The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod

Almost all drugs approved for use in humans possess potentially beneficial ‘off‐target’ effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re‐purposing FTY720 (also known as fingolimod, Gilenya^?), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1‐phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer‐associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti‐cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer‐related cellular processes, and discuss its potential use as an anti‐cancer drug.     

Killing cancer with platycodin D through multiple mechanisms

Cancer is a multi‐faceted disease comprised of a combination of genetic, epigenetic, metabolic and signalling aberrations which severely disrupt the normal homoeostasis of cell growth and death. Rational developments of highly selective drugs which specifically block only one of the signalling pathways have been associated with limited therapeutic success. Multi‐targeted prevention of cancer has emerged as a new paradigm for effective anti‐cancer treatment. Platycodin D, a triterpenoid saponin, is one the major active components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties including, anti‐nociceptive, anti‐atherosclerosis, antiviral, anti‐inflammatory, anti‐obesity, immunoregulatory, hepatoprotective and anti‐tumour activities. Recently, the anti‐cancer activity of platycodin D has been extensively studied. The purpose of this review was to give our perspectives on the current status of platycodin D and discuss its anti‐cancer activity and molecular mechanisms which may help the further design and conduct of pre‐clinical and clinical trials to develop it successfully into a potential lead drug for oncological therapy. Platycodin D has been shown to fight cancer by inducing apoptosis, cell cycle arrest, and autophagy and inhibiting angiogenesis, invasion and metastasis by targeting multiple signalling pathways which are frequently deregulated in cancers suggesting that this multi‐target activity rather than a single effect may play an important role in developing platycodin D into potential anti‐cancer drug.     

SnoN functions as a tumour suppressor by inducing premature senescence

SnoN represses TGF‐β signalling to promote cell proliferation and has been defined as a proto‐oncogene partly due to its elevated expression in many human cancer cells. Although the anti‐tumourigenic activity of SnoN has been suggested, the molecular basis for this has not been defined. We showed here that high levels of SnoN exert anti‐oncogenic activity by inducing senescence. SnoN interacts with the promyelocytic leukaemia (PML) protein and is recruited to the PML nuclear bodies where it stabilizes p53, leading to premature senescence. Furthermore, overexpression of SnoN inhibits oncogenic transformation induced by Ras and Myc in vitro and significantly blocks papilloma development in vivo in a carcinogen‐induced skin tumourigenesis model. The few papillomas that were developed displayed high levels of senescence and spontaneously regressed. Our study has revealed a novel Smad‐independent pathway of SnoN function that mediates its anti‐oncogenic activity.     

The FDA approved PI3K inhibitor GDC‐0941 enhances in vitro the anti‐neoplastic efficacy of Axitinib against c‐myc‐amplified high‐risk medulloblastoma

Aberrant receptor kinase signalling and tumour neovascularization are hallmarks of medulloblastoma development and are both considered valuable therapeutic targets. In addition to VEGFR1/2, expression of PDGFR α/β in particular has been documented as characteristic of metastatic disease correlating with poor prognosis. Therefore, we have been suggested that the clinically approved multi‐kinase angiogenesis inhibitor Axitinib, which specifically targets these kinases, might constitute a promising option for medulloblastoma treatment. Indeed, our results delineate anti‐neoplastic activity of Axitinib in medulloblastoma cell lines modelling the most aggressive c‐myc‐amplified Non‐WNT/Non‐SHH and SHH‐TP53‐mutated tumours. Exposure of medulloblastoma cell lines to Axitinib results in marked inhibition of proliferation and profound induction of cell death. The differential efficacy of Axitinib is in line with target expression of medulloblastoma cells identifying VEGFR 1/2, PDGFR α/β and c‐kit as potential markers for drug application. The high specificity of Axitinib and the consequential low impact on the haematopoietic and immune system render this drug ideal multi‐modal treatment approaches. In this context, we demonstrate that the clinically available PI3K inhibitor GDC‐0941 enhances the anti‐neoplastic efficacy of Axitinib against c‐myc‐amplified medulloblastoma. Our findings provide a rational to further evaluate Axitinib alone and in combination with other therapeutic agents for the treatment of most aggressive medulloblastoma subtypes.     

