Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells

Modica-Napolitano, Josephine S.; Aprille, June R.

doi:10.1016/s0169-409x(01)00125-9

Cited by 510 publications

(394 citation statements)

References 45 publications

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“…Notably, the ki-67 expression level in treated cultures was seen to be 50-60 % lower after 24 -48 h of treatment ( Figure 2G). Since, ki-67 is exclusively expressed in proliferating cells 13 and it is detected only during the active cell cycle phases (it is not detectable in the G0 phase) [26], the results confirm the capability of DLC-carboranes to cause growth inhibition in primary GBM CSCs. Since no detectable levels of active caspase-3 have been observed, it is assumed that although these compounds do not induce apoptosis in CSCs, they have a profound inhibitory cell growth potential.…”

Section: Dlc-carboranes Inhibit the Proliferation Potential Of Primarsupporting

confidence: 57%

“…These molecular structures are guided selectively towards tumors by the higher mitochondrial transmembrane potential (~60 mV difference) that is consequent to the correspondingly higher metabolic activity of cancer cells relative to that of normal cells [12][13][14][15][16]. The resonance-stabilized delocalization of the positive charge of DLCs, coupled with their inherent lipophilicity, leads to a decrease in the cost associated with the free energy change that accompanies the diffusion of DLCs through cell membranes, and provides the 5 driving force for their observed highly selective accumulation (>100 fold) in the mitochondrial matrix of cancer cells [13,17,18] and the associated high (>5 fold) difference between their cytoplasmic and extracellular concentrations [11]. Towards the development of highly selective target-specific anticancer agents that are applicable to boron neutron capture therapy (BNCT) of cancer, this study builds on preliminary evaluations that indicated the selective accumulation of boronated DLC compounds in cancer cells [19,20].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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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Section: Dlc-carboranes Inhibit the Proliferation Potential Of Primarsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…However, because of poor solubility and bioavailability of the conventional ceramides, novel pyridinium ceramides (Pyr-Cer) have been synthesized with greater water solubility and cell permeability (26,35,36). In addition, the positively charged pyridinium ring of these novel ceramides permits them to target and accumulate in negatively charged intracellular compartments, especially the mitochondria and nucleus (37). L-t-C 6 -Pyr-Cer, alone or in combination with gemcitabine, has been shown in vivo to preferentially accumulate in the tumor site and modulate telomerase, decrease telomeric length, and inhibit HNSCC tumor growth (26).…”

Section: Discussionmentioning

confidence: 99%

Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

Senkal¹,

Ponnusamy²,

Rossi³

et al. 2007

Molecular Cancer Therapeutics

152

126

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In this study, quantitative isobologram studies showed that treatment with gemcitabine and doxorubicin, known inducers of ceramide generation, in combination, supraadditively inhibited the growth of human UM-SCC-22A cells in situ. Then, possible involvement of the human homologue of yeast longevity assurance gene 1 (LASS1)/ C 18 -ceramide in chemotherapy-induced cell death in these cells was examined. Gemcitabine/doxorubicin combination treatment resulted in the elevation of mRNA and protein levels of LASS1 and not LASS2-6, which was consistent with a 3.5-fold increase in the endogenous (dihydro)ceramide synthase activity of LASS1 for the generation of C 18 -ceramide. Importantly, the overexpression of LASS1 (both human and mouse homologues) enhanced the growth-inhibitory effects of gemcitabine/ doxorubicin with a concomitant induction of caspase-3 activation. In reciprocal experiments, partial inhibition of human LASS1 expression using small interfering RNA

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“…[5] [6] where C c , C m , and C b are cytosolic, mitochondrial, and basolateral concentration, V m , and V b are volumes of cytosolic, mitochondrial, and basolateral compartments respectively. The passive diffusion flux of neutral molecules across membranes is described by Fick's First Law: [7] where J is the molecular flux from the out side to the inside (i) ('negative' side) of the membrane, P is the permeability of the molecules across cellular membranes, and a is the activity of the molecules. For electrolytes the driving forces across cellular membrane are not only chemical potential but also electrical potential, which is described by the Nernst-Planck equation.…”

Section: Methodsmentioning

confidence: 99%

A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration

2006

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In the body, cell monolayers serve as permeability barriers, determining transport of drug molecules from one organ or tissue compartment to another. After oral administration, for example, drug transport across the epithelial cell monolayer lining the lumen of the intestine determines the fraction of drug in the gut that is absorbed by the body. By modeling passive transcellular transport properties in the presence of an apical to basolateral concentration gradient, we demonstrate how a computational, cell-based molecular transport simulator can be used to define a physicochemical property space occupied by molecules with desirable permeability and intracellular retention characteristics. Considering extracellular domains of cell surface receptors located on the opposite side of a cell monolayer as a drug's desired site-of-action, simulation of transcellular transport can be used to define the physicochemical properties of molecules with maximal transcellular permeability but minimal intracellular retention. Arguably, these molecules would possess very desirable features: least likely to exhibit non-specific toxicity, metabolism and side effects associated with high (undesirable) intracellular accumulation; and, most likely to exhibit favorable bioavailability and efficacy associated with maximal rates of transport across cells and minimal intracellular retention, resulting in (desirable) accumulation at the extracellular site-of-action. Calculated permeability predictions showed good correlations with PAMPA, Caco2, and intestinal permeability measurements, without "training" the model and without resorting to statistical regression techniques to "fit" the data. Therefore, cell-based molecular transport simulators could be useful in silico screening tools for chemical genomics and drug discovery.

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Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells

Cited by 510 publications

References 45 publications

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

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

Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration

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