Targeting p53 to mitochondria for cancer therapy

[Cell Cycle 7:13, 1949-1955; 1 July 2008]; ©2008 Landes Bioscience

Review

Targeting p53 to mitochondria for cancer therapy Lorenzo Galluzzi,1-3,† Eugenia Morselli,1-3,† Oliver Kepp,1-3 Nicolas Tajeddine1-3 and Guido Kroemer1-3 1INSERM, †These

U848; Villejuif, France; 2Institut Gustave Roussy; Villejuif, France; 3Université Paris-Sud XI; Villejuif, France

authors contributed equally to this work.

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Abbreviations: ANT, adenine nucleotide translocase; ATM, ataxia-telangiectasia mutated kinase; BH, Bcl-2 homology; CsA, cyclosporine A; HK, hexokinase; MOMP, mitochondrial outer membrane permeabilization; OM, mitochondrial outer membrane; PBR, peripheral-type benzodiazepine receptor; PTPC, permeability transition pore complex; ROS, reactive oxygen species; VDAC, voltage-dependent anion channel; wt, wild type

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Logically, cancer therapy aims at reverting one or more of these hallmarks. As an example, the tumor suppressor protein p53 is inactivated or mutated in at least half of all cancers, and its reintroduction into cancer cells by means of adenoviral vectors has been widely advocated as a therapeutic measure and has received government approval for the treatment of head and neck carcinoma in China.3,4 The p53 tumor suppressor protein is able to mediate permanent cell cycle arrest (senescence) as well as apoptosis, meaning that its reintroduction into proliferating cancer cells may lead to irreversible growth arrest or tumor cell killing.5 Another example is provided by a plethora of small compounds that target proteins and/ or lipids contained in mitochondria.6,7 Indeed, mitochondrial outer membrane permeabilization (MOMP) is (one of ) the main checkpoints of programmed cell death,8,9 and lethal pathways of signal transduction are often interrupted in cancer cells, either upstream or at the level of MOMP.10,11 Hence, pharmacological agents that target mitochondria to subvert oncogenic MOMP inhibition or directly induce MOMP are being evaluated as therapeutic approaches for the treatment or cancer.6,7 In a seminal paper by Ute Moll and colleagues published in the current issue of Cell Cycle,12 the two aforementioned approaches have now been merged, by designing an adenoviral vector that encodes a mitochondrion-targeted variant of p53, which induces MOMP and exhibits a formidable therapeutic efficacy on human cancer xenografts implanted into immunodeficient mice. The present mini-review provides some background information on this study and discusses putative modes of action that may account for the improved efficacy of mitochondrially-targeted p53.

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Although the tumor suppressor protein p53 is a major senescence- and cell death-inducing transcription factor, recent work has clearly demonstrated that p53 has additional, extranuclear effects that contribute to its cell cycle-arresting and proapoptotic functions. Mitochondrial outer membrane permeabilization (MOMP) is (one of) the most prominent apoptotic checkpoint(s), and cytoplasmic p53 can induce MOMP by direct interactions with multidomain proteins from the Bcl-2 family present at the mitochondrial outer membrane (OM). Since MOMP is commonly disabled in cancer cells, its pharmacological induction constitutes a therapeutic goal, and this has stimulated the design of mitochondriotropic inducers of apoptosis, both inhibitors of antiapoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL) or activators of their proapoptotic counterparts (e.g., Bak, Bax). Moreover, novel approaches of gene therapy have been designed in which p53 is specifically targeted to mitochondria and have been demonstrated to inhibit the growth of human cancer xenografts in immunodeficient mice. Thus, a number of distinct strategies can be employed to achieve the therapeutic induction of MOMP in cancer cells.

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Key words: apoptosis, Bcl-2, caspases, mitochondrial outer membrane permeabilization (MOMP), permeability transition pore complex (PTPC)

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Introduction

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Any biomedical investigator and clinical oncologist can enumerate the six cell-intrinsic hallmarks of cancer, as formulated by Hanahan and Weinberg:1 provision of autonomous growth factors, insensitivity to antiproliferative signals, disabled apoptosis, limitless replication, production of angiogenic modulators and tissue invasion with metastasis. The escape from immunosurveillance can be regarded as a seventh hallmark, which allows tumor cells to passively avoid or to actively subvert anticancer immune responses.2 *Correspondence to: Guido Kroemer; INSERM U848; Institut Gustave Roussy, PR1; 39 rue Camille Desmoulins; Villejuif F-94805; France; Tel.: +33.1.4211.6046; Fax: +33.1.4211.6047; Email: [email protected] Submitted: 03/22/08; Revised: 04/26/08; Accepted: 04/30/08 Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/6233 www.landesbioscience.com

Pharmacological Targeting of Mitochondria for MOMP Induction Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function,13 and this may lead to MOMP inhibition and hence invalidation of apoptosis. Thus, in cancer cells, the signal transduction pathways that normally trigger apoptosis may be interrupted upstream of MOMP or at MOMP itself.

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Extranuclear activities of p53