Regulated proteolysis of Candida albicans Ras1 is involved in morphogenesis and quorum sensing regulation

In Candida albicans, a fungal pathogen, the small G‐protein Ras1 regulates many important behaviors including white‐opaque switching, biofilm formation, and the induction and maintenance of hyphal growth. Like other Ras proteins, Ras1 is activated upon guanine triphosphate binding, and its activity is further modulated by post‐translational lipid modifications. Here, we report that the levels of membrane‐associated, full‐length Ras1 were higher in hyphae than in yeast, and that yeast contained a shorter, soluble Ras1 species that resulted from cleavage. Deletion of the putative cleavage site led to more rapid induction of hyphal growth and delayed hypha‐to‐yeast transitions. The cleaved Ras1 species was less able to activate its effector, adenylate cyclase (Cyr1), unless tethered to the membrane by a heterologous membrane‐targeting domain. Ras1 cleavage was repressed by cAMP‐signalling, indicating the presence of a positive feedback loop in which Cyr1 and cAMP influence Ras1. The C. albicans quorum sensing molecule farnesol, which inhibits Cyr1 and represses filamentation, caused an increase in the fraction of Ras1 in the cleaved form, particularly in nascent yeast formed from hyphae. This newly recognized mode of Ras regulation may control C. albicans Ras1 activity in important ways.     

Polysaccharides derived from Balanophora polyandra significantly suppressed the proliferation of ovarian cancer cells through P53‐mediated pathway

Ovarian cancer (OC) is ranked the first among the cancers threatening women's health. It attracts tremendous attention of cancer researchers because of its extremely high mortality rate. Recent studies have indicated that traditional herbal medicines (THMs) can play a pivotal role in cancer prevention and treatment. THMs are gaining popularity as a source of anti‐cancer agents. The plant of Balanophora polyandra, which has been used as a traditional herbal medicine, has been known for exhibiting potential haemostatic, analgesic, anti‐inflammatory and anti‐cancer properties. However, few studies on inhibitory effect of B. polyandra on OC have been performed. In the present study, we found that B. polyandra polysaccharides (BPP) induced cell cycle arrest at S phase, triggered apoptosis and inhibited migration and invasion of OC cells. Furthermore, we also found that there was a potential and close relationship between BPP and P53‐mediated pathway. Overall, these findings suggest that BPP can be a potential therapeutic agent for the treatment of OC.     

Mechanistic study of the anti‐cancer effect of Gynostemma pentaphyllum saponins in the ApcMin/+ mouse model

Gynostemma pentaphyllum saponins (GpS) have been shown to have anti‐cancer activity. However, the underlying mechanisms remain unclear. In this study, we used the Apc^Min/+ colorectal cancer (CRC) mouse model to investigate the anti‐cancer effect of GpS and we demonstrated that GpS treatment could significantly reduce the number and size of intestinal polyps in Apc^Min/+ mice. In order to identify the potential targets and mechanisms involved, a comparative proteomics analysis was performed and 40 differentially expressed proteins after GpS treatment were identified. Bioinformatics analyses suggested a majority of these proteins were involved in processes related to cellular redox homeostasis, and predicted Raf‐1 as a potential target of GpS. The upregulation of two proteins known to be involved in redox homeostasis, peroxiredoxin‐1 (Prdx1) and peroxiredoxin‐2 (Prdx2), and the downregulation of Raf‐1 were validated using Western blot analysis. After further investigation of the associated signaling networks, we postulated that the anti‐cancer effect of GpS was mediated through the upregulation of Prdx1 and Prdx2, suppression of Ras, RAF/MEK/ERK/STAT, PI3K/AKT/mTOR signaling and modulation of JNK/p38 MAPK signaling. We also examined the potential combinatorial effect of GpS with the chemotherapeutic 5‐fluorouracil (5‐FU) and found that GpS could enhance the anti‐cancer efficacy of 5‐FU, further suppressing the number of polyps in Apc^Min/+ mice. Our findings highlight the potential of GpS as an anti‐cancer agent, the potential mechanisms of its anti‐cancer activities, and its effect as an adjuvant of 5‐FU in the chemotherapy of CRC.     

