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Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2013; 17: 1658-1664 - and -based : from molecule cargo cytoskeletal logistics to management of castration-resistant prostate carcinoma

C. ALBERTI

L.D. of Surgical Semeiotics, Parma, Italy

Abstract. – Challenges in the discovery of tures such as cytoskeleton-related molecule cargo more potent agents to treat the castration-resis - logistics, are preliminary taken into consideration . tant prostate carcinoma (CRPC) reflect the frus - trating condition due to development of its drug- Key Words: resistance in addition to hormone-refractori - Nanotechnology, Cytoskeletal logistics, Androgen resistance, Cancer stem cells, Radiation therapy. ness. Although among the different CRPC thera - py modalities, the chemotherapy regimens might seem conceptually outclassed as exhibiting a Introduction scant tumor cell-selectivity if compared with new molecular mechanism-based agents (so- Prostate carcinoma (PC) is the most common called “smart drugs”), nevertheless, combo- and second most letal male cancer in USA and Eu - therapies which combine the chemotherapeutic highly killing potential with specific mechanism- ropean countries , although most recently both diag - targeting products, seem to be effective antitu - nostic and therapeutic advances have been made in mor measures. Thus, both (, lowering its mortality 1. Despite initial organ-con - , noscapine, Vinca-derivatives) and fined tumor therapy with surgery or radiation, actin filament (pertenotoxins, cytochalasin D)- sometimes PC runs into a recurrence that temporar - targeting agents may supply valuable outcomes in CRPC, either alone or in combination with ily may be controlled by androgen-deprivation “smart drugs” such as tyrosine- or multi-kinase modalities. Even though such treatment, both re - receptor blockers, mTOR (mammalian target of ducing blood testosterone levels through Gn-RH pi - rapamicin) inhibitors, monoclonal antibodies tuitary receptor agonists (triptorelin, leuprorelin, against various growth factor signaling recep - goserelin, buserelin ) or antagonists (Degarelix, tors. Among the microtubule-inhibiting drugs, Abarelix ), and preventing DHT (dihydrotestos - taxanes are able, by binding the , to cause polymerization and stabilization of the mi - terone)-binding to peripheral nuclear androgen re - crotubules with following suppression of their ceptor (AR) through anti-androgens (bicalutamide, dynamic properties at the mitotic spindle, that nicalutamide, flutamide , MDV 3100, the last show - results in cancer cell cycle block at G2/M phase ing an effectiveness even in bicalutamide -resistant together with apoptosis. , a novel PC) , might induce a rapid biochemical/clinical re - taxane-based agent, unlike other taxane com - sponses, inescapably, after an average of 18 to 24 pounds, exhibits low propensity for P-glycopro - tein (Pgp)-mediated plasmalemmal drug efflux months, the disease becomes refractory to hormone pump, thus, avoiding the development of taxane- therapy – castration-resistant prostate carcinoma , resistance. Epothylones are a family of novel mi - CRPC – with subsequently a median survival of 12 crotubule-targeting drugs, like taxane inhibiting mi - to 18 months 2-8 . CRPC refers to the condition of crotubule dynamic behaviour at mitotic spindle prostate cancer growth at castrate androgen levels and, therefore, preventing cancer cells from mito - sis. Unlike and , epothilones (serum testosterone less than 50 ng/ml), biochemi - maintain their cytotoxic performance even in can - cally shown by a continuous PSA rise, on three cer overexpressing Pgp. Epothilone B-promoted consecutive measurements, after antiandrogen with- radiosensitivity enhancement has been shown in drawal for at least 28 days or following an addition - radioresistant human prostate cancer cells, be - al secondary hormone manipulation. cause such agent is able to delay DNA- strand Constant efforts are in progress to identify new break repair together with prolonging cell cycle block. To insightfully understand either micro - cancer cell, either molecular or structural, targets to - tubule or actin filament meshwork-targeting drug wards which direct more effective therapeutical pharmacodynamics, functional cytoskeletal fea - measures 3-5 .

