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Rigosertib is a small molecule in preclinical development that, due to its characteristics as a dual PLK1 and PI3K inhibitor, is particularly effective in counteracting the advance of different types of tumors. In this work, we evaluated the efficacy of Rigosertib and the expression of p53 in five different human tumor cell lines in vitro, A549 (lung adenocarcinoma), MCF-7 and MDA-MB231 (breast cancer cells), RPMI 8226 (multiple myeloma), and U87-MG (glioblastoma). We demonstrated that in all cell lines, the effect was dose- and time-dependent, but A549 cells were the most sensible to the treatment while higher concentrations were required for the most resistant cell line U87-MG. Moreover, the highest and lowest p53 levels have been observed, respectively, in A459 and U87-MG cells. The alterations in the cell cycle and in cell-cycle-related proteins were observed in A549 at lower concentrations than U87-MG. In conclusion, with this article we have demonstrated that Rigosertib has different efficacy depending on the cell line considered and that it could be a potential antineoplastic agent against lung cancer in humans.

Neuroactive steroids, molecules produced from cholesterol in steroidogenic cells (i.e., peripheral glands and nervous system) are physiological modulators and protective agents of nervous function. A possible role for neuroactive steroids in the sex-dimorphic clinical manifestation, onset and progression of Multiple Sclerosis (MS) has been recently suggested. To explore this possibility, we assessed the synthesis of the first steroidogenic product (pregnenolone; PREG) in the spinal cord of experimental autoimmune encephalomyelitis rats, a MS model. Data obtained indicate that the synthesis of PREG in the spinal cord is altered by the pathology in a sex-dimorphic way and depending on the pathological progression. Indeed, in male spinal cord the synthesis was already decreased at the acute phase of the disease (i.e., 14 days post induction - dpi) and maintained low during the chronic phase (i.e., 45 dpi), while in females this effect was observed only at the chronic phase. Substrate availability had also a role in the sex-dimorphic kinetics. Indeed, at the chronic phase, male animals showed a reduction in the levels of free cholesterol coupled to alteration of cholesterol metabolism into oxysterols; these effects were not observed in female animals. These findings suggest that the comprehension of the neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS and to possibly design sex-oriented therapeutic strategies based on neuroactive steroids., We also acknowledge support from Agencia Estatal de Investigación, Spain (grant number BFU2017-82754-R), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder to LM.G-S.

Multiple Myeloma (MM) is an aggressive tumor causing millions of deaths every year and currently available therapies are often unsuccessful or correlated with severe side effects. In our previous work we demonstrated that the Hibiscus sabdariffa hydroalcoholic extract inhibits the growth of the MM cell line and we isolated two metabolites responsible for the activity: Hib-ester and Hib-carbaldehyde. Herein we report their interaction with proteasome, one of the main targets in the fight against MM. The molecular modelling study outlined a good interaction of both compounds with the target and these results prompted us to investigate their potential to inhibit proteasome. Metabolites were then isolated from the calyces and an extract with a high content of Hib-ester and Hib-carbaldehyde was prepared. An anticancer profile was drawn, evaluating apoptosis, autophagy and proteasome inhibition, with the anticancer properties being mainly attributed to the Hib-ester and Hib-carbaldehyde, while the proteasome inhibition of the extract could also be ascribed to the presence of anthocyanins, a class of secondary metabolites already known for their proteasome inhibitory activity.

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient’s survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.

