Autophagy Inhibition with Chloroquine Increased Pro-Apoptotic Potential of New Aziridine-Hydrazide Hydrazone Derivatives against Glioblastoma Cells

Abstract

Tumor therapy escape due to undesired side effects induced by treatment, such as prosurvival autophagy or cellular senescence, is one of the key mechanisms of resistance that eventually leads to tumor dormancy and recurrence. Glioblastoma is the most frequent and practically incurable neoplasm of the central nervous system; thus, new treatment modalities have been investigated to find a solution more effective than the currently applied standards based on temozolomide. The present study examined the newly synthesized compounds of aziridine–hydrazide hydrazone derivatives to determine their antineoplastic potential against glioblastoma cells in vitro. Although the output of our investigation clearly demonstrates their proapoptotic activity, the cytotoxic effect appeared to be blocked by treatment-induced autophagy, the phenomenon also detected in the case of temozolomide action. The addition of an autophagy inhibitor, chloroquine, resulted in a significant increase in apoptosis triggered by the tested compounds, as well as temozolomide. The new aziridine–hydrazide hydrazone derivatives, which present cytotoxic potential against glioblastoma cells comparable to or even higher than that of temozolomide, show promising results and, thus, should be further investigated as antineoplastic agents. Moreover, our findings suggest that the combination of an apoptosis inducer with an autophagy inhibitor could optimize chemotherapeutic efficiency, and the addition of an autophagy inhibitor should be considered as an optional adjunctive therapy minimizing the risk of tumor escape from treatment.

A Study on the Biological Activity of Optically Pure Aziridine Phosphines and Phosphine Oxides

“…The antiproliferative effect of 5 and 7 can be explained by the cell cycle arrest in the S phase, resulting in the inhibition of replication. Additionally, an apoptotic effect of these compounds was observed, which is also consistent with our previous research on this group of compounds [15]. Both effects on cancer cells may be attributed to the generation of reactive oxygen species by the tested aziridine derivatives.…”

“…This phenomenon may be attributed to elevated levels of reactive oxygen species (ROS) and apoptosis, the latter manifested by a subpopulation of cells in the sub-G1 phase of the cell cycle, observed even at lower concentrations corresponding to IC 50 values (Figures 4 and 5). This apoptotic effect aligns with our previous research on this class of compounds [15]. A similar mechanism in cancerous cells was observed for another aziridine derivative, imexon.…”

“…increases the biological activity of aziridine derivatives [14,15]. Organophosphorus compounds have been intensively investigated but, surprisingly, only few reports on the in vitro antiproliferative properties of phosphine oxides and phosphines are available today [18][19][20].…”

“…The most bactericidal aziridine derivatives also showed the highest toxic activity against both tested cell lines with no selectivity for tumor cells. Recently, we also reported aziridine-hydrazide hydrazone derivatives with antineoplastic potential against glioblastoma cells [15]. Although, in the chemical literature, there are numerous examples of research on the biological activity (including anticancer) of phosphines and phosphine oxides, there are slightly fewer reports on biological research on systems based on the aziridine skeleton; however, systems with both mentioned structural motifs in their structure are practically non-existent in the literature (only Dogan's work on biological research on aziridine phosphonates deserves mention [7]).…”

“…Based on our previous studies, the inclusion of an additional polar subunit Continuing our research on the therapeutic potential of aziridine derivatives, we decided to verify the antibacterial and anticancer activity of the previously synthesized aziridine phosphines [16] and aziridine phosphine oxides [17] in L929, HeLa, and Ishikawa cell lines. Based on our previous studies, the inclusion of an additional polar subunit increases the biological activity of aziridine derivatives [14,15]. Organophosphorus compounds have been intensively investigated but, surprisingly, only few reports on the Molecules 2024, 29, 1430 3 of 13 in vitro antiproliferative properties of phosphine oxides and phosphines are available today [18][19][20].…”