Abstract
Gliomas and glioblastomas are very aggressive forms of brain tumors, prone to the development of a multitude of resistance mechanisms to therapeutic treatments, including cytoprotective autophagy. In this work, we investigated the role and mechanism of action of the combination of a ruthenacarborane derivative with 8-hydroxyquinoline (8-HQ), linked via an ester bond (complex 2), in rat astrocytoma C6 and human glioma U251 cells, in comparison with the two compounds alone, i.e., the free carboxylic acid (complex 1) and 8-HQ, and their non-covalent combination ([1 + 8-HQ], in 1:1 molar ratio). We found that only complex 2 was able to significantly affect cellular viability in glioma U251 cells (IC50 11.4 μM) via inhibition of the autophagic machinery, most likely acting at the early stages of the autophagic cascade. Contrary to 8-HQ alone, complex 2 was also able to impair cellular viability under conditions of glucose deprivation. We thus suggest different mechanisms of action of ruthenacarborane complex 2 than purely organic quinoline-based drugs, making complex 2 a very attractive candidate for evading the known resistances of brain tumors to chloroquine-based therapies.
Highlights
From a chemical biology perspective, little is known about the mechanisms of action of seemingly biologically activecarborane-containing compounds, in terms of effects on physiological and pathophysiological biochemical processes at the cellular and sub-cellular level [1,2,3]
We had shown that ruthenacarborane complex 2, which contains a quinolyl residue, displays a dual mode of action in vitro against human glioblastoma LN229 cells, namely it strongly inhibited proliferation and cytoprotective autophagy, with IC50 values in the same concentration range as for the clinically approved drug chloroquine, which is often associated with the development of drug resistance mechanisms [14,15,16]
2 inhibited expression of microtubule-associated protein light chain 3B (LC3B), which is one of the established biomarkers of the cellular autophagic machinery, since it forms a stable association complex with the membrane of autophagosomes. This dual mode of action of 2 is very promising for the treatment of autophagy-prone cancers, where autophagic processes often contribute to the establishment and/or development of drug resistances, such as in brain tumors of the glioma and glioblastoma types [23]
Summary
From a chemical biology perspective, little is known about the mechanisms of action of seemingly biologically active (metalla)carborane-containing compounds, in terms of effects on physiological and pathophysiological biochemical processes at the cellular and sub-cellular level [1,2,3]. We have recently published an extensive review on (metalla)carboranes as “new” nanomedicine platforms [12], urging the boron community to consistently treat such compounds as potential colloidal aggregators in aqueous environment, and as such to implement standardized and homogeneous biophysical and biological tests. In this short communication, we focus our attention on further biological testing of a small series of compounds (see Figure 1), using a consistent and complementary approach to our earlier investigations [13]. We aim at investigating further the role and mechanism of action of the combination of a ruthenacarborane derivative with hydroxyquinoline, i.e., the aromatic building block of chloroquine, in two different types of brain tumor cells, namely rat astrocytoma (C6) and human glioma (U251) cells, using analogous testing protocols to those used with the LN229 cell line
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