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 (EGFR pos , EGFR neg ) 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, 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. CONCLUSIONS:Overall, the data presented in this work indicates the potential of the DLC-functionalized carboranes to act as new selective anticancer therapeutics that 3 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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Correction for “Boron-containing delocalised lipophilic cations for the selective targeting of cancer cells” by Gianpiero Calabrese et al., Med. Chem. Commun., 2017, 8, 67–72.

To limit the incidence of relapse, cancer treatments must not promote the emergence of drug resistance in tumour and cancer stem cells.