1658 Corresponding Author: Contardo Alberti, MD; e-mail: [email protected] Cytoskeleton targeting chemotherapy

Overall View on Both Current and inhibitory effects 2,19 . VEGFR multikinase in - Emerging Novel Therapies in CRPC hibitors (Sorafenib, Sunitinib) as well as anti- First and foremost, it has been pointed out, in VEGF monoclonal antibodies (Bevacizumab) several clinical experiences, that the progression or VEGF-decoy receptor Aflibercept, by play - from hormone-dependent to hormone-indepen - ing an antiangiogenic role, may induce indi - dent PC may be delayed by intermittent andro - rect antitumoral effects 19,25,26 . gen-deprivation therapy and , on the other hand, as • Bone (metastasis )- targeted therapy through ei - soon as a biochemical relapse arises , the antian - ther RANKL (receptor activator of NF-kB lig - drogen (flutamide) withdrawal may sometimes and) antagonist Denosumab or endothelin-A induce a temporary decline in blood PSA levels. receptor antagonist 2,12,24-26 ; also But the unreliability and the transience of such ef - bone-seeking α-emitter Ra-223 seems to be fects suggest a timely carrying out of more suit - useful, intravenously administered, in bone able current approaches mean-while looking at metastatic CRPC; pipeline measures, all together including: •Immunotherapy: anti-prostate cancer autolo - gous dendritic cell-based vaccine (e.g., Sip - •Combination of estrogens (ethinyl-estradiol) and uleucel-T, made-up of autologous dendritic somatostatin analogs (lanreotide, pasireotide) as cells loaded ex vivo with PAP, prostatic acid neuroendocrine targeting therapy, to affect, be - phosphatase, tumor-associated antigen), anti- sides the tumor cells, also their microenviron - cytotoxic T-lymphocyte-associated a ntigen- 4 ment that can play an antiapoptotic role 9; (CTLA-4) monoclonal antibody Ipilimubab 27-30 , • Inhibition over 17- α-hydroxylase/17-20 lyase to overcome chemotherapy-resistance; (Cyp17)-aromatase through abiraterone, a selec - • Gene-therapy on the basis of gene expression tive blocker of adrenal androgen generation 10,11 ; profiling: replacement or inactivation of defec - • Chemotherapy with cytotoxic drugs , among tive genes, induction of cell death by aden - which cytoskeleton -targeted agents such as ovirus-mediated delivery of pro-apoptotic Mda- Vinca alkaloids (, , vinf - 7/IL-24 gene, cytoreductive gene-treatment , 31-33 lumine), noscapine, taxanes and epothilones, gene-silencing by interfering short RNA S ; pertenotoxins 4,12-17 ; • Epigene-therapy through hystone -deacetylase • Molecular mechanism-based strategy with inhibitors, such as suberoylanilide, or DNA- “smart drugs ” capable of either blocking cell methyltransferase blockers 18,34 ; proliferation signaling pathways or inducing • Targeting the pluripotent stem cell (PSC)-like apoptosis . To the former group belong recep - cancer cells as expressing PSC-transcription tor tyrosine- kinase or multikinase inhibitors factors such as OCT3/4 and SOX2, that can among which those interfering with HER-1 start the prostate tumorigenesis 35 . (human epidermal growth factor receptor-1, EGFR), HER-2 (human epidermal growth fac - Cytoskeletal Molecule Cargo Logistics tor receptor -2, also called c-erbB-2/ neu as a The cytoskeletal complex includes cell interior omolog of the rat neu oncogene), PDGFR and cell cortex actin microfilaments (plateled-derived growth factor receptor), together with wide microtrabecular reticulum. VEGFR (vascular endothelial growth factor The microtubules are hollow cylindrical struc - receptor) whereas to the latter group, recombi - tures, whose wall is made up of a series of small nant TRAIL (tumor necrosis factor-related protein heterodimeric subunits, a negatively apoptosis inducing ligand) and poly (ADP-ri - charged α-tubulin and a positively charged β- bose) polymerase (PARP) inhibitors 2,3,13,16,18,19 tubulin, thus, such dimer sets acting as dipoles. Death cell receptor-mediated anoikis/apoptosis Showing a dynamic