Herein, we describe the preparation of liposomes with folate-targeting properties for the encapsulation of anti-sarcosine antibodies (antisarAbs@LIP) and sarcosine (sar@LIP). The competitive inhibitory effects of exogenously added folic acid supported the role of folate targeting in liposome internalization. We examined the effects of repeated administration on mice PC-3 xenografts. Sar@LIP treatment significantly increased tumor volume and weight compared to controls treated with empty liposomes. Moreover, antisarAbs@LIP administration exhibited a mild antitumor effect. We also identified differences in gene expression patterns post-treatment. Furthermore, Sar@LIP treatment resulted in decreased amounts of tumor zinc ions and total metallothioneins. Examination of the spatial distribution across the tumor sections revealed a sarcosine-related decline of the MT1X isoform within the marginal regions but an elevation after antisarAbs@LIP administration. Our exploratory results demonstrate the importance of sarcosine as an oncometabolite in PCa. Moreover, we have shown that sarcosine can be a potential target for anticancer strategies in management of PCa.

Central European Institute of Technology Brno University of Technology Purkynova 123 CZ 612 00 Brno Czech Republic

Department of Biochemistry Faculty of Science Charles University Albertov 2030 CZ 128 40 Prague 2 Czech Republic

Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czech Republic

Department of Chemistry and Toxicology Veterinary Research Institute Hudcova 296 70 CZ 621 00 Brno Czech Republic

Department of Pathological Physiology Faculty of Medicine Masaryk University Kamenice 5 Brno CZ 625 00 Czech Republic

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol 5 Uvalu 84 CZ 150 06 Prague 5 Czech Republic

Zobrazit více v PubMed

Siegel R. L., Miller K. D. & Jemal A. Cancer Statistics, 2015. CA-Cancer J. Clin. 65, 5–29 (2015). PubMed

Abate-Shen C. & Shen M. M. Molecular genetics of prostate cancer. Genes Dev. 14, 2410–2434 (2000). PubMed

Sreekumar A. et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910–914 (2009). PubMed PMC

Cao D. L. et al. Efforts to resolve the contradictions in early diagnosis of prostate cancer: a comparison of different algorithms of sarcosine in urine. Prostate Cancer Prostatic Dis. 14, 166–172 (2011). PubMed

Cao D. L. et al. A Multiplex Model of Combining Gene-Based, Protein-Based, and Metabolite-Based With Positive and Negative Markers in Urine for the Early Diagnosis of Prostate Cancer. Prostate 71, 700–710 (2011). PubMed

Heger Z. et al. Determination of common urine substances as an assay for improving prostate carcinoma diagnostics. Oncol. Rep. 31, 1846–1854 (2014). PubMed

Lucarelli G. et al. Serum sarcosine increases the accuracy of prostate cancer detection in patients with total serum PSA less than 4.0?ng/ml. Prostate 72, 1611–1621 (2012). PubMed

Jentzmik F. et al. Sarcosine in Urine after Digital Rectal Examination Fails as a Marker in Prostate Cancer Detection and Identification of Aggressive Tumours. Eur. Urol. 58, 12–18 (2010). PubMed

Khan A. P. et al. The Role of Sarcosine Metabolism in Prostate Cancer Progression. Neoplasia 15, 491–501 (2013). PubMed PMC

Cernei N. et al. Effect of sarcosine on antioxidant parameters and metallothionein content in the PC-3 prostate cancer cell line. Oncol. Rep. 29, 2459–2466 (2013). PubMed

Heger Z. et al. Paramagnetic Nanoparticles as a Platform for FRET-Based Sarcosine Picomolar Detection. Sci Rep 5, 1–7 (2015). PubMed PMC

Leamon C. P. Folate-targeted drug strategies for the treatment of cancer. Curr. Opin. Investig. Drugs 9, 1277–1286 (2008). PubMed

Pollock S. et al. Uptake and trafficking of liposomes to the endoplasmic reticulum. Faseb J. 24, 1866–1878 (2010). PubMed

Heger Z. et al. 17 beta-estradiol-containing liposomes as a novel delivery system for the antisense therapy of ER-positive breast cancer: An in vitro study on the MCF-7 cell line. Oncol. Rep. 33, 921–929 (2015). PubMed

Hattori Y. & Maitani Y. Folate-linked nanoparticle-mediated suicide gene therapy in human prostate cancer and nasopharyngeal cancer with herpes simplex virus thymidine kinase. Cancer Gene Ther. 12, 796–809 (2005). PubMed

Zhao D. M. et al. Preparation, characterization, and in vitro targeted delivery of folate-decorated paclitaxel-loaded bovine serum albumin nanoparticles. Int. J. Nanomed. 5, 669–677 (2010). PubMed PMC

Bahrami B. et al. Folate-conjugated nanoparticles as a potent therapeutic approach in targeted cancer therapy. Tumor Biol. 36, 5727–5742 (2015). PubMed

Nelson W. G., De Marzo A. M. & Isaacs W. B. Mechanisms of disease: Prostate cancer. N. Engl. J. Med. 349, 366–381 (2003). PubMed

Chen C. et al. Structural basis for molecular recognition of folic acid by folate receptors. Nature 500, 486–489 (2013). PubMed PMC

Chaudhury A. & Das S. Folate Receptor Targeted Liposomes Encapsulating Anti-Cancer Drugs. Curr. Pharm. Biotechnol. 16, 333–343 (2015). PubMed

Sabharanjak S. & Mayor S. Folate receptor endocytosis and trafficking. Adv. Drug Deliv. Rev. 56, 1099–1109 (2004). PubMed

Maeda H. Macromolecular therapeutics in cancer treatment: The EPR effect and beyond. J. Control. Release 164, 138–144 (2012). PubMed

