Repurposing drugs as pro-oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers.

Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro-oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti-inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro-oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

Development of a potent melanoma vaccine capable of stimulating CD8(+) T-cells independently of dendritic cells in a mouse model.

At present, there are no vaccines approved for the prevention or treatment of malignant melanoma, despite the amount of time and resources that has been invested. In this study, we aimed to develop a self-contained vaccine capable of directly stimulating anticancer CD8(+) T-cell immune responses. To achieve this, three whole-cell melanoma vaccines were developed expressing 4-1BBL or B7.1 T-cell co-stimulatory molecules individually or in combination. The ability of engineered vaccine cell lines to stimulate potent anticancer immune responses in C57BL/6 mice was assessed. Mice vaccinated with cells overexpressing both 4-1BBL and B7.1 (B16-F10-4-1BBL-B7.1-IFNγ/ß anticancer vaccine) displayed the greatest increases in CD8(+) T-cell populations (1.9-fold increase versus control within spleens), which were efficiently activated following antigenic stimulation, resulting in a 10.7-fold increase in cancer cell cytotoxicity relative to control. The enhanced immune responses in B16-F10-4-1BBL-B7.1-IFNγ/ß-vaccinated mice translated into highly efficient rejection of live tumour burdens and conferred long-term protection against repeated tumour challenges, which were likely due to enhanced effector memory T-cell populations. Similar results were observed when dendritic cell (DC)-deficient LTα(-/-) mice were treated with the B16-F10-4-1BBL-B7.1-IFNγ/ß anticancer vaccine, suggesting that the vaccine can directly stimulate CD8(+) T-cell responses in the context of severely reduced DCs. This study shows that the B16-F10-4-1BBL-B7.1-IFNγ/ß anticancer vaccine acted as a highly effective antigen-presenting cell and is likely to be able to directly stimulate CD8(+) T-cells, without requiring co-stimulatory signals from either CD4(+) T-cells or DCs, and warrants translation of this technology into the clinical setting.

HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression.

Hypoxic microenvironments frequently exist in many solid tumours with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors (HIFs), a family of transcription factors which orchestrate signalling events leading to angiogenesis and tumorigenesis. Several events conspire together to lead to the stabilization of HIF-α, commonly expressed in many cancer cell types. These events can result from low oxygen tensions occurring within the expanding tumour mass to produce hypoxic microenvironments or from mutations whereby the HIFs cause changes in expression of genes involved in several cellular functions. Hypoxia-mediated HIF-α regulation has gained significant prominence in tumour biology over recent years, and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary to drive the progression of tumours to malignancy. More recently, it has been realized that the hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. In addition, the hypoxic microenvironment promotes many other oncogenic events, such as the metabolic reconfiguration of tumour cells, neovascularization, epithelial to mesenchymal transition (EMT), and cancer stem cell renewal and accumulation. This article reviews the molecular mechanisms underlying tumour hypoxia and their pro-tumour contributions, such as immune suppression, development of nascent and more permeable tumour vasculature, selective cancer stem cell renewal, accumulation, mobilization and promotion of EMT leading to tumour cell metastasis.

Molecular mechanism for the selective impairment of cancer mitochondrial function by a mitochondrially targeted vitamin E analogue.

The effects of α-tocopheryl succinate (α-TOS), α-tocopheryl acetyl ether (α-TEA) and triphenylphosphonium-tagged vitamin E succinate (mitochondrially targeted vitamin E succinate; MitoVES) on energy-related mitochondrial functions were determined in mitochondria isolated from AS-30D hepatoma and rat liver, bovine heart sub-mitochondrial particles (SMPs), and in rodent and human carcinoma cell lines and rat hepatocytes. In isolated mitochondria, MitoVES stimulated basal respiration and ATP hydrolysis, but inhibited net state 3 (ADP-stimulated) respiration and Ca(2+) uptake, by collapsing the membrane potential at low doses (1-10µM). Uncoupled mitochondrial respiration and basal respiration of SMPs were inhibited by the three drugs at concentrations at least one order of magnitude higher and with different efficacy: MitoVES>α-TEA>α-TOS. At high doses (>10µM), the respiratory complex II (CII) was the most sensitive MitoVES target. Acting as an uncoupler at low doses, this agent stimulated total O(2) uptake, collapsed ∆ψ(m), inhibited oxidative phosphorylation and induced ATP depletion in rodent and human cancer cells more potently than in normal rat hepatocytes. These findings revealed that in situ tumor mitochondria are preferred targets of the drug, indicating its clinical relevance.

Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment.

The microenvironment of a tumor is a highly complex milieu, primarily characterized by immunosuppression, abnormal angiogenesis, and hypoxic regions. These features promote tumor progression and metastasis, resulting in poor prognosis and greater resistance to existing cancer therapies. Galectin-1 is a ß-galactoside binding protein that is abundantly secreted by almost all types of malignant tumor cells. The expression of galectin-1 is regulated by hypoxia-inducible factor-1 (HIF-1) and it plays vital pro-tumorigenic roles within the tumor microenvironment. In particular, galectin-1 suppresses T cell-mediated cytotoxic immune responses and promotes tumor angiogenesis. However, since galectin-1 displays many different activities by binding to a number of diverse N- or O-glycan modified target proteins, it has been difficult to fully understand how galectin-1 supports tumor growth and metastasis. This review explores the importance of galectin-1 and glycan expression patterns in the tumor microenvironment and the potential effects of inhibiting galectin-1 as a therapeutic target for cancer treatment.

Therapeutic Targeting of Mitochondrial Plasticity and Redox Control to Overcome Cancer Chemoresistance.

Significance: Mitochondria are subcellular organelles performing essential metabolic functions contributing to cellular bioenergetics and regulation of cell growth or death. The basic mitochondrial function in fulfilling the need for cell growth and vitality is evidenced whereby cancer cells with depleted mitochondrial DNA (rho zero, p0 cells) no longer form tumors until newly recruited mitochondria are internalized into the rho zero cells. Herein lies the absolute dependency on mitochondria for tumor growth. Hence, mitochondria are key regulators of cell death (by apoptosis, necroptosis, or other forms of cell death) and are, therefore, important targets for anticancer therapy. Recent Advances: Mitochondrial plasticity regulating their state of fusion or fission is key to the chemoresistance properties of cancer cells by promoting pro-survival pathways, enabling the mitochondria to mitigate against the cellular stresses and extreme conditions within the tumor microenvironment caused by chemotherapy, hypoxia, or oxidative stress. Critical Issues: This review discusses many characteristics of mitochondria, the processes and pathways controlling the dynamic changes occurring in the morphology of mitochondria, the roles of reactive oxygen species, and their relationship with mitochondrial fission or fusion. It also examines the relationship of redox to mitophagy when mitochondria become compromised and its effect on cancer cell survival, stemness, and the changes accompanying malignant progression from primary tumors to metastatic disease. Future Directions: A challenging question that arises is whether the changes in mitochondrial dynamics and their regulation can provide opportunities for improving drug targeting during cancer treatment and enhancing survival outcomes. Antioxid. Redox Signal. 39, 591-619.

Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II.

Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic 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, whereas 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 pseudohypoxia. 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 Ser(68) 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, optimizing its biological effects as an anti-cancer drug.

Targeting the redox imbalance in mitochondria: A novel mode for cancer therapy.

Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth. Anticancer therapies are exploring inducing supranormal, cytotoxic oxidative stress levels either inhibiting antioxidative capacity or promoting excess ROS to selectively destroy cancer cells, triggering mechanisms such as apoptosis, autophagy, necrosis, or ferroptosis. This review exemplifies pro-oxidants (natural/synthetic/repurposed drugs) and their clinical significance as cancer therapies providing revolutionary approaches.

Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress.