Corilagin suppresses RANKL‐induced osteoclastogenesis and inhibits oestrogen deficiency‐induced bone loss via the NF‐κB and PI3K/AKT signalling pathways

Over‐activated osteoclastogenesis, which is initiated by inflammation, has been implicated in osteoporosis. Corilagin, a natural compound extracted from various medicinal herbaceous plants, such as Cinnamomum cassia, has antioxidant and anti‐inflammatory activities. We found that Corilagin suppressed osteoclast differentiation in a dose‐dependent manner, significantly decreased osteoclast‐related gene expression and impaired bone resorption by osteoclasts. Moreover, phosphorylation of members of the nuclear factor‐kappaB (NF‐κB) and PI3K/AKT signalling pathways was reduced by Corilagin. In a murine model of osteoporosis, Corilagin inhibited osteoclast functions in vivo and restored oestrogen deficiency‐induced bone loss. In conclusion, our findings suggested that Corilagin inhibited osteoclastogenesis by down‐regulating the NF‐κB and PI3K/AKT signalling pathways, thus showing its potential possibility for the treatment of osteoporosis.     

Conifer responses to a stylet‐feeding invasive herbivore and induction with methyl jasmonate: impact on the expression of induced defences and a native folivore

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Defective autophagy in multidrug resistant cells may lead to growth inhibition by BH3‐mimetic gossypol

The clinical efficacy of many chemotherapeutic agents has been reduced due to the development of drug resistance. In this article, we aimed to validate gossypol, a natural BH3 mimetic found in cottonseeds, as a potential therapeutic to overcome multidrug resistance (MDR). Gossypol was found to retain its efficacy in v‐Ha‐ras‐transformed NIH 3T3 cells that overexpressed P‐glycoprotein (Ras‐NIH 3T3/Mdr), which was similar to the efficacy observed in their parental counterparts (Ras‐NIH 3T3). A rhodamine assay revealed that the alteration of MDR activity did not contribute to the cytotoxic effect of gossypol. Gossypol caused a G₂/M arrest by the induction of p21^Cip1 and the down‐regulation of p27^Kip1 expression in Ras‐NIH 3T3 cells, whereas no significant G₂/M arrest was exhibited in Ras‐NIH 3T3/Mdr cells. Surprisingly, a 48‐h treatment with gossypol induced apoptotic cell death in Ras‐NIH 3T3 cells; however, gossypol induced both apoptosis and necrosis in Ras‐NIH 3T3/Mdr cells, as determined with flow cytometry analysis. More notably, gossypol preferentially induced autophagy in Ras‐NIH 3T3 cells but not in Ras‐NIH 3T3/Mdr cells. Coimmunoprecipitation and flow cytometric analysis revealed that gossypol‐induced autophagy is independent of the dissociation of Beclin 1 from Bcl‐2 in Ras‐NIH 3T3 cells. Taken together, these results suggest that the antiproliferative activity of gossypol appears to be due to cell‐cycle arrest at the G₂/M phase, with the induction of apoptosis in Ras‐NIH 3T3 cells. In addition, defective autophagy might contribute to apoptotic and necrotic cell death in response to gossypol in Ras‐NIH 3T3/Mdr cells. J. Cell. Physiol. 228: 1496–1505, 2013. © 2012 Wiley Periodicals, Inc.     

MicroRNA‐132/212 family enhances arteriogenesis after hindlimb ischaemia through modulation of the Ras‐MAPK pathway

Arteriogenesis is a complicated process induced by increased local shear‐and radial wall‐stress, leading to an increase in arterial diameter. This process is enhanced by growth factors secreted by both inflammatory and endothelial cells in response to physical stress. Although therapeutic promotion of arteriogenesis is of great interest for ischaemic diseases, little is known about the modulation of the signalling cascades via microRNAs. We observed that miR‐132/212 expression was significantly upregulated after occlusion of the femoral artery. miR‐132/212 knockout (KO) mice display a slower perfusion recovery after hind‐limb ischaemia compared to wildtype (WT) mice. Immunohistochemical analysis demonstrates a clear trend towards smaller collateral arteries in KO mice. Although Ex vivo aortic ring assays score similar number of branches in miR‐132/212 KO mice compared to WT, it can be stimulated with exogenous miR‐132, a dominant member of the miR‐132/212 family. Moreover, in in vitro pericyte‐endothelial co‐culture cell assays, overexpression of miR‐132 and mir‐212 in endothelial cells results in enhanced vascularization, as shown by an increase in tubular structures and junctions. Our results suggested that miR‐132/212 may exert their effects by enhancing the Ras‐Mitogen‐activated protein kinases MAPK signalling pathway through direct inhibition of Rasa1, and Spred1. The miR‐132/212 cluster promotes arteriogenesis by modulating Ras‐MAPK signalling via direct targeting of its inhibitors Rasa1 and Spred1.     