plastic behaviour, they are seems to be also achieved, according to recent capable of self-polymerization or, instead, self- studies, by quinazoline-derived α1-adrenocep - depolymerization, depending on the various cell tor antagonists 19,20-23 . Also the inhibition of conditions. The energy needed for their polymer - IGF-1R signaling (Insulin-like growth factor-1 ization is supplied by GTP (guanosine triphos - receptor  → activation of both MAPK S, mito - phate) hydrolysis to GDP. Actin microfilaments gen-activated protein kinases, and PI3K, phos - are helicoidal temporary structures – dissipative phatidil-inositol 3-kinase/AKT) can exert can - structures – of G-actin globular protein, which cer cell growth decrease. Regarding it, anti- rapidly develop, by polymerization, from a cy - IGF-1R antibodies may provide tumor growth tosolic stock of their subunits, and, just as rapidly

1659 C. Alberti dissolve as soon as they are no longer necessary. mic reticulum where PI3P (phosphatidylinositol- The energy required for their polymerization is 3, 4, 5- triphosphate), is synthesized, triggering, provided by ATP (adenosine triphosphate) hy - in turn, the PI3P/AKT-mTOR signaling pathway. drolysis to ADP. Some drugs are able to specifi - Quite recently, it has been demonstrated that cally enhance or inhibit both microtubule- and TFEB (transcriptor factor EB), a master gene for actin microfilament-polymerization. The micro - lysosomal biogenesis, coordinates the whole lo - trabecular reticulum consists of 3-D intertwined gistics of autophagic pathway, from the forma - actin filament network, that interconnects all cell tion of autophagosomes (cell scavenger or - structures including the nucleus cytoskeleton and ganelles) and their intracell ride to fusion with chromosomes, with following feed-back control the lysosomes, where the substrate degradation is system between nucleus and cytoplasm, more - performed 43 . over contributing to intra-cell dynamic organiza - The biochemical pattern of cytoskeletal mole - tion of organelles. cule cargo translocation must be today integrated Cytoskeletal functions exceed that of sheer with a biophysical model , where charged parti - mechanical cell scaffold, because the cytoskele - cles (electrons, protons, ions), photons (optical ton plays an important role in cell contractility, and infraoptical radiations) and quantized vibra - cytokinetics and, given its links with the inner tional -mechanical waves are looked as signal- part of plasmalemmal receptors, in intra-cell sig - messengers travelling on the cytoskeloton. Fur - nal transduction 36 . Microtubules, as filamentary thermore, microtubules, as electrical polar struc - oscillating structures (Fröhlich’s coherent vibra - tures – oriented dipoles – are able to direct the tions), cooperate with mitochondria in generating molecule cargoes towards specific targets, their cell electromagnetic fields. charge-energy resulting from GTP (guanosine Molecular motors that transport molecule triphosphate ) hydrolysis to GDP. What’s more, a cargoes – protein complexes, receptor-ligand fraction of such energy can induce cytoskeleton sets, secretory vesicles, organelles – along the vibrations with following generation of electro - cytoskeleton , include myosin family com - magnetic fields. Just in this regard, some mecha - pounds , running on cell cortex actin filaments , nisms of malignancy – anoikis of cancer cells, lo - and kinesin/cytoplasmic dynein , travelling on cal invasion and distant metastasis – may be as - cell interior microtubules, both paths represent - sumed as dependent on the cell abnormal electro- ing polarized mono-rails for the cargo bidirec - magnetic influences 36,44 . tional, either endocytic or exocytic, transloca - tion , mean-while the motor proteins converting Cytoskeleton Targeting Chemotherapy the ATP-to-ADP-hydrolysis-derived energy in - Until the mid- 1990 s, CRPC was considered re - to motion 37, 38 . fractory to chemotherapy regimens while