Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy

Dong, Lan-Feng; Jameson, Victoria J.A.; Tilly, David; Procházka, Lubomír; Rohlena, Jakub; Vališ, Karel; Truksa, Jaroslav; Zobalova, Renata; Mahdavian, Elahe; Kľučková, Katarína; Stantic, Marina; Štursa, Jan; Freeman, Ruth; Witting, Paul K.; Norberg, Erik; Goodwin, Jacob; Salvatore, Brian A.; Novotná, Jana; Tuřánek, Jaroslav; Ledvina, M; Hozák, Pavel; Zhivotovsky, Boris; Coster, Mark J.; Ralph, Stephen John; Smith, Robin A.J.; Neužil, Jiřı́

doi:10.1016/j.freeradbiomed.2011.02.032

Cited by 100 publications

(111 citation statements)

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“…This evidence shows that mitochondrial targeting using a linker of the right length between the targeting and the effector group is a plausible approach to increase effectivity of VE analogs while preserving the same or similar molecular mechanism, whereas the short-linker compounds lose effectivity, as their bioactive group cannot reach the target. Further downstream events, although not studied here, are likely to be mechanistically similar to those induced by a-TOS and MitoVES in cancer cells, where oxidative stress induced by the agents causes activation of the Hippo/Mst1 kinase, activation of the transcription factor FoxO1, and the subsequent increase in the expression of the Noxa protein, ultimately resulting in the generation of Bak-dependent channels in the mitochondrial outer membrane (8,34,44). Thus, since mitochondrial targeting also makes MitoVES an efficient and selective cancer cell killer (7), this modification produces an anticancer compound that promises to target tumors at multiple levels (direct tumor cell elimination and The data shown are mean values -SD (n = 3), the images are representative of three independent experiments.…”

Section: Discussionmentioning

confidence: 95%

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Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Rohlena

Dong

Kľučková

et al. 2011

Antioxidants & Redox Signaling

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Aims: A plausible strategy to reduce tumor progress is the inhibition of angiogenesis. Therefore, agents that efficiently suppress angiogenesis can be used for tumor suppression. We tested the antiangiogenic potential of a mitochondrially targeted analog of a-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis. Results: MitoVES was found to efficiently kill proliferating endothelial cells (ECs) but not contact-arrested ECs or ECs deficient in mitochondrial DNA, and suppressed angiogenesis in vitro by inducing accumulation of reactive oxygen species and induction of apoptosis in proliferating/angiogenic ECs. Resistance of arrested ECs was ascribed, at least in part, to the lower mitochondrial inner transmembrane potential compared with the proliferating ECs, thus resulting in the lower level of mitochondrial uptake of MitoVES. Shorterchain homologs of MitoVES were less efficient in angiogenesis inhibition, thus suggesting a molecular mechanism of its activity. Finally, MitoVES was found to suppress HER2-positive breast carcinomas in a transgenic mouse as well as inhibit tumor angiogenesis. The antiangiogenic efficacy of MitoVES was corroborated by its inhibitory activity on wound healing in vivo. Innovation and Conclusion: We conclude that MitoVES, a mitochondrially targeted analog of a-tocopheryl succinate, is an efficient antiangiogenic agent of potential clinical relevance, exerting considerably higher activity than its untargeted counterpart. MitoVES may be helpful against cancer but may compromise wound healing. Antioxid. Redox Signal. 15, 2923Signal. 15, -2935

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Section: Discussionmentioning

confidence: 95%

“…This mitochondrially targeted analog of a-TOS, MitoVES, is superior to its untargeted counterpart a-TOS in apoptosis induction and cancer suppression (7,8). In this communication, we investigated whether MitoVES efficiently and selectively kills angiogenic ECs.…”

Section: Innovationmentioning

confidence: 99%

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Rohlena

Dong

Kľučková

et al. 2011

Antioxidants & Redox Signaling

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“…For breast carcinomas and Ras overexpression-induced tumor, the in vivo dose of α-TOS varied from 6 μM to 15 μM. 29,35 Thus, for different tumors, an optimized in vivo dose of TDF NPs should be explored.…”