Mitochondrial Effects of Wild Type p53 Protein

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p53, which is often considered only as a nuclear transcription factor, has been shown to trans-activate a broad range of proapoptotic proteins from the Bcl-2 family (in particular Bax, but also the BH3-only proteins Bid, Puma and Noxa), to downregulate Bcl-2, as well as to induce the upregulation of proteins that locate to mitochondria and favor MOMP through oxidative reactions (e.g., ferredoxin reductase, proline oxidase)28,29 or via still unknown mechanisms (e.g., p53AIP1, mtCLIC).30,31 In addition, p53 may initiate apoptosis through proteins that localize to the endoplasmic reticulum (e.g., scotin)32 or to the plasma membrane (such as the death receptor Fas/CD95).33 Thus, p53 can engage multiple, in part cell type-specific, proapoptotic pathways and it “overkills” cells by transactivating a wide array of genes with apoptosis-inducing products.34,35 Nonetheless, p53 also exerts transcription-independent proapoptotic effects. This notion is based on the fact that particular mutations that abolish the transactivating functions of p53 (e.g., L22Q, W23S) and/or the deletion of p53 nuclear localization signal (which causes its retention in the cytoplasm) do not completely abolish p53 apoptogenic potential.36,37 A small molecule that activates p53 (called PRIMA-1) has been shown to induce the death of tumor cells expressing p53 (or the tumor-derived p53 mutants M246I and R373H), in the absence of transcription.37 Moreover, the dissociation of a particular p53-estrogen receptor chimera from the endoplasmic reticulum (as induced by 4-hydroxytamoxifen) can induce apoptosis in the presence of the protein synthesis inhibitor cycloheximide, as well as upon enucleation of the cells.37 What are then the cytoplasmic targets of p53? Subcellular fractionation studies revealed that upon an apoptotic insult a sizeable fraction of p53 interacts with mitochondria, thus launching the search for the mitochondrial target of p53.38 Of note, some posttranslational modifications of p53 (such as monoubiquitylation) appear to stimulate its translocation to mitochondria,39 but this issue requires further in-depth investigation. Ute Moll and collaborators first reported that p53 would preferentially engage the BH1234 proteins Bcl-2 and Bcl-XL and obstacle their apoptosis-inhibitory function, thereby promoting MOMP.40 Some p53 mutations that are found in human tumors (e.g., R175H, L194F, R273H) constitute “double hits” in the sense that they simultaneously abolish p53 nuclear (transcription-dependent) and cytoplasmic (transcription independent) effects, the latter relying on the interaction with Bcl-2/ Bcl-XL. As a possibility, p53 may promote MOMP by releasing BH3-only and/or BH123 proteins from inhibitory complexes with Bcl-2/Bcl-XL.40,41 The research group of Douglas Green proposed Bax as one of the principal cytoplasmic targets of p53.41 This interpretation was mainly derived from in vitro assays showing that recombinant p53 and Bax proteins together (but neither of them alone) trigger the permeabilization of model liposomes whose lipid composition mimics that of mitochondrial inner/outer membrane contact sites. This is accompanied by Bax full OM insertion and oligomerization, and it would be due to a “hit and run” mechanism, involving a conformational change of Bax but not a stable interaction between Bax and p53.41 Donna George and collaborators indicated Bak rather than Bax as the principal extranuclear target of p53.42 The interaction of p53 with Bak would liberate Bak from its

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MOMP is controlled by the permeability transition pore complex (PTPC)14 as well as by proteins from the Bcl-2 family.15,16 Tumor-associated alterations in the expression level of PTPC components have been described for the adenine nucleotide translocase (ANT),17,18 hexokinase (HK),19,20 the peripheral-type benzodiazepine receptor (PBR)21 and the voltage-dependent anion channel (VDAC).22 The overexpression of the HKII isoform reportedly leads to an enhanced interaction between HKII and VDAC, which in turn limits the translocation of Bax to mitochondria and hence inhibits Bax-mediated MOMP.23 The upregulation of antiapoptotic members of the Bcl-2 family (e.g., Bcl-2, Bcl-XL, Mcl-1) and/or the downregulation of their proapoptotic counterparts (e.g., Bax, Bak) have been amply documented in patients affected by a plethora of distinct tumor types.24 Bcl-2 is the prototype of a family of proteins containing at least one Bcl-2 homology (BH) region. These proteins can be sub-classified into antiapoptotic multidomain proteins (prototypes: Bcl-2, Bcl-XL), which contain four BH domains (BH1234), proapoptotic multidomain proteins (prototypes: Bax, Bak), which contain three BH domains (BH123), and proapoptotic BH3-only proteins (prototypes: Bad, Bid).15,16 The principal site of action of all Bcl-2-like proteins is probably the mitochondrial membrane.11 BH1234 members (e.g., Bcl-2, Bcl-XL, Mcl-1) are normally inserted into the mitochondrial outer membrane (OM), and play a role in the maintenance of its integrity. In healthy cells, also Bak is associated with the OM (in an inactive conformation), whereas Bax resides in the cytosol. Either of these two BH123 proteins (i.e., Bax and Bak) are required for MOMP, in a series of different models of apoptosis induction,25 although both proteins can also be activated in a hierarchical fashion (Bak upstream of Bax).26 The precise mechanisms of MOMP are still matter of debate. According to one model, MOMP results from a conformational change of Bax or Bak (with exposure of their N-terminus), which allow them to fully insert into mitochondrial membranes as homooligomerized multimers and to form giant protein-permeable pores.15 BH3-only proteins exert their proapoptotic function by two different mechanisms. Some of them, known as “activators” (prototype: Bid), directly trigger BH123-mediated MOMP, either by stimulating the translocation of Bax to OM or by local effects on Bak. Others, also called “derepressors” (prototype: Bad), preferentially interact with BH1234 proteins, thereby dissociating them from BH3-only or BH123 proteins, which in turn mediate MOMP.27 Specific therapeutic interventions are being developed to target the mitochondrial Achilles’ heel of cancer cells, thereby rendering them metabolically unviable or subverting endogenous MOMP inhibition. Several experimental agents have been shown to directly target mitochondria, thus triggering apoptosis. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged α-helical peptides, molecules designed to mimic the BH3 domain of Bcl-2 like proteins, ampholytic cations and steroid-like compounds (Table 1). Such MOMP inducers/ facilitators may initiate apoptosis by themselves (monotherapy) or sensitize cancer cells in combination regimens, thereby bypassing the chemoresistance against other therapeutic agents.6,7

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Table 1 Examples of mitochondrial outer membrane permeabilization (MOMP) inducers in preclinical or clinical development Agent

Stage

Antitumor activity

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5-aminolevulinic Currently used to treat several Non-melanoma skin carcinoma.55,56 acid cutaneous diseases ABT-263 Phase II clinical trials Non-Hodgkin lymphoma, CLL and SCLC.59 ABT-737 Preclinical development

In vitro and in vivo, in models of ALL, myeloma and SCLC.62,63

Associated with photodynamic therapy. Induces MOMP via the accumulation of ROS and cardiolipin oxidation.57,58 Small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w. Closely related to ABT-737.60,61 Small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w.61