Talmadge J. E., Singh R. K., Fidler I. J. & Raz A. Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am. J. Pathol. 170, 793–804 (2007). PubMed PMC

Chames P., Van Regenmortel M., Weiss E. & Baty D. Therapeutic antibodies: successes, limitations and hopes for the future. Br. J. Pharmacol. 157, 220–233 (2009). PubMed PMC

Cernei N. et al. Sarcosine as a Potential Prostate Cancer Biomarker-A Review. Int. J. Mol. Sci. 14, 13893–13908 (2013). PubMed PMC

Trudel D., Fradet Y., Meyer F., Harel F. & Tetu B. Significance of MMP-2 expression in prostate cancer: An immunohistochemical study. Cancer Res. 63, 8511–8515 (2003). PubMed

Peng B. et al. AP-1 Transcription Factors c-FOS and c-JUN Mediate GnRH-Induced Cadherin-11 Expression and Trophoblast Cell Invasion. Endocrinology 156, 2269–2277 (2015). PubMed

Kaukoniemi K. M. et al. Epigenetically altered miR-193b targets cyclin D1 in prostate cancer. Cancer Med. 4, 1417–1425 (2015). PubMed PMC

Adams S. J., Aydin I. T. & Celebi J. T. GAB2-a Scaffolding Protein in Cancer. Mol. Cancer Res. 10, 1265–1270 (2012). PubMed PMC

Ding C. B., Yu W. N., Feng J. H. & Luo J. M. Structure and function of Gab2 and its role in cancer (Review). Mol. Med. Rep. 12, 4007–4014 (2015). PubMed PMC

Mignard V., Lalier L., Paris F. & Vallette F. M. Bioactive lipids and the control of Bax pro-apoptotic activity. Cell Death Dis. 5, 1–8 (2014). PubMed PMC

Schmid M. et al. The role of biomarkers in the assessment of prostate cancer risk prior to prostate biopsy: Which markers matter and how should they be used? World J. Urol. 32, 871–880 (2014). PubMed

Tisman G. & Garcia A. Control of prostate cancer associated with withdrawal of a supplement containing folic acid, L-methyltetrahydrofolate and vitamin B12: a case report. J Med. Case Rep. 5, 413–418 (2011). PubMed PMC

Pan T. J. et al. Elevated expression of glutaminase confers glucose utilization via glutaminolysis in prostate cancer. Biochem. Biophys. Res. Commun. 456, 452–458 (2015). PubMed

Wang Q. et al. Targeting Amino Acid Transport in Metastatic Castration-Resistant Prostate Cancer: Effects on Cell Cycle, Cell Growth, and Tumor Development. JNCI-. Natl. Cancer Inst. 105, 1463–1473 (2013). PubMed

Beauchamp E. M. & Platanias L. C. The evolution of the TOR pathway and its role in cancer. Oncogene 32, 3923–3932 (2013). PubMed

Hasumi M. et al. Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues. Cancer Lett. 200, 187–195 (2003). PubMed

Franklin R. B. et al. hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol. Cancer 4, 1–13 (2005). PubMed PMC

Heger Z. et al. Metallothionein as a Scavenger of Free Radicals - New Cardioprotective Therapeutic Agent or Initiator of Tumor Chemoresistance? Current Drug Targets In press (2015). PubMed

Vogel C. & Marcotte E. M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13, 227–232 (2012). PubMed PMC

Leitao R. G. et al. Study of human prostate spheroids treated with zinc using X ray microfluorescence. 2014 Ieee International Symposium on Medical Measurements and Applications (Memea) 599–603 (2014).

Song Y. H., Shiota M., Kuroiwa K., Naito S. & Oda Y. The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer. Mod. Pathol. 24, 1272–1280 (2011). PubMed

Bradford M. M. Rapid and sensitive method for quantification of microgram quantities of protein utilizing principle of protein-dye binding. Anal. Biochem. 72, 248–254 (1976). PubMed

Heger Z. et al. 3D-printed biosensor with poly(dimethylsiloxane) reservoir for magnetic separation and quantum dots-based immunolabeling of metallothionein. Electrophoresis 36, 1256–1264 (2015). PubMed

Nejdl L. et al. Interaction study of arsenic (III and V) ions with metallothionein gene (MT2A) fragment. Int. J. Biol. Macromol. 72, 599–605 (2015). PubMed

Roth K. M., Peyvan K., Schwarzkopf K. R. & Ghindilis A. Electrochemical detection of short DNA oligomer hybridization using the CombiMatrix ElectraSense Microarray reader. Electroanalysis 18, 1982–1988 (2006).

Kaushal V., Herzog C., Haun R. S. & Kaushal G. P. In Caspases, Paracaspases, and Metacaspases: Methods and Protocols Vol. 1133 Methods in Molecular Biology (eds Bozhkov P. V. & Salvesen G.) 141–154 (Humana Press Inc, 2014).

Casadonte R. & Caprioli R. M. Proteomic analysis of formalin-fixed paraffin-embedded tissue by MALDI imaging mass spectrometry. Nat. Protoc. 6, 1695–1709 (2011). PubMed PMC

Tmejova K. et al. Structural effects and nanoparticle size are essential for quantum dots-metallothionein complex formation. Colloid Surf. B-Biointerfaces 134, 262–272 (2015). PubMed

Comparison of Dietary Oils with Different Polyunsaturated Fatty Acid n-3 and n-6 Content in the Rat Model of Cutaneous Wound Healing

Comparative gene expression profiling of human metallothionein-3 up-regulation in neuroblastoma cells and its impact on susceptibility to cisplatin

Zinc-Modified Nanotransporter of Doxorubicin for Targeted Prostate Cancer Delivery