Triggering Ras signalling by intracellular Francisella tularensis through recruitment of PKCα and βI to the SOS2/GrB2 complex is essential for bacterial proliferation in the cytosol

Intracellular proliferation of Francisella tularensis is essential for manifestation of the fatal disease tularaemia, and is classified as a category A bioterrorism agent. The F. tularensis‐containing phagosome (FCP) matures into a late endosome‐like phagosome with limited fusion to lysosomes, followed by rapid bacterial escape into the cytosol. The Francisella pathogenicity island (FPI) encodes a type VI‐like secretion system, and the FPI‐encoded IglC is essential for evasion of lysosomal fusion and phagosomal escape. Many host signalling events are likely to be modulated by F. tularensis to render the cell permissive for intracellular proliferation but they are not fully understood. Here we show that within 15 min of infection, intracellular F. tularensis ssp. novicida triggers IglC‐dependent temporal activation of Ras, but attached extracellular bacteria fail to trigger Ras activation, which has never been shown for other intracellular pathogens. Intracellular F. tularensis ssp. novicida triggers activation of Ras through recruitment of PKCα and PKCβI to the SOS2/GrB2 complex. Silencing of SOS2, GrB2 and PKCα and PKCβI by RNAi has no effect on evasion of lysosomal fusion and bacterial escape into the cytosol but renders the cytosol non‐permissive for replication of F. tularensis ssp. novicida. Since Ras activation promotes cell survival, we show that silencing of SOS2, GrB2 and PKCα and βI is associated with rapid early activation of caspase‐3 within 8 h post infection. However, silencing of SOS2, GrB2 and PKCα and βI does not affect phosphorylation of Akt or Erk, indicating that activation of the PI3K/Akt and the Erk signalling cascade are independent of the F. tularensis‐triggered Ras activation. We conclude that intracellular F. tularensis ssp. novicida triggers temporal and early activation of Ras through the SOS2/GrB2/PKCα/PKCβI quaternary complex. Temporal and rapid trigger of Ras signalling by intracellular F. tularensis is essential for intracellular bacterial proliferation within the cytosol, and this is associated with downregulation of early caspase‐3 activation.     

Targeting of K-Ras 4B by S-trans,trans-farnesyl thiosalicylic acid

Ras proteins regulate cell growth, differentiation and apoptosis. Their activities depend on their anchorage to the inner surface of the plasma membrane, which is promoted by their common carboxy-terminal S-farnesylcysteine and either a stretch of lysine residues (K-Ras 4B) or S-palmitoyl moieties (H-Ras, N-Ras and K-Ras 4A). We previously demonstrated dislodgment of H-Ras from EJ cell membranes by S-trans,trans-farnesylthiosalicylic acid (FTS), and proposed that FTS disrupts the interactions between the S-prenyl moiety of Ras and the membrane anchorage domains. In support of this hypothesis, we now show that FTS, which is not a farnesyltransferase inhibitor, inhibits growth of NIH3T3 cells transformed by the non-palmitoylated K-Ras 4B(12V) or by its farnesylated, but unmethylated, K-Ras 4B(12) CVYM mutant. The growth-inhibitory effects of FTS followed the dislodgment and accelerated degradation of K-Ras 4B(12V), leading in turn to a decrease in its amount in the cells and inhibition of MAPK activity. FTS did not affect the rate of degradation of the K-Ras 4B, SVIM mutant which is not modified post-translationally, suggesting that only farnesylated Ras isoforms are substrates for facilitated degradation. The putative Ras-recognition sites (within domains in the cell membrane) appear to tolerate both C(15) and C(20) S-prenyl moeities, since geranylgeranyl thiosalicylic acid mimicked the growth-inhibitory effects of FTS in K-Ras 4B(12V)-transformed cells and FTS inhibited the growth of cells transformed by the geranylgeranylated K-Ras 4B(12V) CVIL isoform. The results suggest that FTS acts as a domain-targeted compound that disrupts Ras-membrane interactions. The fact that FTS can target K-Ras 4B(12V), which is insensitive to inhibition by farnesyltransfarase inhibitors, suggests that FTS may target Ras (and other prenylated proteins important for transformed cell growth) in an efficient manner that speaks well for its potential as an anticancer therapeutic agent.     