AT-101 Phase I/II clinical trials Different hematologic and solid malignancies

Arsenic trioxide

In vitro and in vivo, in models of mesothelioma, NSCLC and esophageal cancer.68 Promyelocytic leukemia.66

Currently in use

CD437 Preclinical development

Synthetic retinoid (triterpenoid) able to promote MOMP independently from nuclear receptors.76-78

Metastatic or unresectable solid tumors and lymphoma

Synthetic retinoid (triterpenoid), induces MOMP in isolated mitochondria.79

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Breast and prostate cancer, bone metastases.80 Adenosine metabolite, binds to and inhibits ANT.81

Phase III clinical trials Phase III clinical studies for multiple sclerosis

In vitro and in vivo, in models of hepatoma, bladder and prostate cancer.82-84

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FTY720

Steroid-like structure. Induces MOMP in isolated mitochondria.72

In vitro and in vivo, in different models of human tumors.73-75

CDDO Phase I clinical trials Clodronate

Able to induce MOMP in isolated mitochondria.71

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Betulinic acid Phase I/II clinical trials Dysplastic nevi syndrome

BH3 mimetics, particularly toxic for cancer cells overexpressing Bcl-XL.69,70

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Antimycin and its Preclinical development methoxy derivative

Can induce MOMP by binding to ANT, independently from nuclear receptors.67

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all-trans-retinoic Currently in use Promyelocytic leukemia.66 acid

(-)-gossypol derivative, inhibits Bcl-2 and Bcl-XL.64,65

GSAO Preclinical development

In vitro and in vivo, in models of pancreatic cancer.86

Immunosuppressive lipophilic agent, induces opening of the PTPC, MOMP and apoptosis.85

Angiogenesis inhibitor, exerts direct effects at mitochondria by promoting ANT thiols oxidation.87 Bcl-2 ligand, induces apoptosis via a ROS-dependent mechanism91-93

Jasmonates Preclinical development In vitro and in vivo, in models of CLL, melanoma and other neoplastic diseases.94,95

Plant hormones, induce MOMP in isolated mitochondria. Disrupt the HK-VDAC interaction.96,97

Glioblastoma and benign prostatic hyperplasia.98

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Lonidamine Phase II clinical trials (TH-070)

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HA14-1 Preclinical development In vitro, in different human tumor cell lines.88-90

Currently used to treat cardiovascular diseases. Phase I/II clinical trials for cancer.

Several human tumors, including leukemia, melanoma, gastric, ovarian and breast cancer.101-103

Statin, induces p53-independent apoptosis, also by a direct action on mitochondria.104-106

In vitro and in vivo, in models of hepatoma, neuroblastoma and NSCLC.107-109

COX-2 inhibitor, promotes MOMP also on isolated mitochondria.107,110

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Lovastatin

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Nimesulide Currently in use as an NSAID

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Obatoclax Phase I/II clinical trials (GX15-070)

Hematological malignancies (e.g., non-Hodgkin Broad spectrum inhibitor of BH1234 antiapoptotic lymphoma, advanced solid tumors and proteins (e.g. Bcl-2, Bcl-XL, Mcl-1, etc…).111 refractory SCLC).59

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PK11195 Preclinical development In vitro and in vivo, in models of cholangiocarcinoma and SCLC.112,113 Resveratrol Phase I clinical trials Chemoprevention.115,116

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Induces apoptosis via a direct, Bcl-2-inhibitable effect on the PTPC99,100

PBR ligand, promotes MOMP and apoptosis by direct mitochondrial effects that do not depend on PBR.114 Polyphenolic compound found in grapes, induces apoptosis by directly targeting mitochondria.117,118

In vitro and in vivo, in murine models of human leukemia.119

Mimics the BH3 domain of proapoptotic Bcl-2 proteins.119,120

Trypticene synthetic Preclinical development analogs

In vitro, in HL-60 and L1210 human leukemic cells.121,122

Induce MOMP via direct mitochondrial effect.123

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SAHB peptide Preclinical development

Verteporfin Phase I/II clinical trials Advanced melanoma

Associated with photodynamic therapy. Induces apoptosis via a direct, ROS-mediated effect at mitochondria.124

Please note that only drugs that have been shown to have direct membrane-permeabilizing effects on mitochondria are listed in this table. Abbreviations: ALL, acute lymphoblastic leukemia; ANT, adenine nucleotide translocase, AT-101, R-(-)-gossypol; BH3, Bcl-2 homology domain 3; CD437, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid; CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; CLL, chronic lymphocytic leukemia; COX-2, cyclooxygenase 2; FTY720, 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol; GSAO, 4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide; HA14-1, 2-amino-6-bromo-4-(1-cyano-2ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; HK, hexokinase; MOMP, mitochondrial outer membrane permeabilization; NSAID, non-steroidal anti-inflammatory drug; NSCLC, non-small cell lung cancer; PBR, peripheral-type benzodiazepine receptor; PK11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide; PTPC, permeability transition pore complex; ROS, reactive oxygen species; SAHB, stabilized alpha-helix of Bcl-2 domains; SCLC, small cell lung cancer; VDAC, voltage-dependent anion channel. www.landesbioscience.com

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interaction with the BH1234 protein Mcl-1, its endogenous inhibitor. Disruption of the Mcl-1-Bak interaction would then unleash the MOMP-triggering potential of Bak.42 Of note, while Bcl-XL interacts with the DNA binding site of p53,40 NMR spectroscopy studies indicate that the same does not hold true for Bak.43 Altogether, these results suggest that p53 can trigger MOMP through a pathway that implicates any of the Bcl-2 multidomain proteins (Fig. 1), depending on the specific conditions of the Bcl-2 network, which is modulated in a cell- and activation state-dependent fashion.

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Figure 1. Extranuclear p53 mediates apoptosis by interacting with Bcl-2 family members at mitochondria. The role of p53 as a cell death-inducing nuclear factor has been extensively characterized, and involves both the transactivation of proapoptotic Bcl-2 family members (e.g., Bax, Noxa, Puma) as well as the transcriptional repression of antiapoptotic factors (such as Bcl-2 itself). Moreover, p53 can trigger mitochondrial outer membrane permeabilization (MOMP) from the cytosol, in a transcription-independent fashion that relies on the interaction with proteins from the Bcl-2 family. Thus, p53 can directly activate the pore-forming functions of Bax and Bak. Alternatively, p53 might displace Bax/Bak or BH3-only proteins from inhibitory complexes with antiapoptotic Bcl-2-like proteins (e.g., Bcl-2, Bcl-XL, Mcl-1), thereby unleashing their proapoptotic potential.