Oxaliplatin is a cornerstone chemotherapeutic used in the treatment of colorectal cancer, the third leading cause of death in Western countries. Most side effects of this platinum-containing drug are adequately managed in the clinic, although acute and long-term neurotoxicity still severely compromises the quality of life of patients treated with oxaliplatin. We have previously demonstrated that therapeutically relevant concentrations/doses of oxaliplatin lead to a reduction in intracellular pH in mouse dorsal root ganglion (DRG) neurons in vitro and in vivo and that this alteration sensitizes TRPA1 and TRPV1 channels, which most likely mediate the allodynia associated with treatment. In this study, we show that oxaliplatin leads to a reduction of intracellular pH by forming adducts with neuronal haemoglobin, which acts in this setting as a proton buffer. Furthermore, we show that FDA-approved drugs that inhibit carbonic anhydrase (an enzyme that is linked to haemoglobin in intracellular pH homeostasis), ie, topiramate and acetazolamide, revert (1) oxaliplatin-induced cytosolic acidification and TRPA1 and TRPV1 modulation in DRG neurons in culture, (2) oxaliplatin-induced cytosolic acidification of DRG of treated animals, and (3) oxaliplatin-induced acute cold allodynia in mice while not affecting OHP-induced cytotoxicity on cancer cells. Our data would therefore suggest that reversal of oxaliplatin-induced cytosolic acidification is a viable strategy to minimize acute oxaliplatin-induced symptoms.

Despite advances in cancer therapies, nanomedicine approaches including the treatment of glioblastoma (GBM), the most common, aggressive brain tumor, remains inefficient. These failures are likely attributable to the complex and not yet completely known biology of this tumor, which is responsible for its strong invasiveness, high degree of metastasis, high proliferation potential, and resistance to radiation and chemotherapy. The intimate connection through which the cells communicate between them plays an important role in these biological processes. In this scenario, tunneling nanotubes (TnTs) are recently gaining importance as a key feature in tumor progression and in particular in the re-growth of GBM after surgery. In this context, we firstly identified structural differences of TnTs formed by U87-MG cells, as model of GBM cells, in comparison with those formed by normal human astrocytes (NHA), used as a model of healthy cells. Successively, we have studied the possibility to exploit U87-MG TnTs as drug-delivery channels in cancer therapy, using liposomes composed of cholesterol/sphingomyelin and surface functionalized with mApoE and chlorotoxin peptides (Mf-LIP) as nanovehicle model. The results showed that U87-MG cells formed almost exclusively thick and long protrusions, whereas NHA formed more thin and short TnTs. Considering that thick TnTs are more efficient in transport of vesicles and organelles, we showed that fluorescent-labeled Mf-LIP can be transported via TnTs between U87-MG cells and with less extent through the protrusions formed by NHA cells. Our results demonstrate that nanotubes are potentially useful as drug-delivery channels for cancer therapy, facilitating the intercellular redistribution of this drug in close and far away cells, thus reaching isolated tumor niches that are hardly targeted by simple drug diffusion in the brain parenchyma. Moreover, the differences identified in TnTs formed by GBM and NHA cells can be exploited to increase treatment precision and specificity.

ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin Lymphoma whose treatment benefited from crizotinib development, a dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/ mTOR, indispensable for survival of ALK-driven tumors. Despite the positive impact of targeted treatment in ALCL, resistant clones are often selected during therapy. Strategies to overcome resistance include the design of second generation drugs and the use of combined therapies that simultaneously target multiple nodes essential for cells survival. We investigated the effects of combined ALK/mTOR inhibition. We observed a specific synergistic effect of combining ALK inhibitors with an mTOR inhibitor (temsirolimus), in ALK+ lymphoma cells. The positive cooperation resulted in an increased inhibition of mTOR effectors, compared to single treatments, a block in G0/G1 phase and induction of apoptosis. The combination was able to prevent the selection of resistant clones, while longterm exposure to single agents led to the establishment of resistant cell lines, with either ALK inhibitor or temsirolimus. In vivo, mice injected with Karpas 299 cells and treated with low dose combination showed complete regression of tumors, while only partial inhibition was obtained in single agents-treated mice. Upon treatment stop the combination was able to significantly delay tumor relapses. Re-challenge of relapsed tumors at a higher dose led to full regression of xenografts in the combination group, but not in mice treated with lorlatinib alone. In conclusion, our data suggest that the combination of ALK and mTOR inhibitors could be a valuable therapeutic option for ALK+ ALCL patients.