after - The endocytosis plays a leading role in plas - wards it has been demonstrated that the mitox - malemmal receptor-ligand complex internaliza - antrone-prednisone combined treatment can have tion , thus driving extra -cell molecular signals to a palliative effectiveness in CRPC -diseased men. induce specific changes in gene expression 39 . Seven years ago, taxane (docetaxel )-based That’s how occurs also for the stepwise endocyt - chemotherapy showed to carry a significant sur - ic movements, along actin-to-tubulin pathway, of vival advantage in CRPC, further improved by several signaling receptors, such as HER-1, recent resorting to cabazitaxel 13,14 . Efforts intend - HER-2 and other growth factor receptors 40,41 . ed to develop novel agents capable of overcom - In both endocytic and exocytic routes, selec - ing drug resistance-related mechanisms have led tive logistic mechanisms put the vesicular car - to try the effectiveness of epothilones in taxane- goes with high specificity dependently on their refractory tumours . coat protein components (clathrin, COP-I and Among the microtubule-inhibiting drugs, tax - COP-II) while protein adaptors are able to bind anes – docetaxel, paclitaxel, cabazitaxel – are cargoes to specific coat pits 40,41 . Moreover , to al - able, by binding the tubulin, to cause microtubule low a selective recruitment of protein cargoes polymerization-stabilization with following sup - from the cytosol , membrane , acting as spe - pression of their dynamic properties at the mitotic cific “rafts“, sort them at sequential steps of both spindle, that induces cancer cell mitotic arrest (cell endocytic and exocytic paths 42 . Just like this, the cycle block at G2/M phase) and apoptosis 45-47 . tyrosine kinase receptors, through a specific en - Survival benefit achieved by docetaxel-based docytic rafts, are brought to the endoplas - chemotherapy in patients with CRPC have denied

1660 Cytoskeleton targeting chemotherapy the burden of CRPC as a chemoresistant cancer 48 . Epothilones are a family of novel microtubule- However, tumors characterized by P-glycoprotein targeting agents originally identified as metabo - (Pgp) overexpression show usually a docetaxel-re - lites of myxobacterium . fractoriness. Cabazitaxel, a novel taxane drug, un - Like taxanes, epothilones stabilize the micro - like other taxane-based agents, exhibits low propen - tubules and inhibit their dynamic function at the sity for Pgp-mediated plasmalemmal drug efflux mitotic spindle, thus preventing cancer cells from pump, thus avoiding the development of taxane-re - mitosis. Particularly, once epothilones bind to α/β- sistance, therefore showing an antitumor activity tubulin subunit, the rate of its dissociation decreas - even in docetaxel-resistant CRPC. Cabazitaxel es with following tubulin polymerization, hence combined with prednisone can induce a median microtubule stabilization and suppression of mi - survival of 15.1 months, compared with that of 12.7 crotubule detachment from centrosomes, with cell months achieved through , as it results cycle arrest at the G2/M transition phase 48,60-63 . from phase III-TROPIC trial 3,14,49-51 . Both semisynthetic and total-synthetic Intriguingly, in the treatment of CRPC, micro - epothilone analogs (, sagopilone, tubule-targeted taxane chemotherapy seems also patupilone ), currently undergoing various clinical to interfere with androgen-mediated signaling develpment phases to treat different cancers, ex - because taxanes may prevent the androgen-de - hibit a cytotoxic activity even towards taxane-re - pendent nuclear translocation of the androgen-re - fractory cancer cell lines, without showing tax - ceptor (AR) by targeting AR connection with ane-like endotoxin-properties 48,60-63 . tubulin 52 . In fact AR, in the absence of ligand Differences between epothilones and taxanes DHT, is primarly located, bound with Hsp90 in drug-resistance mechanisms have been eluci - (heat shock protein 90) chaperone, onto the cy - dated by recent research findings on the which toskeleton, while the link with the ligand results basis epothilone cytotoxicity appears to be unaf - in AR homodimerisation and translocation in the fected by alanine-to-threonine substitution at re - nucleus, where binds to specific androgen-depen - side 3 64 – microtubule β-tubulin which, instead , dent genes with following proliferative and is responsible for chemoinsensitivity to taxanes. trophic effects. Incidentally, Hsp90 chaperone It follows that epothilones , unlike taxanes, main - plays a critical role in prostate cancer cell sur - tain their cytotoxic performance even in cancers vival response to chemotherapy and radiation , overexpressing Pgp . whereas Hsp90 inhibitors, such as I7-AAG (17 - Given their good water solubility, epothilones allylamino- 17 -demethoxygeldanamycin) , can do no need cremophor-based solvents sometimes sensitize cancer cells to cytotoxic agents , includ - causing hypersensitivity reactions 48,61,62 . ing taxanes and radiation therapy 53 . It has been demonstrated an epothilone-in -

RNA i (RNA interfering)-mediated STMN1 duced radiosensitivity enhancement in radiore - microtubule-gene silencing can have synergistic sistant human prostate cancer cells , because effects with paclitaxel against the prostate cancer such agent is able to delay DNA-strand break re - cells 54 . Also histone deacetylase inhibitors , such pair together with prolonging cell cycle arrest as suberoylanilide hydroxamic acid , potentiate and enhancing cell death 63 . the taxane (docetaxel) anticancer activity in CR - Noscapine , a microtubule-modulating alkaloid, PC, by both acetylating tubulin and inhibiting displays synergistic effects with docetaxel in anti - Bcl-2 antiapoptotic protein 34 . cancer chemotherapy, moreover exhibiting cytotox - Unfortunately, cremophor, a nonionic poly - ic activity even in paclitaxel-resistant tumors 15,64 . ethoxylated castor oil used as solubilizer/emulsi- Pertenotoxins , besides targeting cytoskeletal fier of taxanes, has been associated with severe actin , can induce apoptotic effects by increasing hypersensitivity reactions, sometimes including caspase-3 activity together with poly (ADP-ri - anaphylaxis and cardiac collapse. Recently, to bose) polymerase (PARP) cleavage 17 . avoid such drawbacks, it has been shown that pa - clitaxel delivery in cancer cells may result signif - Implications for Current Approaches and icantly enhanced by its binding with albumin- Future Research Directions nanoparticles (Abraxane) 54,55 . Nevertheless, en - Although among the different CRPC therapy dotoxin-like properties of taxol in itself, such as modalities, the chemotherapy regimens might ap - macrofage activation with production of inflam - pear conceptually outclassed as exhibiting a scant matory cytokines and nitric oxide, can induce hy - tumor cell-selectivity if compared with new molec - persensitivity conditions. ular mechanism-targeting agents – so-called smart

1661 C. Alberti drugs – nevertheless “combo-strategies ”, that com - py resulting to be excluded from the treatment of bine the chemotherapeutic highly killing potential metastatic CRPC while it might have therapeutic with specific mechanism-based products, seem to effects on locally-advanced CRPC 63 . be effective antitumor measures , moreover allowing The application of chemotherapy regimens in a lower cytotoxic drug doses with following more CRPC, as well as of other anticancer modalities, limited drug-related toxic side effects . So, both mi - requires a preventive assessment of their possible crotubule (taxanes, epothilones, Vinca-derivatives)- effectiveness, individually considering tumor dis - and actin filament meshwork (pertenotoxins, cy - tant invasive propensity, about it today playing an tochalasin D )- targeting agents may supply valuable important role the detection of both circulating outcomes in CRPC – as well as in other advanced prostate cancer cells through PSAmRNA/RT- malignancies – either alone or in combination with PCRC (reverse transcriptase-polymerase chain re - “smart drugs” such as tyrosine- or multi-kinase re - action) assay and, more thoroughly, circulating ceptor blockers , mTOR (mammalian target of ra - cancer stem cells (CSC S) responsible for resis - pamicin) inhibitors, monoclonal antibodies against tance to chemotherapy and radiation. Indeed, can - various growth factor signaling receptors 48,65,70 . cer cells expressing pluripotent stem cell tran - Currently, other cytoskeleton targeting products scription factors, such as OCT3/4 and SOX2, ex - are under investigation to use them in cancer hibit quite uncontrollable aggressive aptitudes 35 . chemotherapy, among which some antimycotics (benomyl, ) and antimicrobials (sulfon - amides), that , what ’s more, seem to exhibit less tox - Conclusions ic side effects than taxanes and Vinca alcaloids 67 . Recent studies show that microtubule-targeting The development of techniques capable of drugs , besides the suppression of microtubule di - molecularly identifying prostate CSC S not only namics with following cell cycle arrest at G2/M may provide relevant predictive informations to phase, can promote cell apoptosis via intrinsic mi - make proper clinical-therapeutic decisions, to - tochondrial, cell death-receptor-independent, path - gether with allowing potential indications of effi - way by inducing the translocation of Bax (Bcl as - cacy, but also can entail the expansion of studies sociated x-protein) from cytosol into mitochondria on CSC-targeted drugs 3,71,73 . The constant strong and, sequentially, Bak (Bcl-2 antagonist killer) mi - challenges in the discovery of more and more ef - tochondrial protein activation with release into cy - ficacious agents to manage CRPC, moreover tai - tosol of some pro-apoptotic factors such as Mg 2+ - loring the treatment to the individual patient dependent endonuclease G and SMAC (second gene-molecular cancer cell features, reflect the mitochondria-derived activator of caspase), that, in frustrating condition due to drug-resistance devel - 68,69 73,75 turn, promote the 9 →3 caspase cascade . opment in addition to hormone-refractoriness . As far as taxanes are concerned, it’s now arous - ing a great interest that their microtubule-inhibit - ––––––––––––– –– ––– –– Conflict of Interest ing effects may be enhanced by albumin nanopar - ticle carriers that, moreover, allow to avoid the None to declare. use of solubilizing cremophors sometimes induc - ing severe hypersensitivity effects 54,72 . Other References nanoparticle – based carriers, such as nanoporous 1) JEMAL A, B RAY F, C ENTER MM, F ERLAY J, W ARD E, F OR - silicon particles, for chemotherapeutic shutting, MAN D. Global cancer statistics. Ca Cancer J Clin have been recently proposed 72 . 2011; 61: 69-90. Epothilones , as well as other microtubule-sta - 2) VAN DER POEL HG . Smart drugs in prostate cancer. bilizing agents (taxanes, noscapine), prolong ac - Eur Urol 2004; 45: 1-17. tivation of the spindle assembly checkpoint with 3) VISHNU P, T AN WW . Update on options for treat - following cancer cell death in mitosis, and, in ad - ment of metastatic castration-resistant prostate dition, show a certain activity also in truly tax - cancer. Onco Target Ther 2010; 24: 39-51. ane-refractory patient cohorts, thus representing 4) ALBIGES L, L ORIOT Y, G ROSS -G OUPIL M, DE LA MOTTE ROUGE T, B LESIUS A, E SCUDIER B, M ASSARD C, F IZAZI K. a potential therapeutic niche when a Ppg-induced New drugs in metastatic castration-resistant 70 taxane-resistance unfortunately develops . It has prostate cancer. Bull Cancer 2010; 97: 149-159. also been demonstrated an epothilone B-induced 5) WU Y, R OSENBERG JE, T APLIN ME. Novel agents and radiosensitivity enhancement in radiorefractory new therapeutics in castration-resistant prostate prostate cancer cells, however the radiation thera - cancer. Curr Opin Oncol 2011; 23: 290-296.

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