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In cancer cells, the p53 system is often disrupted. This can result from several distinct phenomena including mutational inactivation of p53 protein,44 epigenetic silencing of p53 gene,44 loss-of-function of p53 targets or activators (such as the DNA damage sensor ataxiatelangiectasia mutated kinase, i.e., ATM, or the checkpoint kinases Chk1 or Chk2, among many other proteins),45 and amplification of the mdm2 gene (which encodes for the ubiquitin ligase that targets p53 to degradation).46 Based on this observation, multiple groups have attempted to reintroduce p53 into cancer cells, and a p53-expressing adenovirus has been approved by the Chinese government for the therapy of head and neck carcinoma.3,4 While most research groups have limited themselves to (re) introduce wt p53 into cancer cells, Ute Moll and collaborators have chosen an alternative approach, in which they deliberately targeted p53 to mitochondria (hence excluding it from the nucleus). This has been achieved by fusing the C-terminus of human p53 with the mitochondrion-targeted transmembrane domain of Bcl-2 or Bcl-XL, which resulted in two chimeric proteins that the authors called “p53CTM” and “p53CTB”, respectively. When retroviral vectors encoding p53CTM or p53CTB were introduced into p53-/Eμ-myc B cell lymphomas, they efficiently inhibited the growth of tumor cells that were injected into syngenic recipient mice, while inducing lymphoma cell apoptosis.47 Similar results were obtained when p53CTM or p53CTB were introduced into Eμ-myc B cell lymphomas expressing mutant p53 variants (i.e., R279P, V135A and D278G). However, another mitochondrion-targeted p53 construct, based on the mitochondrial import leader sequence of ornithine transcarbamylase (called “Lp53wt”), turned out to be more efficient than p53CTB and p53CTM in suppressing the growth of p53 deficient and p53-R279P-expressing Eμ-myc B cell lymphomas.48 As shown in this issue of Cell Cycle, an adenovirus expressing Lp53wt (but not p53CTB) was highly efficient in triggering apoptosis and hence in reducing the growth of human p53-/- HCT116 colon cancer cells, both in vitro (in cell cultures) and in vivo (upon xenograft into immunodeficient mice).12 In this system, Lp53wt was nearly as efficient in inhibiting tumor growth as wild type (wt) p53, thus establishing the proof-of-principle that mitochondrion-targeted p53 might be used as an alternative to wt p53 for the gene therapy of neoplastic diseases. At the theoretical level, mitochondriontargeted p53 is more advantageous than its wt counterpart because it induces apoptosis without cell cycle arrest (which would induce a desensitization against drugs that kill preferentially proliferating cells).12 However, this remains a pure conjecture that requires urgent experimental verification.

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A Novel Gene Therapy of Cancer in which p53 is Targeted to Mitochondria

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In contrast to p53CTB and p53CTM, which only insert in the OM (similarly to Bcl-2 and Bcl-XL), Lp53wt is both found in the OM and imported into the mitochondrial matrix.49 Its increased (~5-fold) proapoptotic potency (as compared to p53CTB and p53CTM) hence points to a MOMP-triggering action of Lp53wt that is conditioned by its intramitochondrial localization (Fig. 2A). As an alternative and equally plausible explanation, tethering p53 to the OM by its N-terminus (as in the Lp53wt fusion protein) as opposed to its C-terminus (which is the case of p53CTB and p53CTM chimeras) may impose steric constraints on the molecule that influence its ability to engage in highly efficient (stable or hitand-run) interactions with multidomain proteins from the Bcl-2 family (Fig. 2B). Irrespective of these considerations, the present data demonstrate the feasibility to generate therapeutic MOMP inducers that are derivatives of p53.

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Conclusions and Perspectives As discussed in this mini-review, therapeutic MOMP induction can be achieved by the use of pharmacological inducers as well as by p53-based gene therapy. One particular strategy for the pharmacological reactivation of mutated p53 may implicate its direct targeting to mitochondria. Thus, several pharmaceutical companies have developed small compounds that interact with mutant p53, force it into a normal conformation and reestablish its tumor suppressive function. Among these, the styrylquinazoline derivative CP-31398 has been shown to reactivate the proapoptotic mitochondrial function of a mutant p53 protein, beyond enhancing its transactivating nuclear function. Thus, the addition of CP-31398 to human skin carcinoma A431 cells (which express the p53-R273H mutant) enhances the mitochondrial translocation of this p53 variant, thereby leading to MOMP and apoptosis.50 Intriguingly, the effect of CP-31398

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Figure 2. The proapoptotic potential of mitochondrial p53 may vary due to its localization or to conformational constraints. Although the underlying molecular details have not been elucidated yet, two distinct models can be put forward to explain the different proapoptotic potential exhibited by p53CTM/CTB and Lp53wt chimeric proteins. The transmembrane domains of Bcl-2 and Bcl-XL allow p53CTB and p53CTM, respectively, to insert into the outer mitochondrial membrane, while Lp53wt is actively imported into mitochondria thanks to the mitochondrial localization signal (MLS) of ornithine transcarbamylase. Thus, Lp53wt might be more efficient than p53CTB/CTM in promoting mitochondrial outer membrane permeabilization (MOMP) due to its submitochondrial localization (A). As an alternative, p53CTM/CTB might be less efficient than Lp53wt in triggering MOMP due to the fact that ornithine transcarbamylase MLS (as opposite to Bcl-2/XL transmembrane domains) is removed upon mitochondrial import. Accordingly, p53CTB/CTM might be characterized by conformational constraints that limit their ability to interact with proteins from the Bcl-2 family and/or PTPC components (B).