Mesoporous silica materials (MSM) have been proposed as promising tools for cell specific drug delivery or fluorescent cell tracking. In cancer therapy there is an urgent need to develop a cancer cell specific drug carrier able to limit the non-specific uptake of the drug by normal cells thereby reducing serious side effects. Chemotherapy induced peripheral neurotoxicity (CIPN) is one of the most clinically relevant side effects linked to the use of several antineoplastic drugs. In this study we showed that the uptake of MSM (synthesized using a PEG surfactant-based interfacial synthesis procedure), functionalised with folic acid (MSM-FOL) after 1, 6 and 24 hours is very limited in neuronal-like cellular systems such as differentiated SH-SY5Y human neuroblastoma cells and rat embryonic dorsal root ganglia sensory neurons. By contrast, the nanoparticles are highly internalized in A549 and IGROV-1 cancer cells. The 6 hour-treatment of A549 and IGROV-1 cells with nanoparticles loaded with the antineoplastic drug cisplatin (CP) induced significant cytotoxicity with respect to CP alone. These results were observed treating IGROV-1 cells with 25 and 50 μg/ml nanoparticles doses (corresponding respectively to CP 6.25 and 12.5 μM) and treating A549 with 50 μg/ml.Our results demonstrated a selective uptake of functionalized MSM suggesting them as promising tools for targeted antineoplastic therapy. Further studies will be necessary in order to confirm if this approach may be useful in reducing neurotocity of anticancer drugs.

Solid lipid nanoparticles (SLN) are colloidal drug delivery systems characterized by higher entrapment efficiency, good scalability of the preparation process and increased sustained prolonged release of the payload compared to other nanocarriers. The possibility to functionalize the surface of SLN with ligands to achieve a site specific targeting makes them attractive to overcome the limited blood-brain barrier (BBB) penetration of therapeutic compounds. SLN are prepared for brain targeting by exploiting the adaptability of warm microemulsion process for the covalent surface modification with an Apolipoprotein E-derived peptide (SLN-mApoE). Furthermore, the influence of the administration route on SLN-mApoE brain bioavailability is here evaluated. SLN-mApoE are able to cross intact a BBB in vitro model. The pulmonary administration of SLN-mApoE is related to a higher confinement in the brain of Balb/c mice compared to the intravenous and intraperitoneal administration routes, without inducing any acute inflammatory reaction in the lungs. These results promote the pulmonary administration of brain-targeted SLN as a feasible strategy for improving brain delivery of therapeutics.

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting over 2.000.000 individuals around the world. Although MS etiopathogenesis is still not completely defined environmental factor exposure and genetic background are relevant in disease development. Moreover, MS shows heterogeneous onset and course so that different disease forms can be described which are all characterized by motor and/or sensory and even cognitive impairment. Two steps in the disease progression can be described. First MS lesions are originated by the activated immune system which recognizes CNS myelin as a foreign element thus leading to the formation of demyelinated plaques that evolve into axonal damage and subsequent neurodegeneration over the time. Since the beginning MS therapy has been focused on counteracting immune system action. Nevertheless, besides the immunosuppressive/immunomodulating drugs such as Glatiramer Acetate, Beta-interferons and steroids, the advance in the comprehension of the immune-mediated mechanisms has sustained the development and use of molecular and cellular-focused approaches, e.g. monoclonal antibodies and stem cells. At the same time very few weapons are specifically available for fighting MS neurodegenerative progression. We report an overview on MS and both old and new therapeutic approaches to the disease

Observations so far obtained in experimental autoimmune encephalomyelitis (EAE) have revealed the promising neuroprotective effects exerted by progesterone (PROG). The findings suggest that this neuroactive steroid may potentially represent a therapeutic tool for multiple sclerosis (MS). However, up to now, the efficacy of PROG has been only tested in the acute phase of the disease, whereas it is well known that MS expresses different features depending on the phase of the disease. Accordingly, we have evaluated the effect of PROG treatment in EAE induced in Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction show that PROG treatment exerts a beneficial effect on clinical score, confirming surrogate parameters of spinal cord damage in chronic EAE (i.e. reactive microglia, cytokine levels, activity of the Na(+) ,K(+) -ATPase pump and myelin basic protein expression). An increase of the levels of dihydroprogesterone and isopregnanolone (i.e. two PROG metabolites) was also observed in the spinal cord after PROG treatment. Taken together, these results indicate that PROG is effective in reducing the severity of chronic EAE and, consequently, may have potential with respect to MS treatment.