Insulin‐like growth factor axis targeting in cancer and tumour angiogenesis – the missing link

Numerous molecular players in the process of tumour angiogenesis have been shown to offer potential for therapeutic targeting. Initially denoted to be involved in malignant transformation and tumour progression, the insulin‐like growth factor (IGF) signalling axis has been subject to therapeutic interference, albeit with limited clinical success. More recently, IGFs and their receptors have received attention for their contribution to tumour angiogenesis, which offers novel therapeutic opportunities. Here we review the contribution of this signalling axis to tumour angiogenesis, the mechanisms of resistance to therapy and the interplay with other pro‐angiogenic pathways, to offer insight in the renewed interest in the application of IGF axis targeting agents in anti‐cancer combination therapies.     

Apoptosis‐inducing effects of Morinda citrifolia L. and doxorubicin on the Ehrlich ascites tumor in Balb‐c mice

Morinda citrifolia L. (Noni) is a herbal remedy with promising anti‐cancer properties. However, its effects on various cancers are to be investigated to make a firm conclusion before implementing it into the clinical practice. Therefore, we investigated the cytotoxic potential of noni on Ehrlich ascites tumor grown in female Balb‐c mice and also combined it with a potent anti‐cancer agent, doxorubicin. One group received noni only (n = 8), another one doxorubicin (n = 8), and the other one noni + doxorubicin (n = 8) for 14 days after the inoculation of cells. The control group (n = 7) received 0.9% NaCl only. We found that short and long diameters of the tumor tissues were about 40–50% smaller, compared to those in control group. This anti‐growth effect resulted from the induction of apoptosis, which was confirmed by the positive results from the Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) analysis and the active caspase‐3 cells in tissues. Apoptosis also confirmed by caspase‐cleaved cytokeratin 18 elevation in serum of the treated groups. Further, the proliferation was decreased, which was immunohistochemically shown by the PCNA staining. We conclude that noni may be useful in the treatment of breast cancer either on its own or in combination with doxorubicin. Further studies are warranted to assess the dosage and safety of using noni fruit juice in conjuction with anti‐cancer drugs against breast cancer. Copyright © 2009 John Wiley & Sons, Ltd.     

SH3‐class Ras guanine nucleotide exchange factors are essential for Aspergillus fumigatus invasive growth

Proper hyphal morphogenesis is essential for the establishment and progression of invasive disease caused by filamentous fungi. In the human pathogen Aspergillus fumigatus, signalling cascades driven by Ras and Ras‐like proteins orchestrate a wide variety of cellular processes required for hyphal growth. For activation, these proteins require interactions with Ras‐subfamily‐specific guanine nucleotide exchange factors (RasGEFs). Although Ras‐protein networks are essential for virulence in all pathogenic fungi, the importance of RasGEF proteins is largely unexplored. A. fumigatus encodes four putative RasGEFs that represent three separate classes of RasGEF proteins (SH3‐, Ras guanyl nucleotide‐releasing protein [RasGRP]–, and LTE‐class), each with fungus‐specific attributes. Here, we show that the SH3‐class and RasGRP‐class RasGEFs are required for properly timed polarity establishment during early growth and branch emergence as well as for cell wall stability. Further, we show that SH3‐class RasGEF activity is essential for polarity establishment and maintenance, a phenotype that is, at least, partially independent of the major A. fumigatus Ras proteins, RasA and RasB. Finally, loss of both SH3‐class RasGEFs resulted in avirulence in multiple models of invasive aspergillosis. Together, our findings suggest that RasGEF activity is essential for the integration of multiple signalling networks to drive invasive growth in A. fumigatus.     

Plant lectins,from ancient sugar‐binding proteins to emerging anti‐cancer drugs in apoptosis and autophagy

Ubiquitously distributed in different plant species, plant lectins are highly diverse carbohydrate‐binding proteins of non‐immune origin. They have interesting pharmacological activities and currently are of great interest to thousands of people working on biomedical research in cancer‐related problems. It has been widely accepted that plant lectins affect both apoptosis and autophagy by modulating representative signalling pathways involved in Bcl‐2 family, caspase family, p53, PI3K/Akt, ERK, BNIP3, Ras‐Raf and ATG families, in cancer. Plant lectins may have a role as potential new anti‐tumour agents in cancer drug discovery. Thus, here we summarize these findings on pathway‐ involved plant lectins, to provide a comprehensive perspective for further elucidating their potential role as novel anti‐cancer drugs, with respect to both apoptosis and autophagy in cancer pathogenesis, and future therapy.     

