Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II (original) (raw)
Related papers
Journal of Biological Chemistry, 2011
Mitochondrial complex II (CII) has been recently identified as a novel target for anticancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its proapoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC 50 of 80 μM, while the electron transfer from CII to CIII was inhibited with IC 50 of 1.5 μM. The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1α fused to GFP, indicating promotion of the state of pseudo-hypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site, and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation and SDH activity. Mutation of the UbQ-binding Ser68 within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix optimising its biological effects as an anti-cancer drug.
Molecular Aspects of Medicine, 2007
Mitochondria have recently emerged as new and promising targets for cancer prevention and therapy. One of the reasons for this is that mitochondria are instrumental to many types of cell death and often lie downstream from the initial actions of anti-cancer drugs. Unlike the tumour suppressor gene encoding p53 that is notoriously prone to inactivating 0098-2997/$ -see front matter Ó Molecular Aspects of Medicine 28 mutations but whose function is essential for induction of apoptosis by DNA-targeting agents (such as doxorubicin or 5-fluorouracil), mitochondria present targets that are not so compromised by genetic mutation and whose targeting overcomes problems with mutations of upstream targets such as p53. We have recently proposed a novel class of anticancer agents, mitocans that exert their anti-cancer activity by destabilising mitochondria, promoting the selective induction of apoptotic death in tumour cells. In this communication, we review recent findings on mitocans and propose a common basis for their mode of action in inducing apoptosis of cancer cells. We use as an example the analogues of vitamin E that are proving to be cancer cell-specific and may soon be developed into efficient anti-cancer drugs.
2007
The search for a selective and efficient anti-cancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). Majority of established anti-cancer drugs are either non-selective or lose their efficacy due to the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anti-cancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by α-tocopheryl succinate, belong to the group of 'mitocans' (mitochondrially targeted anti-cancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria and suppress cancer in pre-clinical models. This review focuses on our current understanding of VE analogs in the context of their pro-apoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anti-cancer efficacy) generally do not possess anti-oxidant (redox) activity and are prototypic of the mitocan group of anti-cancer compounds. Therefore, by analogy to Oscar Wilde's play 'The Importance of Being Earnest', we use the motto in the title 'The importance of being redox-silent' to emphasize an essentially novel paradigm for cancer therapy, where redox-silence is a prerequisite property for most of the anti-cancer activities described in this communication.
Molecular Pharmacology, 2007
The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by ␣-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of Article, publication date, and citation information can be found at ABBREVIATIONS: MM, malignant mesothelioma; BH, Bcl-2 homology; DHFR, dihydrofolate reductase; DR, death receptor; ERK, extracellular signal-regulated protein kinase; FLIP, Fas-associated death domain-like interleukin-1-converting enzyme-inhibitory protein; IAP, inhibitor of apoptosis protein; IB, inhibitory subunit of nuclear factor B; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MPTP, mitochondrial permeability transition pore; MTX, methotrexate; NFB, nuclear factor-B; OS, osteosarcoma; PKC, protein kinase C; PP2A, protein phosphatase 2A; ROS, reactive oxygen species; SAR, structure-activity relationship; SMase, sphingomyelinase; TNF, tumor necrosis factor; ␣-TOS, ␣-tocopheryl succinate; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; UbQ, ubiquinone; VDAC, voltage-dependent anionic channel; VE, vitamin E; CD437, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid; 2DG, 2-deoxyglucose; DR4, tumor necrosis factor-related apoptosis-inducing ligand receptor 1; DR5, tumor necrosis factor-related apoptosis-inducing ligand receptor 2.
Free Radical Biology and Medicine, 2011
Malignant mesothelioma (MM) is a fatal neoplastic disease with no therapeutic option. Therefore, the search for novel therapies is of paramount importance. Methods: Since mitochondrial targeting of α-tocopheryl succinate (α-TOS) by its tagging with triphenylphosphonium enhances its cytotoxic effects to cancer cells, we tested its effect on MM cells and experimental mesotheliomas. Results: Mitochondrially targeted vitamin E succinate (MitoVES) was more efficient in killing MM cells than α-TOS with IC 50 lower by up to two orders of magnitude. Mitochondrial association of MitoVES in MM cells was documented using its fluorescently tagged analogue. MitoVES caused apoptosis in MM cells by mitochondrial destabilization, resulting in the loss of mitochondrial membrane potential, generation of reactive oxygen species, and destabilization of respiratory supercomplexes. The role of the mitochondrial complex II in the activity of MitoVES was confirmed by the finding that MM cells with suppressed succinate quinone reductase were resistant to MitoVES. MitoVES suppressed mesothelioma growth in nude mice with high efficacy. Discussion: MitoVES is more efficient in killing MM cells and suppressing experimental mesotheliomas compared with the non-targeted α-TOS, giving it a potential clinical benefit.