Combined anticancer therapy using platinum compounds and antitubulins has increased the risk of neurotoxicity. However, the combination of low-dose cisplatin (CDDP) with toxic doses of paclitaxel significantly reduces cellular death in a human neuroblastoma SH-SY5Y cell line. To analyze the mechanisms of this protection, we evaluated various signaling molecules possibly involved in apoptosis and some relevant cell cycle regulatory proteins. CDDP does not interfere with the tubulin-stabilizing action of paclitaxel. The evaluation of molecular pathways involved in apoptosis indicates that the Bcl-2 but not the caspases may be involved in the CDDP protection of paclitaxel-induced apoptosis. The increase in p53 protein and its nuclear accumulation suggests a possible involvement of p53 in CDDP protection. The use of the chemical inhibitor of p53, pifithrin α, excluded this possibility. The study of cyclins and the flow cytometric analysis (fluorescence-activated cell sorting) suggest that CDDP exerts a protective action by blocking cells early in the cell cycle. The determination of the mitotic index indicates that CDDP prevents cells from reaching the mitosis. We concluded that low doses of CDDP are protective against toxic doses of paclitaxel and that the possible mechanism of this protection is that the CDDP prevents human neuroblastoma SH-SY5Y cells from achieving mitosis.

Several effective antineoplastic drugs are severely neurotoxic and induce the onset of disabling peripheral neuropathies. The clinical presentation of this side effect depends on the type of antineoplastic agent administered. The signs and symptoms shown are predominantly motor (e.g. in the case of vinca alkaloids), sensorimotor (e.g. with the taxanes) or sensory (e.g. using platinum-derived drugs). The pathogenesis of these antineoplastic drug-induced peripheral neuropathies is still poorly understood, although a relationship has been suggested between some neuronal growth factors (neurotrophins) and the toxic action of cisplatin (CDDP) and paclitaxel. In this study we correlated the changes in the circulating levels of Nerve Growth factor (NGF) in a series of 24 women affected by locally advanced squamous cervical carcinoma treated with cisplatin and paclitaxel-based chemotherapy with the severity of chemotherapy-induced peripheral neuropathy (CIPN) as assessed by the Total Neuropathy Score (TNS). After informed consent, blood samples were drawn before chemotherapy and after treatment and NGF circulating levels were determined by ELISA (EmaxTM ImmunoAssay System, Promega, USA; plasma working dilutions NGF 1:80) following the manufacturer protocols. The results obtained in this series of patients evidenced a significant correlation between the severity of CIPN and the reduction in the circulating levels of NGF (r = − 0.480, p = 0.017 by two-tailed Spearman correlation test, 95% CL −0.745 to −0.082), thus confirming similar results previously obtained in a rat model of CDDP peripheral neurotoxicity. In conclusion, our data suggest that a relationship exists between CIPN and NGF circulating levels in patients treated with cisplatin and paclitaxel. Therefore, this preliminary observation support the need for further studies in order to explore the possibility of reducing the severity of platinum-drug sensory neurotoxicity with treatments aimed at increasing the circulating levels of NGF.

