Pharmacological development of target-specific delocalized lipophilic cation-functionalized carboranes for cancer therapy

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

Photo-activation of the delocalized lipophilic cation D112 potentiates cancer selective ROS production and apoptosis

Delocalized lipophilic cations (DLCs) selectively accumulate in cancer cell mitochondria and have long been explored for therapeutic applications. Although targeted effects to cancer cells are demonstrated in vitro, non-specific toxicities in vivo have hampered clinical development. Identifying the molecular mechanisms of action and enhancing selectivity are thus necessary next steps to improve these compounds and evaluate their suitability for further drug development. D112 is one such DLC with promising properties. We previously demonstrated that D112 selectively induced intrinsic apoptosis in transformed versus non-transformed cell lines. Here we show that D112 preferentially entered transformed cells where it interacted with, and damaged mitochondrial DNA, inhibited Complex I respiration and induced reactive oxygen species (ROS). ROS production was critical for Bax activation and subsequent apoptosis. Importantly, photo-activation of D112 potentiated selective ROS production and increased the window of toxicity towards cancer cells over non-transformed cells. Thus photodynamic therapy would be an exciting adjunct to D112 studies and may be generally applicable for other DLCs that are currently under therapeutic investigation