Evaluation of antitumor activity of 6-(triphenylstannyl)hexan-1-ol loaded in SBA-15 mesoporous nanostructured material in the mouse model of melanoma in vitro and in vivo

Uprkos razvoju imunoterapije i ciljanih terapija, globalna incidenca melanoma nastavlja da raste. Konvencionalna hemoterapija, naţalost, pokazuje ograniĉenu efikasnost u leĉenju metastatskog melanoma. Primenu najĉešće korišćenog hemoterapeutskog leka cisplatine, ograniĉava uroĊena rezistencija ovog tipa tumora, što sve naglašava potrebu za razvojem efikasnije hemoterapije melanoma. Progres u medicinskoj organometalnoj hemiji omogućio je racionalni dizajn novih, nekonvencionalnih platinskih kompleksa, kao i neplatinskih antitumorskih jedinjenja, ukljuĉujući organokalajna jedinjenja, ĉija aktivnost ne poĉiva na direktnoj interakciji sa DNK. MeĊutim, nedovoljna rastvorljivost i toksiĉnost organokalajnih jedinjenja ograniĉava kompleksnija istraţivanja i ulazak u kliniĉka ispitivanja. U tom kontekstu, primena nanotehnologije u svrhu povećanja rastvorljivosti lekova i njihove selektivnosti prema maligno transformisanim klonovima u hemoterapiji kancera ima vodeću ulogu. Inkapsulacija hidrofobnih antitumorskih lekova u mezoporozne nanomaterijale silike, predstavlja najperspektivniju strategiju u ovoj oblasti. Zbog visokog potencijala za adsorpciju, nosaĉ SBA-15 je najinteresantniji mezoporozni silikat za ciljanu isporuku lekova. U skladu sa tim, u ovoj studiji je po prvi put ispitivan antitumorski potencijal organokalajnog(IV) jedinjenja [Ph3Sn(CH2)6OH] skladištenog u mezoporozni materijal SBA-15 (SBA-15pSn) in vitro i in vivo u modelu mišjeg melanoma. Imajući u vidu izuzetnu heterogenost melanoma, ispitivan je i njihov uticaj na visoko invazivnu liniju humanog melanoma, A375. Analizirani su ćelijski i molekulski mehanizmi pokrenuti u odgovoru na tretman eksperimentalnim agensima u ćelijama melanoma, kao i mehanizam preuzimanja ĉestica SBA-15pSn u humane ćelije melanoma u sistemu in vitro. [Ph3Sn(CH2)6OH] u slobodnoj formi ali, mnogo potentnije, uskladišten u SBA-15 smanjio je vijabilitet ćelijskih linija melanoma poreklom od miša B16, i ĉoveka A375. Isti trend je zapaţen u singenom modelu mišjeg melanoma in vivo. Pokazalo se da A375 ćelije melanoma preuzimaju SBA-15pSn pasivnim putem i makropinocitozom.Despite rapid development in immunotherapy and targeted therapies, the global incidence of melanoma continues to increase. Besides, conventional chemotherapy demonstrates only limited efficacy in the treatment of advanced melanoma. Clinical application of widely used chemotherapeutic drug cisplatin, is hampered by the intrinsic resistance of this type of tumor, indicating the urgent need for the development of more effective chemotherapies for melanoma. The rapid progress in medicinal organometallic chemistry in the past few years allows rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. Poor solubility and toxicity of organotin compounds, however, restrains more complex studies and further development in the preclinical and subsequently clinical setting. Nanotechnology now becomes an important part of pharmaceutical research and development, for improving the solubility and selective toxicity of cancer therapeutics. Encapsulating hydrophobic antitumor agents in ordered mesoporous silica nanomaterials is an emerging strategy to enhance drug dissolution. Due to its high drug loading capacity, SBA-15 is the most interesting mesoporous silicate for targeted drug delivery. Antitumor potential of organotin(IV) compound [Ph3Sn(CH2)6OH] grafted on nanostructured material SBA-15 (SBA-15pSn) in vitro and in vivo in the mouse model of melanoma, was tested for the first time in this study. Considering the enormous heterogeneity of this type of tumor, it was of interest to test these experimental therapeutics in a highly invasive human A375 melanoma cell line. Given the fact that SBA-15pSn nanoparticles are relatively large, the mechanism of cellular uptake was defined. At the molecular level, main intracellular events triggered by the treatment, as well as the expression of key signaling pathways mediating tumor cell response, were analyzed..