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on A431 cells was blocked by cyclosporine A (CsA), an agent that reportedly does not inhibit Bax- or Bak-mediated MOMP.51 This suggests that other mitochondrial proteins (including cyclophilin D, the pharmacological target of CsA) are implicated in MOMP induction by p53 (at least as triggered by CP-31398). With regard to this, p53 has been shown to increment the intracellular concentration of reactive oxygen species (ROS), presumably via an interaction with the proapoptotic protein pShc66.52,53 Thus, it cannot be excluded that p53 mitochondrial effects depend, at least in part, from a ROS-induced opening of the PTPC, which is reportedly sensitive to CsA inhibition.14,54 Hence, future studies will have to elucidate the exact mechanisms through which wt, mitochondrion-targeted and pharmacologically reactivated p53 variants induce MOMP and exert their tumor suppressive action.

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Acknowledgements

GK is supported by Ligue Nationale contre le cancer (équipe labellisée), Agence National de Recherche, Cancéropôle Ile-deFrance, Institut National du Cancer, Fondation pour la Recherche Médicale, and the European Community (Active p53, Apo-Sys, ChemoRes, DeathTrain, TransDeath, RIGHT). NT and OK are recipient of an FRM and of an EMBO Ph.D. fellowship, respectively. EM is funded by a DeathTrain Ph.D. student fellowship.

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References

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70. 2. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 2006; 6:715-27. 3. Guo J, Xin H. Chinese gene therapy. Splicing out the West? Science 2006; 314:1232-5. 4. Peng Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther 2005; 16:1016-27. 5. Vousden KH. Outcomes of p53 activation—spoilt for choice. J Cell Sci 2006; 119:5015-20. 6. Galluzzi L, Larochette N, Zamzami N, Kroemer G. Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 2006; 25:4812-30. 7. Fantin VR, Leder P. Mitochondriotoxic compounds for cancer therapy. Oncogene 2006; 25:4787-97. 8. Marzo I, Susin SA, Petit PX, Ravagnan L, Brenner C, Larochette N, Zamzami N, Kroemer G. Caspases disrupt mitochondrial membrane barrier function. FEBS Lett 1998; 427:198-202. 9. Ferri KF, Kroemer G. Mitochondria—the suicide organelles. Bioessays 2001; 23:111-5. 10. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305:626-9. 11. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007; 87:99-163. 12. Palacios G, Crawford HC, Vaseva A, Moll UM. Mitochondrially-targeted wild-type p53 induces apoptosis in a solid human tumor xenograft model. Cell Cycle 2008; this issue. 13. Pedersen PL. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers’ most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 2007; 39:211-22. 14. Brenner C, Grimm S. The permeability transition pore complex in cancer cell death. Oncogene 2006; 25:4744-56. 15. Reed JC. Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities. Cell Death Differ 2006; 13:1378-86. 16. Rong Y, Distelhorst CW. Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu Rev Physiol 2008; 70:73-91. 17. Vieira HL, Belzacq AS, Haouzi D, Bernassola F, Cohen I, Jacotot E, Ferri KF, El Hamel C, Bartle LM, Melino G, Brenner C, Goldmacher V, Kroemer G. The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite and 4-hydroxynonenal. Oncogene 2001; 20:4305-16.

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1953


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.

51. Eskes R, Antonsson B, Osen-Sand A, Montessuit S, Richter C, Sadoul R, Mazzei G, Nichols A, Martinou JC. Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J Cell Biol 1998; 143:217-24. 52. Trinei M, Giorgio M, Cicalese A, Barozzi S, Ventura A, Migliaccio E, Milia E, Padura IM, Raker VA, Maccarana M, Petronilli V, Minucci S, Bernardi P, Lanfrancone L, Pelicci PG. A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidationdamaged DNA and oxidative stress-induced apoptosis. Oncogene 2002; 21:3872-8. 53. Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, Pelliccia G, Luzi L, Minucci S, Marcaccio M, Pinton P, Rizzuto R, Bernardi P, Paolucci F, Pelicci PG. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 2005; 122:221-33. 54. Zamzami N, El Hamel C, Maisse C, Brenner C, Munoz-Pinedo C, Belzacq AS, Costantini P, Vieira H, Loeffler M, Molle G, Kroemer G. Bid acts on the permeability transition pore complex to induce apoptosis. Oncogene 2000; 19:6342-50. 55. Fukuda H, Casas A, Batlle A. Aminolevulinic acid: from its unique biological function to its star role in photodynamic therapy. Int J Biochem Cell Biol 2005; 37:272-6. 56. Moseley H, Brancaleon L, Lesar AE, Ferguson J, Ibbotson SH. Does surface preparation alter ALA uptake in superficial non-melanoma skin cancer in vivo? Photodermatol Photoimmunol Photomed 2008; 24:72-5. 57. Hermes-Lima M. How do Ca2+ and 5-aminolevulinic acid-derived oxyradicals promote injury to isolated mitochondria? Free Radic Biol Med 1995; 19:381-90. 58. Kriska T, Korytowski W, Girotti AW. Role of mitochondrial cardiolipin peroxidation in apoptotic photokilling of 5-aminolevulinate-treated tumor cells. Arch Biochem Biophys 2005; 433:435-46. 59. Bayes M, Rabasseda X. Gateways to clinical trials. Methods Find Exp Clin Pharmacol 2008; 30:67-99. 60. Lock R, Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Wu J, Smith MA. Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program. Pediatr Blood Cancer 2008; 50:1181-9. 61. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435:677-81. 62. Del Gaizo Moore V, Schlis KD, Sallan SE, Armstrong SA, Letai A. BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood 2008; 111:2300-9. 63. Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM. Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer. Cancer Res 2008; 68:2321-8. 64. Becattini B, Kitada S, Leone M, Monosov E, Chandler S, Zhai D, Kipps TJ, Reed JC, Pellecchia M. Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L). Chem Biol 2004; 11:389-95. 65. Mohammad RM, Wang S, Aboukameel A, Chen B, Wu X, Chen J, Al-Katib A. Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. Mol Cancer Ther 2005; 4:13-21. 66. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111:2505-15. 67. Notario B, Zamora M, Vinas O, Mampel T. All-trans-retinoic acid binds to and inhibits adenine nucleotide translocase and induces mitochondrial permeability transition. Mol Pharmacol 2003; 63:224-31. 68. Cao X, Rodarte C, Zhang L, Morgan CD, Littlejohn J, Smythe WR. Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma. Cancer Biol Ther 2007; 6:246-52. 69. Manion MK, O’Neill JW, Giedt CD, Kim KM, Zhang KY, Hockenbery DM. Bcl-XL mutations suppress cellular sensitivity to antimycin A. J Biol Chem 2004; 279:2159-65. 70. Tzung SP, Kim KM, Basanez G, Giedt CD, Simon J, Zimmerberg J, Zhang KY, Hockenbery DM. Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 2001; 3:183-91. 71. Larochette N, Decaudin D, Jacotot E, Brenner C, Marzo I, Susin SA, Zamzami N, Xie Z, Reed J, Kroemer G. Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res 1999; 249:413-21. 72. Fulda S, Scaffidi C, Susin SA, Krammer PH, Kroemer G, Peter ME, Debatin KM. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem 1998; 273:33942-8. 73. Joseph B, Marchetti P, Lefebvre O, Schraen-Maschke S, Mereau-Richard C, Formstecher P. The novel retinoid AHPN/CD437 induces a rapid but incomplete apoptotic response in human myeloma cells. Biochim Biophys Acta 2003; 1593:277-82. 74. Sun SY, Yue P, Chen X, Hong WK, Lotan R. The synthetic retinoid CD437 selectively induces apoptosis in human lung cancer cells while sparing normal human lung epithelial cells. Cancer Res 2002; 62:2430-6. 75. Zhang Y, Dawson MI, Mohammad R, Rishi AK, Farhana L, Feng KC, Leid M, Peterson V, Zhang XK, Edelstein M, Eilander D, Biggar S, Wall N, Reichert U, Fontana JA. Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog. Blood 2002; 100:2917-25. 76. Belzacq AS, El Hamel C, Vieira HL, Cohen I, Haouzi D, Metivier D, Marchetti P, Brenner C, Kroemer G. Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 2001; 20:7579-87.