Section: Discussionmentioning

confidence: 99%

“…The dose was referred to the previous report. 28,29 For colony formation assay, HT29 or HeLa cells were seeded at 300 cells per dish in 6 cm cell culture dishes and treated with 2-DG and α-TOS for 6 h, then grew for 7-14 days, and the number of colonies formed was counted. For cell death, annexin V-FITC/PI was used according to the kit manual and analyzed on a flowcytometer Coulter Epics XL/MCL (Beckman Coulter Inc, Brea, CA, USA).…”

Section: In Vitro Anti-tumor Activity Assaymentioning

confidence: 99%

Co-delivery nanocarriers targeting folate receptor and encapsulating 2-deoxyglucose and α-tocopheryl succinate enhance anti-tumor effect in vivo

Li¹,

Li²,

Liu³

et al. 2017

IJN

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A combination administration of chemical agents was highlighted to treat tumors. Recently, tumor cell has been found to be different from normal cell in metabolic manner. Most of cancer cells prefer aerobic glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) to satisfy energy and biomass synthesis requirement to survive, grow and proliferate, which provides novel and potential therapeutic targets for chemotherapy. Here, 2-deoxy- d -glucose (2-DG), a potent inhibitor of glucose metabolism, was used to inhibit glycolysis of tumor cells; α-tocopheryl succinate (α-TOS), a water-insoluble vitamin E derivative, was chosen to suppress OXPHOS. Our data demonstrated that the combination treatment of 2-DG and α-TOS could significantly promote the anti-tumor efficiency in vitro compared with administration of the single drug. In order to maximize therapeutic activity and minimize negative side effects, a co-delivery nanocarrier targeting folate receptor (FR) was developed to encapsulate 2-DG and α-TOS simultaneously based on our previous work. Transmission electron microscope, dynamic light scattering method and UV-visible spectrophotometers were used to investigate morphology, size distribution and loading efficiency of the α-TOS-2-DG-loaded and FR-targeted nanoparticles (TDF NPs). The TDF NPs were found to possess a layer-by-layer shape, and the dynamic size was <100 nm. The final encapsulation efficiencies of α-TOS and 2-DG in TDF NPs were 94.3%±1.3% and 61.7%±7.7% with respect to drug-loading capacities of 8.9%±0.8% and 13.2%±2.6%, respectively. Almost no α-TOS release was found within 80 h, and release of 2-DG was sustained and slow within 72 h. The results of FR binding assay and fluorescence biodistribution revealed that TDF NPs could target FR highly expressed on tumor cell in vitro and in vivo. Further, in vivo anti-tumor experiments showed that TDF NPs had an improved biological function with less toxicity. Thus, our work indicates that the co-delivery TDF NPs have a great potential in tumor therapy.

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“…These compounds were shown to specifically target the Q P site of complex II for ROS generation by enzymatic uncoupling (see above) and elicit apoptosis induction in tumours in vitro and in vivo. The apoptotic cascade initiated by these mitochondrial ROS was demonstrated to involve specific Bcl-2 family members identified as the Noxa-Bak axis and the subsequent mitochondrial outer membrane permeabilization and effector caspase activation (Prochazka et al, 2010;Dong et al, 2011b). Of note, as for the reagents that target glycolysis, a crucial aspect is the specificity of these drugs, and further studies are aimed at increasing their efficiency and decreasing potential side effects.…”

Section: Rc-based Strategies In Cancer Therapy?mentioning

confidence: 99%

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

2011

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Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis. Both protein aggregates are specifically inhibited for apoptosis induction through different means by exploiting with protease activation and pH change, two widespread but independent features of dying cells. Nevertheless, both converge on forming reactive oxygen species for the demise of the cell. Investigations into these mitochondrial processes will remain a rewarding area for unravelling the causes of tumourigenesis and for discovering interference options.

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Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy

Cited by 100 publications

References 53 publications

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Co-delivery nanocarriers targeting folate receptor and encapsulating 2-deoxyglucose and α-tocopheryl succinate enhance anti-tumor effect in vivo

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

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Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy

Cited by 100 publications

References 53 publications

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

Co-delivery nanocarriers targeting folate receptor and encapsulating 2-deoxyglucose and &alpha;-tocopheryl succinate enhance anti-tumor effect in vivo

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

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Co-delivery nanocarriers targeting folate receptor and encapsulating 2-deoxyglucose and α-tocopheryl succinate enhance anti-tumor effect in vivo