Synchrotron-Based Fourier-Transform Infrared Micro-Spectroscopy (SR-FTIRM) Fingerprint of the Small Anionic Molecule Cobaltabis(dicarbollide) Uptake in Glioma Stem Cells.

Miquel Nuez-Martínez,Clara Viñas,Francesc Teixidor,Leire Pedrosa,Elisabetta Stanzani,Avelina Tortosa,Ibraheem Yousef,Diouldé Diao,José Juan Gonzalez,Immaculada Martinez-Rovira,Fina Martínez-Soler,Àngels Sierra

doi:10.3390/ijms22189937

Abstract

The anionic cobaltabis (dicarbollide) [3,3′-Co(1,2-C2B9H11)2]−, [o-COSAN]−, is the most studied icosahedral metallacarborane. The sodium salts of [o-COSAN]− could be an ideal candidate for the anti-cancer treatment Boron Neutron Capture Therapy (BNCT) as it possesses the ability to readily cross biological membranes thereby producing cell cycle arrest in cancer cells. BNCT is a cancer therapy based on the potential of 10B atoms to produce α particles that cross tissues in which the 10B is accumulated without damaging the surrounding healthy tissues, after being irradiated with low energy thermal neutrons. Since Na[o-COSAN] displays a strong and characteristic ν(B-H) frequency in the infrared range 2.600–2.500 cm−1, we studied the uptake of Na[o-COSAN] followed by its interaction with biomolecules and its cellular biodistribution in two different glioma initiating cells (GICs), mesenchymal and proneural respectively, by using Synchrotron Radiation-Fourier Transform Infrared (FTIR) micro-spectroscopy (SR-FTIRM) facilities at the MIRAS Beamline of ALBA synchrotron light source. The spectroscopic data analysis from the bands in the regions of DNA, proteins, and lipids permitted to suggest that after its cellular uptake, Na[o-COSAN] strongly interacts with DNA strings, modifies proteins secondary structure and also leads to lipid saturation. The mapping suggests the nuclear localization of [o-COSAN]−, which according to reported Monte Carlo simulations may result in a more efficient cell-killing effect compared to that in a uniform distribution within the entire cell. In conclusion, we show pieces of evidence that at low doses, [o-COSAN]− translocates GIC cells’ membranes and it alters the physiology of the cells, suggesting that Na[o-COSAN] is a promising agent to BNCT for glioblastoma cells.

Highlights

IntroductionOwing to their fast‐clinical course and uniform lethality after standard treatment—surgical resection followed by chemoradiotherapy regimen [1]—
Glioblastoma (GBM) is the most frequent and aggressive primary tumor in the cen‐tral nervous system (CNS)
Na[o‐COSAN] induced spectral changes at the DNA region in both glioma initiating cells (GICs) cell lines, which are interestingly similar to the changes induced by other metal‐based compounds like cisplatin that disrupt the double helix base pairing [61]

Summary

Introduction

Owing to their fast‐clinical course and uniform lethality after standard treatment—surgical resection followed by chemoradiotherapy regimen [1]—. Toma cell subpopulations with the ability to initiate tumors, when injected orthotopically into mice [5,6]. These glioma initiating cells (GICs) express stemness‐related markers and perform cellular niches supported by the tumor microenvironment recapitulating cellular heterogeneity, chemo‐ and radio‐resistance [7]. G‐CIMP+ GBMs are associated with somatic mutations in the IDH1 or IDH2 genes and show a more favorable prognosis, whereas non‐G‐CIMP GBM patients have the poorest prognosis [8].

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