The isothiocyanate erucin abrogates telomerase in hepatocellular carcinoma cells in vitro and in an orthotopic xenograft tumour model of HCC

In contrast to cancer cells, most normal human cells have no or low telomerase levels which makes it an attractive target for anti‐cancer drugs. The small molecule sulforaphane from broccoli is known for its cancer therapeutic potential in vitro and in vivo. In animals and humans it was found to be quickly metabolized into 4‐methylthiobutyl isothiocyanate (MTBITC, erucin) which we recently identified as strong selective apoptosis inducer in hepatocellular carcinoma (HCC) cells. Here, we investigated the relevance of telomerase abrogation for cytotoxic efficacy of MTBITC against HCC. The drug was effective against telomerase, independent from TP53 and MTBITC also blocked telomerase in chemoresistant subpopulations. By using an orthotopic human liver cancer xenograft model, we give first evidence that MTBITC at 50 mg/KG b.w./d significantly decreased telomerase activity in vivo without affecting enzyme activity of adjacent normal tissue. Upon drug exposure, telomerase decrease was consistent with a dose‐dependent switch to anti‐survival, cell arrest and apoptosis in our in vitro HCC models. Blocking telomerase by the specific inhibitor TMPyP4 further sensitized cancer cells to MTBITC‐mediated cytotoxicity. Overexpression of hTERT, but not enzyme activity deficient DNhTERT, protected against apoptosis; neither DNA damage nor cytostasis induction by MTBITC was prevented by hTERT overexpression. These findings imply that telomerase enzyme activity does not protect against MTBITC‐induced DNA damage but impacts signalling processes upstream of apoptosis execution level.     

Disulfiram combined with copper inhibits metastasis and epithelial–mesenchymal transition in hepatocellular carcinoma through the NF‐κB and TGF‐β pathways

Late‐stage hepatocellular carcinoma (HCC) usually has a low survival rate because of the high risk of metastases and the lack of an effective cure. Disulfiram (DSF) has copper (Cu)‐dependent anticancer properties in vitro and in vivo. The present work aims to explore the anti‐metastasis effects and molecular mechanisms of DSF/Cu on HCC cells both in vitro and in vivo. The results showed that DSF inhibited the proliferation, migration and invasion of HCC cells. Cu improved the anti‐metastatic activity of DSF, while Cu alone had no effect. Furthermore, DSF/Cu inhibited both NF‐κB and TGF‐β signalling, including the nuclear translocation of NF‐κB subunits and the expression of Smad4, leading to down‐regulation of Snail and Slug, which contributed to phenotype epithelial–mesenchymal transition (EMT). Finally, DSF/Cu inhibited the lung metastasis of Hep3B cells not only in a subcutaneous tumour model but also in an orthotopic liver metastasis assay. These results indicated that DSF/Cu suppressed the metastasis and EMT of hepatic carcinoma through NF‐κB and TGF‐β signalling. Our study indicates the potential of DSF/Cu for therapeutic use.     

Anti‐angiogenic effects of the blue‐green alga Arthrospira platensis on pancreatic cancer

Arthrospira platensis, a blue‐green alga, is a popular nutraceutical substance having potent antioxidant properties with potential anti‐carcinogenic activities. The aim of our study was to assess the possible anti‐angiogenic effects of A platensis in an experimental model of pancreatic cancer. The effects of an A platensis extract were investigated on human pancreatic cancer cells (PA‐TU‐8902) and immortalized endothelial‐like cells (Ea.hy926). PA‐TU‐8902 pancreatic tumours xenografted to athymic mice were also examined. In vitro migration and invasiveness assays were performed on the tested cells. Multiple angiogenic factors and signalling pathways were analysed in the epithelial, endothelial and cancer cells, and tumour tissue. The A platensis extract exerted inhibitory effects on both migration and invasion of pancreatic cancer as well as endothelial‐like cells. Tumours of mice treated with A platensis exhibited much lesser degrees of vascularization as measured by CD31 immunostaining (P = .004). Surprisingly, the VEGF‐A mRNA and protein expressions were up‐regulated in pancreatic cancer cells. A platensis inhibited ERK activation upstream of Raf and suppressed the expression of ERK‐regulated proteins. Treatment of pancreatic cancer with A platensis was associated with suppressive effects on migration and invasiveness with various anti‐angiogenic features, which might account for the anticancer effects of this blue‐green alga.