©

20

08

LA

ND

ES

BIO

SC

IEN CE

.D

ON

18. Shiio Y, Donohoe S, Yi EC, Goodlett DR, Aebersold R, Eisenman RN. Quantitative proteomic analysis of Myc oncoprotein function. Embo J 2002; 21:5088-96. 19. Rempel A, Mathupala SP, Griffin CA, Hawkins AL, Pedersen PL. Glucose catabolism in cancer cells: amplification of the gene encoding type II hexokinase. Cancer Res 1996; 56:2468-71. 20. Sebastian S, Kenkare UW. Expression of two type II-like tumor hexokinase RNA transcripts in cancer cell lines. Tumour Biol 1998; 19:253-60. 21. Maaser K, Grabowski P, Oezdem Y, Krahn A, Heine B, Stein H, Buhr H, Zeitz M, Scherubl H. Upregulation of the peripheral benzodiazepine receptor during human colorectal carcinogenesis and tumor spread. Clin Cancer Res 2005; 11:1751-6. 22. Shinohara Y, Ishida T, Hino M, Yamazaki N, Baba Y, Terada H. Characterization of porin isoforms expressed in tumor cells. Eur J Biochem 2000; 267:6067-73. 23. Robey RB, Hay N. Mitochondrial hexokinases: guardians of the mitochondria. Cell Cycle 2005; 4:654-8. 24. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007; 26:1324-37. 25. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001; 292:727-30. 26. Tajeddine N, Galluzzi L, Kepp O, Hangen E, Morselli E, Senovilla L, Araujo N, Pinna G, Larochette N, Zamzami N, Modjtahedi N, Harel-Bellan A, Kroemer G. Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death. Oncogene 2008: in press. 27. Willis SN, Adams JM. Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 2005; 17:617-25. 28. Liu G, Chen X. The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. Oncogene 2002; 21:7195-204. 29. Maxwell SA, Rivera A. Proline oxidase induces apoptosis in tumor cells, and its expression is frequently absent or reduced in renal carcinomas. J Biol Chem 2003; 278:9784-9. 30. Fernandez-Salas E, Suh KS, Speransky VV, Bowers WL, Levy JM, Adams T, Pathak KR, Edwards LE, Hayes DD, Cheng C, Steven AC, Weinberg WC, Yuspa SH. mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53. Mol Cell Biol 2002; 22:3610-20. 31. Matsuda K, Yoshida K, Taya Y, Nakamura K, Nakamura Y, Arakawa H. p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Res 2002; 62:2883-9. 32. Bourdon JC, Renzing J, Robertson PL, Fernandes KN, Lane DP. Scotin, a novel p53inducible proapoptotic protein located in the ER and the nuclear membrane. J Cell Biol 2002; 158:235-46. 33. Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Krammer PH. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 1998; 188:2033-45. 34. Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol 2007; 8:275-83. 35. Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer 2002; 2:594-604. 36. Haupt Y, Rowan S, Shaulian E, Vousden KH, Oren M. Induction of apoptosis in HeLa cells by trans-activation-deficient p53. Genes Dev 1995; 9:2170-83. 37. Chipuk JE, Maurer U, Green DR, Schuler M. Pharmacologic activation of p53 elicits Baxdependent apoptosis in the absence of transcription. Cancer Cell 2003; 4:371-81. 38. Mihara M, Moll UM. Detection of mitochondrial localization of p53. Methods Mol Biol 2003; 234:203-9. 39. Marchenko ND, Wolff S, Erster S, Becker K, Moll UM. Monoubiquitylation promotes mitochondrial p53 translocation. Embo J 2007; 26:923-34. 40. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM. p53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003; 11:577-90. 41. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004; 303:1010-4. 42. Leu JI, Dumont P, Hafey M, Murphy ME, George DL. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 2004; 6:443-50. 43. Sot B, Freund SM, Fersht AR. Comparative biophysical characterization of p53 with the pro-apoptotic BAK and the anti-apoptotic BCL-xL. J Biol Chem 2007; 282:29193-200. 44. Soussi T. p53 alterations in human cancer: more questions than answers. Oncogene 2007; 26:2145-56. 45. Kastan MB, Bartek J. Cell cycle checkpoints and cancer. Nature 2004; 432:316-23. 46. Rayburn E, Zhang R, He J, Wang H. MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets 2005; 5:27-41. 47. Talos F, Petrenko O, Mena P, Moll UM. Mitochondrially targeted p53 has tumor suppressor activities in vivo. Cancer Res 2005; 65:9971-81. 48. Palacios G, Moll UM. Mitochondrially targeted wild-type p53 suppresses growth of mutant p53 lymphomas in vivo. Oncogene 2006; 25:6133-9. 49. Marchenko ND, Zaika A, Moll UM. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem 2000; 275:16202-12. 50. Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, Athar M. CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice. J Clin Invest 2007; 117:3753-64.