Cancer cells produce galectin-1 as a tumor promoting protein. Thiodigalactoside (TDG) as a non-metabolised small drug, is shown to suppress tumor growth by inhibiting multiple cancer enhancing activities of galectin-1, including immune cell dysregulation, angiogenesis and protection against oxidative stress. Thus, using B16F10 melanoma and 4T1 orthotopic breast cancer models, intratumoral injection of TDG significantly raised the levels of tumor-infiltrating CD8(+) lymphocytes and reduced CD31(+) endothelial cell content, reducing tumor growth. TDG treatment of tumors in Balb/c nude mice (defective in T cell immunity) reduced angiogenesis and slowed tumor growth by a third less than in immunocompetent mice. Knocking down galectin-1 expression (G1KD) in both cancer cell types significantly impeded tumor growth and the sensitivity of the G1KD tumors to TDG was severely reduced, highlighting a specific role for galectin-1. Endothelial cells were protected by galectin-1 from oxidative stress-induced apoptosis induced by H(2)O(2), but TDG inhibited this antioxidant protective effect of galectin-1 and reduced tube forming activity in angiogenic assays. We show for the first time that the single agent, TDG, concurrently prevents many tumor promoting effects of galectin-1 on angiogenesis, immune dysregulation and protection against oxidative stress, providing a potent and novel small molecule as an anti-cancer drug.

Inhibitors of succinate: quinone reductase/Complex II regulate production of mitochondrial reactive oxygen species and protect normal cells from ischemic damage but induce specific cancer cell death.

Succinate:quinone reductase (SQR) of Complex II occupies a unique central point in the mitochondrial respiratory system as a major source of electrons driving reactive oxygen species (ROS) production. It is an ideal pharmaceutical target for modulating ROS levels in normal cells to prevent oxidative stress-induced damage or alternatively,increase ROS in cancer cells, inducing cell death.The value of drugs like diazoxide to prevent ROS production,protecting normal cells, whereas vitamin E analogues promote ROS in cancer cells to kill them is highlighted. As pharmaceuticals these agents may prevent degenerative disease and their modes of action are presently being fully explored. The evidence that SDH/Complex II is tightly coupled to the NADH/NAD+ ratio in all cells,impacted by the available supplies of Krebs cycle intermediates as essential NAD-linked substrates, and the NAD+-dependent regulation of SDH/Complex II are reviewed, as are links to the NAD+-dependent dehydrogenases, Complex I and the E3 dihiydrolipoamide dehydrogenase to produce ROS. This review collates and discusses diverse sources of information relating to ROS production in different biological systems, focussing on evidence for SQR as the main source of ROS production in mitochondria, particularly its relevance to protection from oxidative stress and to the mitochondrial-targeted anti cancer drugs (mitocans) as novel cancer therapies [corrected].

Tea tree oil extract causes mitochondrial superoxide production and apoptosis as an anticancer agent, promoting tumor infiltrating neutrophils cytotoxic for breast cancer to induce tumor regression.

The antitumor activity of the tea tree oil (TTO) derived product, Melaleuca Alternifolia Concentrate (MAC) was characterized mechanistically at the molecular and cellular level. MAC was analyzed for its anticancer activity against human prostate (LNCaP) and breast (MCF-7) cancer cell lines growing in vitro. MAC (0.02-0.06% v/v) dose-dependently induced the intrinsic (mitochondrial) apoptotic pathway in both the LNCaP and MCF-7 cell lines, involving increased mitochondrial superoxide production, loss of mitochondrial membrane potential (MMP), caspase 3/7 activation, as well as the presence of TUNEL+ and cleaved-PARP+ cell populations. At concentrations of 0.01-0.04% v/v, MAC caused cell cycle arrest in the G0/1-phase, as well as autophagy. The in vivo anticancer actions of MAC were examined as a treatment in the FVB/N c-Neu murine model for spontaneously arising breast cancers. Intratumoral MAC injections (1-4% v/v) significantly suppressed tumor progression in a dose-dependent manner and was associated with greater levels of tumor infiltrating neutrophils exhibiting anticancer cytotoxic activity. Induction of breast cancer cell death by MAC via the mitochondrial apoptotic pathway was also replicated occurring in tumors treated in vivo. In conclusion, our data highlights the potential for the Melaleuca-derived MAC product inducing anticancer neutrophil influx, supporting its application as a novel therapeutic agent.

alpha-Tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channels.

