as well as TMZ-resistant (U87-R) glioma cell lines. Elevated cytotoxicity and reduction in cell migration in both cell lines were observed with SLNP-TMZ as compared to the free drug (p < 0.05). Similar results were obtained in-vivo using an orthotopic xenograft mouse model (XM-S and XM-R), where a reduction in tumor size was observed with SLNP-TMZ treatment compared to TMZ. Concomitantly, higher concentrations of the drug were found in brain tissue resections of mice treated with SLNP-TMZ as compared to other vital organs than mice treated with free TMZ. Expression of inflammatory markers (Interleukin-1β, Interleukin-6 and Tumor Necrosis factor-α) in a resistant cell line (U87-R) and its respective mouse model (XM-R) were also found to be significantly elevated as compared to the sensitive U87-S cell line and its respective mouse model (XM-S). Thus, the in-vitro and in-vivo results of the study strongly support the potential application of SLNP-TMZ for TMZ-sensitive and resistant GBM therapy, indicatively through inflammatory mechanisms, and thus merit further detailed insights

MicroRNA-Dependent Mechanisms Underlying the Function of a β-Amino Carbonyl Compound in Glioblastoma Cells

“…Combining chemotherapy with TMZ and radiotherapy is considered a gold standard therapeutic approach incorporated in the treatment regimens of GB patients with surgical tumor excision . Nasir et al demonstrated that TMZ doses as high as 1000 μM were most effective in inhibiting cell viability in U87MG cells . The use of significantly high drug doses could lead to adverse effects on normal cells resulting in systemic toxicity, alongside intrinsic resistance to cytotoxic therapies.…”

“… 22 Nasir et al demonstrated that TMZ doses as high as 1000 μM were most effective in inhibiting cell viability in U87MG cells. 23 The use of significantly high drug doses could lead to adverse effects on normal cells resulting in systemic toxicity, alongside intrinsic resistance to cytotoxic therapies. Subsequently, this contributes to treatment failure and tumor recurrence.…”

Tumor suppressor role of the complement inhibitor CSMD1 and its role in TNF-induced neuroinflammation in gliomas

“…Studies have indicated that EGFR amplification and/or mutations frequently occur in GBM but targeting EGFR has limited efficacy for GBM treatment [ 50 , 51 ]. Temozolomide treatment increased the levels of proinflammatory cytokines such as TNF, IL-1β and IL-6, which are frequently linked to drug resistance, both in vitro and in vivo [ 52 ]. Consequently, a treatment plan that combines temozolomide with EGFR and TNF inhibition may represent an effective therapeutic approach for gliomas expressing CSMD1.…”

Navigating the brain: the role of exosomal shuttles in precision therapeutics

“…Additionally, some drugs used in glioblastoma treatment, like temozolomide (TMZ), can have severe toxicity and adverse side effects ( 115 ). Even after undergoing complete surgical resection and receiving additional treatment with chemotherapy and radiation, the glioma tumor is likely to reappear within 8 months ( 116 ).…”