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Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer
Eirini D Tseligka1, Aikaterini Rova1, Elsa P Amanatiadou1
1Department of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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 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.
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.
Insights
Delocalized lipophilic cation (DLC)-functionalized carboranes show selective anticancer effects by activating the p53/p21 axis. These compounds offer potential as novel therapeutics for cancer treatment, alone or with neutron radiation therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Tumor cell heterogeneity and microenvironment pose challenges for targeted cancer therapies.
- Developing selective and specific anticancer agents remains a critical clinical need.
Purpose of the Study:
- To evaluate delocalized lipophilic cation (DLC)-functionalized carborane compounds as innovative anticancer agents.
- To assess the cellular and molecular mechanisms of these novel compounds.
Main Methods:
- Anticancer potential was assessed in normal (MRC-5, Vero), cancer (U-87 MG, HSC-3), and glioblastoma stem cell cultures (EGFR(pos), EGFR(neg)).
- Molecular mechanisms of action were analyzed to understand their pharmacological response.
Main Results:
- DLC-carboranes demonstrated marked in vitro selectivity, with lower effective concentrations for cancer cells compared to normal cells.
- Selective growth inhibition was observed in both EGFR(pos) and EGFR(neg) glioblastoma stem cells without inducing apoptosis.
- Normal cells retained their proliferation potential after exposure, highlighting compound safety.
- Pharmacological effects were linked to the activation of the p53/p21 signaling pathway.
Conclusions:
- DLC-functionalized carboranes show potential as selective anticancer therapeutics.
- These compounds may be used independently or in conjunction with neutron radiation therapy.
- The bifunctional capacity of these carboranes could offer significant benefits in cancer treatment strategies.
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