Study of the anticancer properties of methyl- and phenyl-substituted carbon- and silicon-bridged ansa-titanocene complexes

The previously known complexes {[}Ti\{(Me2CMe2C)(eta(5)-C5H4)(2)\}Cl-2] (1), {[}Ti\{Me2C(eta(5)-C5H4)(2)\}Cl-2] (2), {[}Ti \{Me2Si(eta(5)-C5H4)(2)\}Cl-2] (4), {[}Ti\{MePhSi(eta(5)-C5H4)(2)\}Cl-2] (5) and {[}Ti\{MePhSi(eta(5)-C5Me4)(2)\}Cl-2] (6) have been prepared following reported procedures. The novel complex {[}Ti\{MePhC(eta(5)-C5H4)(2)\}Cl-2] (3) has been prepared and characterized. The cytotoxic activity of 1-6 has been tested after 72 h on melanoma A375 and B16, prostate cancer DU145 and LNCaP and colon cancer HCT116, SW620 and CT26CL25 cell lines observing a high cytotoxic activity of complexes 1 and 6 compared to the reference compound ({[}Ti(eta(5)-C5H5)(2)\}Cl-2]). 1 and 6 have also been tested against primary normal mouse keratinocytes and lung fibroblasts. While viability of both type of primary cells was significantly less affected by 1 in comparison to the reference compound {[}Ti(eta(5)-C5H5)(2)Cl-2], compound 6 was completely nontoxic for nonmalignant cells, indicating a potential selectivity of this compound towards cancer cell lines. In addition CFSE staining, cell cycle analysis, AnnexinV-FITC/PI staining, detection of caspase activity and mitochondrial potential showed that 1 and 6 were acting through inhibition of proliferation and subsequent induction of mitochondrial dependent apoptosis in colon cancer cell lines, HCT116 and SW620, which express low sensitivity to cisplatin. Compound 6 was found to be the leading drug in this group since it shows the fastest and most selective anticancer profile. (C) 2013 Elsevier B.V. All rights reserved.Ministerio de Educacion y Ciencia, Spain {[}CTQ-2011-24346, CTQ-2012-30762]; Ministry of Science and Technological Development of the Republic of Serbia {[}173013]; Grant Agency of the Czech Republic {[}P207/12/2368

The NO-modified HIV protease inhibitor as a valuable drug for hematological malignancies: Role of p70S6K

Covalent attachment of NO to the first approved HIV protease inhibitor Saquinavir (Saq-NO) expands the therapeutic potential of the original drug. Apart from retained antiviral activity, the modified drug exerts strong antitumor effects and lower toxicity. In the present study, we have evaluated the sensitivity of different hematological malignancies to Saq-NO. Saq-NO efficiently diminished the viability of Jurkat, Raji, HL-60 and K562 cells. While Jurkat and Raji cells (established from pediatric patients) displayed abrogated proliferative potential, HL-60 and K652 cells (originated from adults) exposed to Saq-NO treatment underwent caspase dependent apoptosis. In addition, similar sensitivity to Saq-NO was observed in mononuclear blood cells obtained from pediatric patients with acute lymphoblastic leukemia (ALL) and adult patients with acute myeloid leukemia (AML). Western blot analysis indicated p70S6 kinase as a possible intracellular target of Saq-NO action. Moreover, the addition of a NO moiety to Lopinavir resulted in improved antitumor potential as compared to the parental compound, suggesting that NO-derived HIV protease inhibitors are a potential new source of anticancer drugs with unique mode of action. (C) 2015 Elsevier Ltd. All rights reserved

Alpha-1-Antitrypsin Antagonizes Cisplatin-Induced Cytotoxicity in Prostate Cancer (PC3) and Melanoma Cancer (A375) Cell Lines