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2008; Vol. 7 Issue 13


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IST RIB

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102. Knox JJ, Siu LL, Chen E, Dimitroulakos J, Kamel-Reid S, Moore MJ, Chin S, Irish J, LaFramboise S, Oza AM. A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer 2005; 41:523-30. 103. Schmidmaier R, Baumann P, Bumeder I, Meinhardt G, Straka C, Emmerich B. First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma. Eur J Haematol 2007; 79:240-3. 104. Cafforio P, Dammacco F, Gernone A, Silvestris F. Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 2005; 26:883-91. 105. Shibata MA, Ito Y, Morimoto J, Otsuki Y. Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma model: a p53-independent mitochondrialmediated apoptotic mechanism. Carcinogenesis 2004; 25:1887-98. 106. Velho JA, Okanobo H, Degasperi GR, Matsumoto MY, Alberici LC, Cosso RG, Oliveira HC, Vercesi AE. Statins induce calcium-dependent mitochondrial permeability transition. Toxicology 2006; 219:124-32. 107. Berson A, Cazanave S, Descatoire V, Tinel M, Grodet A, Wolf C, Feldmann G, Pessayre D. The anti-inflammatory drug, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: protection by albumin. J Pharmacol Exp Ther 2006; 318:444-54. 108. Parashar B, Shafit-Zagardo B. Inhibition of human neuroblastoma in SCID mice by lowdose of selective Cox-2 inhibitor nimesulide. J Neurooncol 2006; 78:129-34. 109. Xing L, Zhang Z, Xu Y, Zhang H, Liu J. The effects of nimesulide combined with cisplatin on lung cancer. J Huazhong Univ Sci Technolog Med Sci 2004; 24:120-3. 110. Mingatto FE, dos Santos AC, Rodrigues T, Pigoso AA, Uyemura SA, Curti C. Effects of nimesulide and its reduced metabolite on mitochondria. Br J Pharmacol 2000; 131:1154-60. 111. Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Belec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 2007; 104:19512-7. 112. Okaro AC, Fennell DA, Corbo M, Davidson BR, Cotter FE. Pk11195, a mitochondrial benzodiazepine receptor antagonist, reduces apoptosis threshold in Bcl-X(L) and Mcl-1 expressing human cholangiocarcinoma cells. Gut 2002; 51:556-61. 113. Decaudin D, Castedo M, Nemati F, Beurdeley-Thomas A, De Pinieux G, Caron A, Pouillart P, Wijdenes J, Rouillard D, Kroemer G, Poupon MF. Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo. Cancer Res 2002; 62:1388-93. 114. Gonzalez-Polo RA, Carvalho G, Braun T, Decaudin D, Fabre C, Larochette N, Perfettini JL, Djavaheri-Mergny M, Youlyouz-Marfak I, Codogno P, Raphael M, Feuillard J, Kroemer G. PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor. Oncogene 2005; 24:7503-13. 115. Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 2007; 16:1246-52. 116. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 2004; 24:2783-840. 117. van Ginkel PR, Sareen D, Subramanian L, Walker Q, Darjatmoko SR, Lindstrom MJ, Kulkarni A, Albert DM, Polans AS. Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria. Clin Cancer Res 2007; 13:5162-9. 118. Sareen D, van Ginkel PR, Takach JC, Mohiuddin A, Darjatmoko SR, Albert DM, Polans AS. Mitochondria as the primary target of resveratrol-induced apoptosis in human retinoblastoma cells. Invest Ophthalmol Vis Sci 2006; 47:3708-16. 119. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 2004; 305:1466-70. 120. Walensky LD, Pitter K, Morash J, Oh KJ, Barbuto S, Fisher J, Smith E, Verdine GL, Korsmeyer SJ. A stapled BID BH3 helix directly binds and activates BAX. Mol Cell 2006; 24:199-210. 121. Perchellet EM, Sperfslage BJ, Wang Y, Huang X, Tamura M, Hua DH, Perchellet JP. Among substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetraones, the lead antitumor triptycene bisquinone TT24 blocks nucleoside transport, induces apoptotic DNA fragmentation and decreases the viability of L1210 leukemic cells in the nanomolar range of daunorubicin in vitro. Anticancer Drugs 2002; 13:567-81. 122. Perchellet EM, Wang Y, Weber RL, Lou K, Hua DH, Perchellet JP. Antitumor triptycene bisquinones induce a caspase-independent release of mitochondrial cytochrome c and a caspase-2-mediated activation of initiator caspase-8 and -9 in HL-60 cells by a mechanism which does not involve Fas signaling. Anticancer Drugs 2004; 15:929-46. 123. Wang Y, Perchellet EM, Ward MM, Lou K, Zhao H, Battina SK, Wiredu B, Hua DH, Perchellet JP. Antitumor triptycene analogs induce a rapid collapse of mitochondrial transmembrane potential in HL-60 cells and isolated mitochondria. Int J Oncol 2006; 28:161-72. 124. Peng TI, Chang CJ, Guo MJ, Wang YH, Yu JS, Wu HY, Jou MJ. Mitochondrion-targeted photosensitizer enhances the photodynamic effect-induced mitochondrial dysfunction and apoptosis. Ann N Y Acad Sci 2005; 1042:419-28.