Mitocans are drugs selectively killing cancer cells by destabilizing mitochondria and many induce apoptosis via generation of reactive oxygen species (ROS). However, the molecular events by which ROS production leads to apoptosis has not been clearly defined. In this study with the mitocan alpha-tocopheryl succinate (alpha-TOS) the role of the Bcl-2 family proteins in the mechanism of malignant cell apoptosis has been determined. Exposure of several different cancer cell lines to alpha-TOS increased expression of the Noxa protein, but none of the other proteins of the Bcl-2 family, an event that was independent of the cellular p53 status. alpha-TOS caused a profound conformational change in the pro-apoptotic protein, Bak, involving oligomerization in all cell types, and this also applied to the Bax protein, but only in non-small cell lung cancer cells. Immunoprecipitation studies indicated that alpha-TOS activates the two BH1-3 proteins, Bak or Bax, to form high molecular weight complexes in the mitochondria. RNAi knockdown revealed that Noxa and Bak are required for alpha-TOS-induced apoptosis, and the role of Bak was confirmed using Bak- and/or Bax-deficient cells. We conclude that the major events induced by alpha-TOS in cancer cells downstream of ROS production leading to mitochondrial apoptosis involve the Noxa-Bak axis. It is proposed that this represents a common mechanism for mitochondrial destabilization activated by a variety of mitocans that induce accumulation of ROS in the early phases of apoptosis.

Suppression of tumor growth in vivo by the mitocan alpha-tocopheryl succinate requires respiratory complex II.

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 alpha-tocopoheryl succinate (alpha-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 alpha-TOS was studied. RESULTS: The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to alpha-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to alpha-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 other hand, alpha-TOS did not inhibit the CII-dysfunctional tumors. CONCLUSIONS: We document in this report a novel paradigm, according to which the mitochondrial CII, which rarely mutates in human neoplasias, is a plausible target for anticancer drugs from the group of vitamin E analogues, providing support for their testing in clinical trials.

Phase I/II parallel double-blind randomized controlled clinical trial of perispinal etanercept for chronic stroke: improved mobility and pain alleviation.

Background: Previous open-label studies showed that chronic post-stroke pain could be abated by treatment with perispinal etanercept, although these benefits were questioned. A randomized double-blind placebo controlled clinical trial was conducted to test perispinal etanercept for chronic post-stroke pain.Research design and methods: Participants received two treatments, either perispinal etanercept (active) or saline (control). Primary outcomes were the differences in daily pain levels between groups analyzed by SPSS.Results: On the 0-100 points visual analog scale, perispinal etanercept reduced mean levels for worst and average daily pain from baseline after two treatments by 19.5 - 24 points (p < 0.05), and pain alleviation was maintained in the etanercept group, with no significant change in the control group. Thirty percent of etanercept participants had near complete pain abatement after first treatment. Goniometry of the paretic arm showed improved mean shoulder rotation by 55 degrees in active forward flexion for the etanercept group (p = 0.003) only.Conclusions: Perispinal etanercept can provide significant and ongoing benefits for the chronic post-stroke management of pain and greater shoulder flexion by the paretic arm. Effects are rapid and highly significant, supporting direct action on brain function.Trial registration: ACTRN12615001377527 and Universal Trial Number U1111-1174-3242.

HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms.

To develop new and more efficient anti-cancer strategies it will be important to characterize the products of transcription factor activity essential for tumorigenesis. One such factor is hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by low oxygen conditions and found in high levels in malignant solid tumors, but not in normal tissues or slow-growing tumors. In fast-growing tumors, HIF-1alpha is involved in the activation of numerous cellular processes including resistance against apoptosis, over-expression of drug efflux membrane pumps, vascular remodeling and angiogenesis as well as metastasis. In cancer cells, HIF-1alpha induces over-expression and increased activity of several glycolytic protein isoforms that differ from those found in non-malignant cells, including transporters (GLUT1, GLUT3) and enzymes (HKI, HKII, PFK-L, ALD-A, ALD-C, PGK1, ENO-alpha, PYK-M2, LDH-A, PFKFB-3). The enhanced tumor glycolytic flux triggered by HIF-1alpha also involves changes in the kinetic patterns of expressed isoforms of key glycolytic enzymes. The HIF-1alpha induced isoforms provide cancer cells with reduced sensitivity to physiological inhibitors, lower affinity for products and higher catalytic capacity (Vmax(f)) in forward reactions because of marked over-expression compared to those isoforms expressed in normal tissues. Some of the HIF1alpha-induced glycolytic isoforms also participate in survival pathways, including transcriptional activation of H2B histone (by LDH-A), inhibition of apoptosis (by HKII) and promotion of cell migration (by ENO-alpha). HIF-1alpha action may also modulate mitochondrial function and oxygen consumption by inactivating the pyruvate dehydrogenase complex in some tumor types, or by modulating cytochrome c oxidase subunit 4 expression to increase oxidative phosphorylation in other cancer cell lines. In this review, the roles of HIF-1alpha and HIF1alpha-induced glycolytic enzymes are examined and it is concluded that targeting the HIF1alpha-induced glucose transporter and hexokinase, important to glycolytic flux control, might provide better therapeutic targets for inhibiting tumor growth and progression than targeting HIF1alpha itself.