Increased circulating alpha-1-antitrypsin (AAT) correlates with cancer stage/aggressiveness, but its role in cancer biology is unclear. We revealed antagonistic effect of AAT to cisplatin-induced cytotoxicity in prostate (PC3) and melanoma (A375) cancer cell lines. Moreover, AAT abrogated cytotoxicity of MEK inhibitor U0126 in PC3 cell line. Weaker antagonistic effect of AAT on cytotoxicity of PI3/Akt and NF-kB inhibitors was also observed. In addition, cisplatin increased AAT gene expression in transfected PC3 cells. However, AAT derived from transfected PC3 cells did not antagonize cisplatin-induced cytotoxicity. In conclusion, these results suggest possible association between high circulating AAT and cisplatin resistance

Alpha-1-Antitrypsin Antagonizes Cisplatin-Induced Cytotoxicity in Prostate Cancer (PC3) and Melanoma Cancer (A375) Cell Lines

Increased circulating alpha-1-antitrypsin (AAT) correlates with cancer stage/aggressiveness, but its role in cancer biology is unclear. We revealed antagonistic effect of AAT to cisplatin-induced cytotoxicity in prostate (PC3) and melanoma (A375) cancer cell lines. Moreover, AAT abrogated cytotoxicity of MEK inhibitor U0126 in PC3 cell line. Weaker antagonistic effect of AAT on cytotoxicity of PI3/Akt and NF-kB inhibitors was also observed. In addition, cisplatin increased AAT gene expression in transfected PC3 cells. However, AAT derived from transfected PC3 cells did not antagonize cisplatin-induced cytotoxicity. In conclusion, these results suggest possible association between high circulating AAT and cisplatin resistance

ALPHA-1 Antitrypsin Affects U0126-Induced Cytotoxicity in Colon Cancer Cell Line (HCT116)

Alpha-1-antitrypsin (AAT), an acute phase protein, is the principal circulatory anti-protease. This multifunctional protein is encoded by the SERPINA1 gene. Although AAT was recognised as a potential tumour marker, its role in cancer biology remains unknown. Given that it has been demonstrated that AAT has an anti-apoptotic property against non-malignant cells, we aimed to investigate whether AAT affects apoptosis in a colon cancer cell line (HCT116). The presence of AAT in the HCT116 cell culture antagonized cytotoxicity of blockers of MEK1/2, PI3K/Akt pathways as well as NF-kappa B. The dominantly recovered cell viability was observed in the co-treatment with MEK1/2 inhibitor U0126. In addition, it was revealed that AAT almost completely abolished U0126-induced apoptosis through maintenance of the autophagy process. Our study revealed for the first time that the observed cyto-protection triggered by AAT was accompanied by sustained autophagy which opposed apoptosis. These results may contribute to understanding of the role of AAT in cancer development and evaluation of efficacy of cancer therapy

Membrane Fluidity, Invasiveness and Dynamic Phenotype of Metastatic Prostate Cancer Cells after Treatment with Soy Isoflavones

Soy isoflavones represent hopeful unconventional remedies in the therapy of prostate cancer. The aim of our study was to determine the effects of genistein and daidzein on the parameters that reflect metastatic potential, membrane fluidity, invasiveness and dynamic phenotype in Matrigel of LNCaP and PC-3 prostate cancer cells. Cell viability tests, using a wide range of concentrations of soy isoflavones (6-75 mu g/ml for 72 h), were conducted to determine their IC50 concentrations. Electron paramagnetic resonance investigations of prostate cancer cell membrane fluidity were performed at IC50 concentrations of genistein and daidzein (12.5 and 25 mu g/ml, respectively, for 10 min). Genistein provoked significant increases in the membrane order parameter (which is reciprocally proportional to membrane fluidity) of 0.722 +/- A 0.006 (LNCaP), 0.753 +/- A 0.010 (LNCaP + genistein), 0.723 +/- A 0.007 (PC-3) and 0.741 +/- A 0.004 (PC-3 + genistein); however, no such effects were observed for daidzein. While both genistein and daidzein reduced the proliferation of prostate cancer cells at their respective IC50 concentrations, during the 72 h of incubation only genistein provoked effects on the dynamic phenotype and decreased invasiveness. The effect was more evident in PC-3 cells compared to LNCaP cells. Our results imply that (1) invasive activity is at least partially dependent on membrane fluidity, (2) genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells and (3) daidzein should be applied at higher concentrations than genistein in order to achieve pharmacological effects.Ministry of Science, Education and Technological Development of the Republic of Serbia [173009, 173013, 173014

