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



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 (EGFR(pos), EGFR(neg)) cultures. Moreover, the molecular mechanism of action underlying their pharmacological response is also analyzed.



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 EGFR(pos) and EGFR(neg) 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.



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.
Department of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
Eirini D
ED
Tseligka
Department of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
Aikaterini
A
Rova
Department of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
Elsa P
EP
Amanatiadou
School of Pharmacy and Chemistry, Kingston University, Kingston-upon Thames, KT1 2EE, UK.
Gianpiero
G
Calabrese
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK.
John
J
Tsibouklis
Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
Dimitrios G
DG
Fatouros
Department of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece. ivizir@pharm.auth.gr.|Department of Life and Health Sciences, University of Nicosia, 1700, Nicosia, Cyprus. ivizir@pharm.auth.gr.
Ioannis S
IS
Vizirianakis
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry*; D002412:Cations; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D066246:ErbB Receptors / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008055:Lipids
D000970:Antineoplastic Agents; D002412:Cations; D004337:Drug Carriers; D008055:Lipids; C512478:EGFR protein, human; D066246:ErbB Receptors
DLC-carboranes; anticancer therapeutics; cancer cells; normal cells; p53/p21 axis