A peptide conjugate of vitamin E succinate targets breast cancer cells with high ErbB2 expression.

Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic alpha-tocopheryl succinate (alpha-TOS). Treating erbB2-low or erbB2-high cells with alpha-TOS induced similar levels of apoptosis, whereas alpha-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. alpha-TOS rapidly accumulated in erbB2-high cells exposed to alpha-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by alpha-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. alpha-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting alpha-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors.

Increased All-Cause Mortality by Antipsychotic Drugs: Updated Review and Meta-Analysis in Dementia and General Mental Health Care.

It is almost ten years since the Banerjee 2009 report established that inappropriate prescribing of antipsychotics in the elderly was occurring in the UK and such patients had an 85% increased risk of adverse events and greater mortality. This report was a critical analysis addressing the outcomes of treatment practices for dementia in UK patients and globally, aimed at reducing prescribing of antipsychotic drugs for dementia. Since 2009, many significant studies worldwide (including several more recent large retrospective studies) provide more extensive longitudinal data for the adverse impacts of antipsychotic drugs in dementia. We have used the data in these studies including from over 380,000 dementia patients, with 85,069 prescribed antipsychotic agents as well as from 359,235 non-dementia antipsychotic drug users to provide an up-dated meta-analysis. This is the first meta-analysis to include evidence from general mental health studies showing that antipsychotic drugs precipitate excessive mortality across the spectrum. Prescribing of antipsychotic drugs for dementia or for other mental health care should be avoided and alternative means sought for handling behavioral disorders of such patients.

Vitamin E analogues as a novel group of mitocans: anti-cancer agents that act by targeting mitochondria.

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 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 anti-cancer 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.

Novel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3.

Dynamic remodelling of the extracellular matrix (ECM) is a key feature of cancer progression. Enzymes that modify the ECM, such as matrix metalloproteinases (MMPs), have long been recognised as important targets of anticancer therapy. Inflammatory cytokines are known to play a key role in regulating protease expression in cancer. Here we describe the identification of gamma-activated site (GAS)-like, signal transducer and activator of transcription (STAT) binding elements (SBEs) within the proximal promoters of the MMP-1 and MMP-3 genes, which in association with AP-1 components (c-Fos or Jun), bind STAT-1 in a homodimer like complex (HDLC). We further demonstrate that MMP expression and binding of this complex to SBEs can either be enhanced by interleukin (IL)-6, or reduced by interferon gamma (IFN-γ), and that IL-6 regulation of MMPs is not STAT-3 dependent. Collectively, this data adds to existing understanding of the mechanism underlying cytokine regulation of MMP expression via STAT-1, and increases our understanding of the links between inflammation and malignancy in colon cancer.

Molecular mechanism of 'mitocan'-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins.

Mitochondria have emerged recently as effective targets for novel anti-cancer drugs referred to as 'mitocans'. We propose that the molecular mechanism of induction of apoptosis by mitocans, as exemplified by the drug alpha-tocopheryl succinate, involves generation of reactive oxygen species (ROS). ROS then mediate the formation of disufide bridges between cytosolic Bax monomers, resulting in the formation of mitochondrial outer membrane channels. ROS also cause oxidation of cardiolipin, triggering the release of cytochrome c and its translocation via the activated Bax channels. This model may provide a general mechanism for the action of inducers of apoptosis and anticancer drugs, mitocans, targeting mitochondria via ROS production.