Glioblastoma Multiforme: Sensitivity to Antimicrobial Peptides LL-37 and PG-1, and Their Combination with Chemotherapy for Predicting the Overall Survival of Patients

Abstract

Background/Objectives: Glioblastomas (GBMs) are the most malignant and intractable of all cancers, with an unfavorable clinical prognosis for affected patients. The objective was to analyze the sensitivity of GBM cells to the antimicrobial peptides (AMPs) cathelicidin (LL-37) and protegrin-1 (PG-1), both alone and in combination with chemotherapy, to predict overall survival (OS) in the patients. Methods: The study was conducted on 27 GBM patients treated in the neurosurgical department of the Almazov Medical Research Centre (Saint Petersburg, Russia) from 2021 to 2024. The cytotoxic effects of chemotherapy, AMPs, and their combinations on brain tumor cells were assessed by an MTT assay using a 50% inhibitory concentration (IC₅₀). Results: In GBM cells from the patients, LL-37 and PG-1 exhibited strong anticancer effects, surpassing those of chemotherapy drugs. These LL-37 and PG-1 anticancer effects were associated with a statistically significant increase in life expectancy and OS in GBM patients. These findings were confirmed by experiments on rats with C6 glioma, where the intranasal administration of LL-37 (300 μM) and PG-1 (600 μM) increased the life expectancy of the animals to 69 and 55 days, respectively, compared to 24 days in the control group (HR = 4.139, p = 0.0005; HR = 2.542, p = 0.0759). Conclusions: Additionally, the combination of LL-37 and PG-1 with chemotherapy drugs showed that a high IC₅₀ of LL-37 with cisplatin (cutoff > 800 μM) in GBM cells was associated with increased life expectancy (19 vs. 5 months, HR = 4.708, p = 0.0101) and OS in GBM patients. These combinations could be used in future GBM treatments.

Keywords: LL-37; PG-1; PG-1 with chemotherapy; chemotherapy drugs; combinations of LL-37; cytotoxicity; glioblastoma; overall survival of GBM patients.

Figure 1

Overall survival of GBM patients, based on high and low IC₅₀ levels of chemotherapy drugs. The OS of GBM patients was assessed according to their IC₅₀ levels for various chemotherapy drugs: (A) carboplatin, (B) cisplatin, (C) doxorubicin, (D) etoposide, (E) temozolomide. The analysis was conducted using the Mantel–Cox test (χ²), with the following abbreviations: CARB (carboplatin), CIS (cisplatin), DOX (doxorubicin), ETO (etoposide), and TMZ (temozolomide). * Statistically significant (p < 0.05) differences high and low levels IC₅₀ between groups.

Figure 2

Overall survival of GBM patients, based on high and low IC₅₀ levels of (A) LL-37 and its combinations with chemotherapy drugs: (B) doxorubicin, (C) carboplatin, (D) cisplatin, (E) etoposide, (F) temozolomide. Mantel–Cox test, χ². * Statistically significant (p < 0.05) differences high and low levels IC₅₀ between groups.

Figure 3

Overall survival of GBM patients based on high and low IC₅₀ levels of (A) PG-1 and its combinations with chemotherapy drugs: (B) doxorubicin, (C) carboplatin, (D) cisplatin, (E) etoposide, (F) temozolomide. Mantel–Cox test, χ². * Statistically significant (p < 0.05) differences high and low levels IC₅₀ between groups.

Figure 4

Overall survival of Wistar rats with C6 glioma following the administration of (A) LL-37 and (B) PG-1. Tumor volume following the administration of (C) LL-37 and (D) PG-1. The survival analysis was performed using the Mantel–Cox test with the χ² values indicated. ** Statistically significant (p < 0.01) and **** (p < 0.0001) differences between tumor volume and overall survival rats under LL-37 administration from control group.