Membrane Fluidity, Invasiveness and Dynamic Phenotype of Metastatic Prostate Cancer Cells after Treatment with Soy Isoflavones

Soy isoflavones represent hopeful unconventional remedies in the therapy of prostate cancer. The aim of our study was to determine the effects of genistein and daidzein on the parameters that reflect metastatic potential, membrane fluidity, invasiveness and dynamic phenotype in Matrigel of LNCaP and PC-3 prostate cancer cells. Cell viability tests, using a wide range of concentrations of soy isoflavones (6-75 mu g/ml for 72 h), were conducted to determine their IC50 concentrations. Electron paramagnetic resonance investigations of prostate cancer cell membrane fluidity were performed at IC50 concentrations of genistein and daidzein (12.5 and 25 mu g/ml, respectively, for 10 min). Genistein provoked significant increases in the membrane order parameter (which is reciprocally proportional to membrane fluidity) of 0.722 +/- A 0.006 (LNCaP), 0.753 +/- A 0.010 (LNCaP + genistein), 0.723 +/- A 0.007 (PC-3) and 0.741 +/- A 0.004 (PC-3 + genistein); however, no such effects were observed for daidzein. While both genistein and daidzein reduced the proliferation of prostate cancer cells at their respective IC50 concentrations, during the 72 h of incubation only genistein provoked effects on the dynamic phenotype and decreased invasiveness. The effect was more evident in PC-3 cells compared to LNCaP cells. Our results imply that (1) invasive activity is at least partially dependent on membrane fluidity, (2) genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells and (3) daidzein should be applied at higher concentrations than genistein in order to achieve pharmacological effects.Ministry of Science, Education and Technological Development of the Republic of Serbia [173009, 173013, 173014

Nanostructured silica functionalized with an organotin compound induces differentiation of B16 melanoma cells

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Anticancer Potential of (Pentamethylcyclopentadienyl)chloridoiridium(III) Complexes Bearing kappa P and kappa P,kappa S-Coordinated Ph2PCH2CH2CH2S(O)(x)Ph (x=0-2) Ligands

Iridium(III) complexes of the type {[}Ir(eta(5)-C5Me5)Cl-2\{Ph2PCH2-CH2CH2S(O)(x)Ph-kappa P\}] (x=0-2; 1-3) and {[}Ir(eta(5)-C5Me5)Cl\{Ph2PCH2-CH2CH2S(O)(x)Ph-kappa P,kappa S\}]{[}PF6] (x=0-1; 4 and 5) with 3-(diphenyl-phosphino)propyl phenyl sulfide, sulfoxide, and sulfone ligands Ph2PCH2CH2CH2S(O)(x)Ph were designed, synthesized, and characterized fully, including X-ray diffraction analyses for complexes 3 and 4. In vitro studies against human thyroid carcinoma (8505C), submandibular carcinoma (A253), breast adenocarcinoma (MCF-7), colon adenocarcinoma (SW480), and melano-ma (518A2) cell lines provided evidence for the high biological potential of the neutral and cationic iridium(III) complexes. Neutral iridium(III) complex 5 proved to be the most active, with IC50 values up to about 0.1 mu m, representing activities of up to one order of magnitude higher than cisplatin. Using 8505C cells, apoptosis was shown to be the main mechanism through which complex 5 exerts its tumoricidal action. The described iridium(III) complexes represent potential leads in the search for novel metal-based anticancer agents.Graduiertenforderung des Landes Sachsen-Anhalt (Germany); Ministry of Science and Technological Development of the Republic of Serbia {[}173013