Oncogene, 2008
α-Tocopheryl succinate (α-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of α-TOS has not been identified. Here we show that α-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ) binding site (Q P and Q D , respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of α-TOS compared to that of UbQ for the Q P and Q D sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and undergo apoptosis in the presence of α-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to α-TOS. We propose that α-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.
Clinical Cancer Research, 2009
Purpose: Vitamin E analogues are potent novel anticancer drugs. The purpose of this study was to elucidate the cellular target by which these agents, represented by α-tocopoheryl succinate (α-TOS), suppress tumors in vivo, with the focus on the mitochondrial complex II (CII). Experimental Design: Chinese hamster lung fibroblasts with functional, dysfunctional, and reconstituted CII were transformed using H-Ras. The cells were then used to form xenografts in immunocompromized mice, and response of the cells and the tumors to α-TOS was studied. Results: The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to α-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to α-TOS. Thus, growth of CII-functional and CII-reconstituted tumors was strongly suppressed by the agent, and this was accompanied by high level of apoptosis induction in the tumor cells. On the o...
Biochemical and Biophysical Research Communications, 2005
a-Tocopheryl succinate (a-TOS) is a redox-silent vitamin E (VE) analog with high pro-apoptotic and anti-neoplastic activity. Here we investigated whether a-TOS and several novel VE analogs kill breast cancer cells over-expressing the anti-apoptotic receptor protein HER2/erbB2. The agents induced apoptosis at comparable levels in both erbB2-low and-high cells. Generation of reactive oxygen species (ROS) preceded mitochondrial destabilization and execution of apoptosis, as evidenced by the anti-apoptotic effects of exogenous superoxide dismutase and mitochondrially targeted coenzyme Q. Dissipation of DW m was followed by cytochrome c and Smac/Diablo re-localization and caspase-dependent cleavage of death substrate. A resistance to apoptosis for the corresponding q 0 counterparts confirmed a critical dependency for mitochondria during the induction of apoptosis in breast cancer cells mediated by VE analogs and linked apoptosis to generation of radicals as judged by the delayed accumulation of ROS in the cybrid cell types. We conclude that a-TOS causes efficient apoptosis in breast cancer cells independent of their erbB2 status. Since erbB2 is frequently overexpressed in breast cancers and renders the neoplastic disease resistant to established treatment, our findings are of clinical interest.
PLOS ONE, 2019
To determine the target of the recently identified lead compound NSC130362 that is responsible for its selective anti-cancer efficacy and safety in normal cells, structure-activity relationship (SAR) studies were conducted. First, NSC13062 was validated as a starting compound for the described SAR studies in a variety of cell-based viability assays. Then, a small library of 1,4-naphthoquinines (1,4-NQs) and quinoline-5,8-diones was tested in cell viability assays using pancreatic cancer MIA PaCa-2 cells and normal human hepatocytes. The obtained data allowed us to select a set of both non-toxic compounds that preferentially induced apoptosis in cancer cells and toxic compounds that induced apoptosis in both cancer and normal cells. Anti-cancer activity of the selected non-toxic compounds was confirmed in viability assays using breast cancer HCC1187 cells. Consequently, the two sets of compounds were tested in multiple cell-based and in vitro activity assays to identify key factors responsible for the observed activity. Inhibition of the mitochondrial electron transfer chain (ETC) is a key distinguishing activity between the non-toxic and toxic compounds. Finally, we developed a mathematical model that was able to distinguish these two sets of compounds. The development of this model supports our conclusion that appropriate quantitative SAR (QSAR) models have the potential to be employed to develop anti-cancer compounds with improved potency while maintaining non-toxicity to normal cells.
Anticancer Drugs Targeting the Mitochondrial Electron Transport Chain
Antioxidants & Redox Signaling, 2011
Treatment of cancer is by no means universally successful and often manifests harmful side effects. The best way to improve the success rate and reduce the side effects would be to develop compounds that are able to kill cancer cells while leaving normal cells unaffected. In this respect, mitocans (an acronym from 'mitochondria' and 'cancer'), a summary term we proposed for compounds that induce cell death by targeting mitochondria, show an encouraging trend.