In this study the potential anticancer effect of 2 flavonoids, myiricetin (MYR) and naringenin (NAR) has been evaluated on an oral squamous cell carcinoma (OSCC) cell line, SCC-25, and HaCaT cells. Both the flavonoids inhibited SCC-25 cell growth, although NAR selectively affected cancer cells without impairing HaCaT cell growth. The cell proliferation inhibition by MYR and NAR was not related to apoptosis induction, but on cell cycle impairment, because a G0/G1 and a G2/M blockage was highlighted following 24 h of treatment in SCC-25 and HaCaT cells, respectively. Western blot analysis showed that MYR induced a decrease of Cyclin D1 in SCC-25 and of Cyclin B1b in HaCaT cells, while NAR negatively modulated Cyclin D1 expression in SCC-25 cells. Wound-healing and cell invasion assays demonstrated that both the flavonoids were able to reduce motility on both SCC-25 and HaCaT cells. In conclusion the results of the present study show the anticancer potential of NAR and MYR on OSCC because they exert cytostatic effect by the impairment of cell cycle progression. Moreover both the flavonoids inhibit cell migration, thus highlighting their potential effect as antimetastatic agents. Therefore, MYR and NAR appear as promising candidate as oral cancer chemopreventive agents.

Actively induced Lewis rat Experimental Autoimmune Encephalomyelitis (EAE) is a highly reproducible model for portraying the acute phase of multiple sclerosis. Our aim was to get more information about this model by means of flow cytometry looking at potential markers for tracing new treatments' efficacy. Thus we characterized the changes occurring in encephalitogenic TCR Vbeta8.2(+) frequency and the adhesion molecule alpha4 integrin expression in both spleen and spinal cord T cells. The increase in both these parameters was observed only in spinal cord infiltrating T cells while relevant changes in spleen cell composition were observed as early as disease onset.

Most of Anaplastic Large Cell Lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein nucleophosmin (NPM)-ALK. NPM provides an oligomerization domain that causes the spontaneous dimerization and ligand-independent activation of the ALK. NPM-ALK deregulated kinase activity drives several pathways involved in cellular proliferation and survival and sustains the process of malignant transformation. NPM-ALK is localized both in the cytoplasm and the nucleus, but the role of NPM-ALK cytoplasmic or nuclear fractions on ALCL phenotype maintenance is undetermined. We found that in all ALK+ ALCL cell lines and in primary ALCL NPM-ALK was equally distributed between cytoplasm and nucleus, but only the cytoplasmic portion, formed by NPM-ALK homodimers, was kinetically active and had transforming properties. The nuclear portion, formed by NPM/NPM-ALK heterodimers, was inactive. Thus, about 50% of the NPM-ALK fusion is sequestered and inactivated in the nucleus of ALCL cells by WT NPM1. Indeed, relocalization of NPM-ALK entirely to the cytoplasm in NPM-/- cells or its overexpression in several ALK+ ALCL cell lines resulted in cell death through activation of the ERK1/2 pathway and of γ-H2AX, a key player of the DNA damage response pathway. Thus, excessive oncogenic ALK signaling induces a cell stress leading to apoptosis and a balanced amount of ALK activation is necessary for optimal ALCL growth. Interestingly, we selected three human NPM-ALK positive cell lines resistant to the dual ALK/EGFR inhibitor AP26113. Resistance was due to genomic NPM-ALK amplification that caused overexpression of NPM-ALK and consequently hyperactivation of downstream ALK-dependent pathways. These cell lines were not only resistant, but also drug-dependent, meaning that addition of a low amount of AP26113 was required for cellular growth and to keep “normal” NPM-ALK signalling levels. Indeed, upon drug withdrawal, NPM-ALK and its downstream pathways were hyperactivated. The viability of all three drug-addicted cell lines dramatically dropped, confirming that an excess of NPM-ALK signaling was detrimental for cell growth. In two resistant cell lines out of three a new population recovered in the absence of the drug and was re-sensitized to AP26113. Notably, in these new drug-sensitive populations NPM-ALK overexpression was abrogated. All together, these findings support the idea that deregulation of NPM-ALK localization might be an attractive therapeutic option. Moreover, for a subset of patients that may develop drug dependency as well as drug resistance as a consequence of NPM-ALK overexpression, a discontinuous tyrosine kinase inhibitor therapeutic schedule may be more effective than a continuous one, as it is usually proposed. Citation Format: Monica Ceccon, Maria Elena Boggio Merlo, Luca Mologni, Lydia Varesio, Teresa Poggio, Matteo Menotti, Silvia Bombelli, Roberta Rigolio, Andrea Manazza, Chiara Ambrogio, Giovanni Giudici, Cesare Casati, Mara Compagno, Suzanne Turner, Carlo Gambacorti Passerini, Roberto Chiarle, Claudia Voena. Excess of cytoplasmic NPM-ALK driven oncogenic signaling is toxic and promotes cellular apoptosis and drug dependency. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2920. doi:10.1158/1538-7445.AM2015-2920

