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Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy

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Abstract

Purpose

Tumor cell heterogeneity and microenvironment represent major hindering factors in the clinical setting toward achieving the desired selectivity and specificity to malignant tissues for molecularly targeted cancer therapeutics. In this study, the cellular and molecular evaluation of several delocalized lipophilic cation (DLC)-functionalized carborane compounds as innovative anticancer agents is presented.

Methods

The anticancer potential assessment of the DLC-carboranes was performed in established normal (MRC-5, Vero), cancer (U-87 MG, HSC-3) and primary glioblastoma cancer stem (EGFRpos, EGFRneg) cultures. Moreover, the molecular mechanism of action underlying their pharmacological response is also analyzed.

Results

The pharmacological anticancer profile of DLC-functionalized carboranes is characterized by: a) a marked in vitro selectivity, due to lower concentration range needed (ca. 10 fold) to exert their cell growth-arrest effect on U-87 MG and HSC-3, as compared with that on MRC-5 and Vero; b) a similar selective growth inhibition behavior towards EGFRpos and EGFRneg cultures (>10 fold difference in potency) without, however, the activation of apoptosis in cultures; c) notably, in marked contrast to cancer cells, normal cells are capable of recapitulating their full proliferation potential following exposure to DLC-carboranes; and, d) such pharmacological effects of DLC-carboranes has been unveiled to be elicited at the molecular level through activation of the p53/p21 axis.

Conclusions

Overall, the data presented in this work indicates the potential of the DLC-functionalized carboranes to act as new selective anticancer therapeutics that may be used autonomously or in therapies involving radiation with thermal neutrons. Importantly, such bifunctional capacity may be beneficial in cancer therapy.

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Abbreviations

APL:

Acute promyelocytic leukemia

BNCT:

Boron neutron capture therapy

CSCs:

Cancer stem cells

CLL:

Chronic lymphocytic leukemia

DLCs:

Delocalized lipophilic cations

GBM:

Glioblastoma

HCC:

Hepatocellular carcinoma

ICC:

Immunocytochemistry

IC50 :

Inhibition concentration fifty

qPCR:

Real-time polymerase chain reaction

TPPs:

Triphenylphosphonium ions

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was partially funded by interdepartmental public funds of Aristotle University Research Committee to ISV. EDT is recipient of a STSM fellowship from the COST 1106 action to work at Rosella Galli’s lab (San Raffaele Scientific Institute, Milan). We would like to thank Dr. Rosella Galli, (Group Leader at Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan), for her kind offer of EGFRneg and EGFRpos primary GBM CSCs and also for allowing us to perform that experiments in her laboratory. Also, we thank Dr. Narayanan Ashwin (Postdoctoral fellow at Rosella Galli’s lab) for his help in the EGFRneg and EGFRpos handling and the immunofluorescence microscopy.

The authors disclose no conflict of interest. This work was partially funded by interdepartmental public funds of Aristotle University Research Committee to ISV and STSM fellowship from the CMST COST Action CM1106 to EDT.

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Eirini D. Tseligka, Aikaterini Rova, Elsa P. Amanatiadou & Ioannis S. Vizirianakis

  2. School of Pharmacy and Chemistry, Kingston University, Kingston-upon Thames, KT1 2EE, UK

    Gianpiero Calabrese

  3. School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK

    John Tsibouklis

  4. Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Dimitrios G. Fatouros

  5. Department of Life and Health Sciences, University of Nicosia, 1700, Nicosia, Cyprus

    Ioannis S. Vizirianakis

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  1. Eirini D. Tseligka
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Correspondence to Ioannis S. Vizirianakis.

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Tseligka, E.D., Rova, A., Amanatiadou, E.P. et al. Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy. Pharm Res 33, 1945–1958 (2016). https://doi.org/10.1007/s11095-016-1930-4

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  • DOI: https://doi.org/10.1007/s11095-016-1930-4

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