©

20

08

LA

ND

ES

BIO

SC

IEN CE

.D

ON

77. Marchetti P, Zamzami N, Joseph B, Schraen-Maschke S, Mereau-Richard C, Costantini P, Metivier D, Susin SA, Kroemer G, Formstecher P. The novel retinoid 6-[3-(1-adamantyl)-4hydroxyphenyl]-2-naphtalene carboxylic acid can trigger apoptosis through a mitochondrial pathway independent of the nucleus. Cancer Res 1999; 59:6257-66. 78. Parrella E, Gianni M, Fratelli M, Barzago MM, Raska I Jr, Diomede L, Kurosaki M, Pisano C, Carminati P, Merlini L, Dallavalle S, Tavecchio M, Rochette-Egly C, Terao M, Garattini E. Antitumor activity of the retinoid-related molecules (E)-3-(4'-hydroxy-3'adamantylbiphenyl-4-yl)acrylic acid (ST1926) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]2-naphthalene carboxylic acid (CD437) in F9 teratocarcinoma: Role of retinoic acid receptor gamma and retinoid-independent pathways. Mol Pharmacol 2006; 70:909-24. 79. Konopleva M, Tsao T, Estrov Z, Lee RM, Wang RY, Jackson CE, McQueen T, Monaco G, Munsell M, Belmont J, Kantarjian H, Sporn MB, Andreeff M. The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia. Cancer Res 2004; 64:7927-35. 80. Dando TM, Wiseman LR. Clodronate: a review of its use in the prevention of bone metastases and the management of skeletal complications associated with bone metastases in patients with breast cancer. Drugs Aging 2004; 21:949-62. 81. Lehenkari PP, Kellinsalmi M, Napankangas JP, Ylitalo KV, Monkkonen J, Rogers MJ, Azhayev A, Vaananen HK, Hassinen IE. Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adeninecontaining metabolite. Mol Pharmacol 2002; 61:1255-62. 82. Azuma H, Takahara S, Horie S, Muto S, Otsuki Y, Katsuoka Y. Induction of apoptosis in human bladder cancer cells in vitro and in vivo caused by FTY720 treatment. J Urol 2003; 169:2372-7. 83. Chua CW, Lee DT, Ling MT, Zhou C, Man K, Ho J, Chan FL, Wang X, Wong YC. FTY720, a fungus metabolite, inhibits in vivo growth of androgen-independent prostate cancer. Int J Cancer 2005; 117:1039-48. 84. Ho JW, Man K, Sun CK, Lee TK, Poon RT, Fan ST. Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma. Mol Cancer Ther 2005; 4:1430-8. 85. Nagahara Y, Ikekita M, Shinomiya T. Immunosuppressant FTY720 induces apoptosis by direct induction of permeability transition and release of cytochrome c from mitochondria. J Immunol 2000; 165:3250-9. 86. Dilda PJ, Decollogne S, Rossiter-Thornton M, Hogg PJ. Para to ortho repositioning of the arsenical moiety of the angiogenesis inhibitor 4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide results in a markedly increased cellular accumulation and antiproliferative activity. Cancer Res 2005; 65:11729-34. 87. Don AS, Kisker O, Dilda P, Donoghue N, Zhao X, Decollogne S, Creighton B, Flynn E, Folkman J, Hogg PJ. A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell 2003; 3:497-509. 88. Oliver L, Mahe B, Gree R, Vallette FM, Juin P. HA14-1, a small molecule inhibitor of Bcl-2, bypasses chemoresistance in leukaemia cells. Leuk Res 2007; 31:859-63. 89. Srimatkandada P, Loomis R, Carbone R, Srimatkandada S, Lacy J. Combined proteasome and Bcl-2 inhibition stimulates apoptosis and inhibits growth in EBV-transformed lymphocytes: a potential therapeutic approach to EBV-associated lymphoproliferative diseases. Eur J Haematol 2008; 80:407-18. 90. Wlodkowic D, Skommer J, Pelkonen J. Brefeldin A triggers apoptosis associated with mitochondrial breach and enhances HA14-1- and anti-Fas-mediated cell killing in follicular lymphoma cells. Leuk Res 2007; 31:1687-700. 91. An J, Chen Y, Huang Z. Critical upstream signals of cytochrome C release induced by a novel Bcl-2 inhibitor. J Biol Chem 2004; 279:19133-40. 92. Doshi JM, Tian D, Xing C. Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)4H-chromene-3-carboxylate (HA 14-1), a prototype small-molecule antagonist against antiapoptotic Bcl-2 proteins, decomposes to generate reactive oxygen species that induce apoptosis. Mol Pharm 2007; 4:919-28. 93. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, Croce CM, Alnemri ES, Huang Z. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 2000; 97:7124-9. 94. Heyfets A, Flescher E. Cooperative cytotoxicity of methyl jasmonate with anti-cancer drugs and 2-deoxy-D-glucose. Cancer Lett 2007; 250:300-10. 95. Reischer D, Heyfets A, Shimony S, Nordenberg J, Kashman Y, Flescher E. Effects of natural and novel synthetic jasmonates in experimental metastatic melanoma. Br J Pharmacol 2007; 150:738-49. 96. Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 2008. 97. Rotem R, Heyfets A, Fingrut O, Blickstein D, Shaklai M, Flescher E. Jasmonates: novel anticancer agents acting directly and selectively on human cancer cell mitochondria. Cancer Res 2005; 65:1984-93. 98. Oudard S, Carpentier A, Banu E, Fauchon F, Celerier D, Poupon MF, Dutrillaux B, Andrieu JM, Delattre JY. Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J Neurooncol 2003; 63:81-6. 99. Li YC, Fung KP, Kwok TT, Lee CY, Suen YK, Kong SK. Mitochondrial targeting drug lonidamine triggered apoptosis in doxorubicin-resistant HepG2 cells. Life Sci 2002; 71:272940. 100. Ravagnan L, Marzo I, Costantini P, Susin SA, Zamzami N, Petit PX, Hirsch F, Goulbern M, Poupon MF, Miccoli L, Xie Z, Reed JC, Kroemer G. Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene 1999; 18:2537-46. 101. Kim WS, Kim MM, Choi HJ, Yoon SS, Lee MH, Park K, Park CH, Kang WK. Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest New Drugs 2001; 19:81-3.

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