In previous studies we demonstrated that resveratrol acts in an antiapoptotic manner on the paclitaxel-treated human neuroblastoma (HN) SH-SY5Y cell line inhibiting the apoptotic pathways induced by the antineoplastic drug. In the present study we evaluated the antiapoptotic effect of resveratrol, studying its activity on cell cycle progression. We determined the mitotic index of cultures exposed to resveratrol and paclitaxel alone or in combination, the cell cycle distribution by flow cytometric analysis (FACS), and the modulation of some relevant cell cycle regulatory proteins. Resveratrol is able to induce S-phase cell arrest and this interference with the cell cycle is associated with an increase of cyclin E and cyclin A, a downregulation of cyclin D 1, and no alteration in cyclin B1 and cdk 1 activation. The resveratrol-induced S-phase block prevents SH-SY5Y from entering into mitosis, the phase of the cell cycle in which paclitaxel exerts its activity, explaining the antiapoptotic effect of resveratrol. (C) 2004 Elsevier Ltd. All rights reserved

Paclitaxel, an anticancer drug, induces apoptosis in human neuroblastoma cell line SH-SY5Y. The addition of trans-resveratrol, a natural antioxidant present in grapes and red wine, to SH-SY5Y cultures exposed to paclitaxel significantly reduces cellular death. The neuroprotective action of trans-resveratrol is due neither to its antioxidant capacity nor to interference with the polymerization of tubulin induced by paclitaxel. However, trans-resveratrol is able to inhibit the activation of caspase 7 and degradation of poly-(ADP-ribose)-polymerase which occur in SH-SY5Y exposed to paclitaxel. Resveratrol, therefore, exerts its anti-apoptotic effect by modulating the signal pathways that commit these neuronal-like cells to apoptosis.

We have demonstrated in the SH-SY5Y human neuroblastoma cell line that the antineoplastic drug paclitaxel induces apoptosis associated with the phosphorylation of c-raf and Bcl-2, thus causing Bcl-2 inactivation. In addition, we have observed the cleavage of caspase 7 and PARP, and the involvement of JNK/SAPK cascade. In this study, we investigated the possible anti-apoptotic effect of resveratrol on paclitaxel-induced apoptosis. Resveratrol is a natural antioxidant occurring in grapes and wine that as been shown to have anticancer and anti-inflammatory effects. Studies on the effect(s) of resveratrol on nervous cells are very few and limited to testing its ability in preventing oxidative stress in rat pheocromocytoma PC12 cells. However, the biological and pharmacological properties of resveratrol suggest that this natural compound might act on neuronal cells with a mode of action that is different from the antioxidant ones. To confirm this hypothesis, we studied the possible antagonist effect(s) of resveratrol on paclitaxel-induced apoptosis pathways. Our results indicate that the simultaneous treatment of 50M resveratrol and 1M paclitaxel induces a significant reduction of the percentage of apoptotic cells in comparison with 1M paclitaxel alone. Furthermore, we have demonstrated that resveratrol treatment determines a significant reduction of the phosphorylation of c-raf and Bcl-2 and a partial reduction of cleavage of caspase 7 and PARP. Finally, we observed an evident reduction of activation of JNK/SAPK in the presence of resveratrol. On the contrary, resveratrol does not affect the tubulin polymerization induced by paclitaxel. In conclusion, our results suggest that resveratrol is able to partially antagonize a nonoxidative stress apoptotic stimulus by influencing the typical signal pathways involved in apoptosis.