Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance.

• Klíčová slova
• V-ATPase, V-ATPase inhibitors, chemoresistance of cancer cells, lysosomal sequestration, lysosomotropic agents, metallothioneins,
• MeSH
• antitumorózní látky farmakologie   MeSH
• chemorezistence * účinky léků   MeSH
• exocytóza MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• lyzozomy účinky léků   enzymologie   MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   enzymologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• vakuolární protonové ATPasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• vakuolární protonové ATPasy MeSH

Prostate cancer cells control energy metabolism by chelating intracellular zinc. Thus, zinc delivery has been a popular therapeutic approach for prostate cancer. Here, we propose the use of the membrane-penetrating peptide Novicidin connected to zinc-Schiff base as a carrier vehicle for the delivery of zinc to prostate cells. Mass spectrometry, electrochemistry and spectrophotometry confirmed the formation/stability of this complex and provided insight regarding the availability of zinc for complex interactions. This delivery system showed minor toxicity in normal PNT1A cells and high potency towards PC3 tumor cells. The complex preferentially penetrated PC3 tumor cells in contrast to confinement to the membranes of PNT1A. Furthermore, zinc uptake was confirmed in both cell lines. Molecular analysis was used to confirm the activation of zinc stress (e.g., ZnT-1) and apoptosis (e.g., CASP-1). Our results strongly suggest that the zinc-Schiff base-Novicidin complex has great potential as a novel anticancer drug.

• MeSH
• antitumorózní látky chemie   farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• exprese genu účinky léků   MeSH
• fluorescenční mikroskopie MeSH
• kaspasa 1 metabolismus   MeSH
• kationické antimikrobiální peptidy chemie   MeSH
• komplexní sloučeniny chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• molekulární konformace MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   MeSH
• proteiny přenášející kationty metabolismus   MeSH
• Schiffovy báze chemie   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• zinek chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• kaspasa 1 MeSH
• kationické antimikrobiální peptidy MeSH
• komplexní sloučeniny MeSH
• novicidin MeSH Prohlížeč
• proteiny přenášející kationty MeSH
• Schiffovy báze MeSH
• SLC30A1 protein, human MeSH Prohlížeč
• zinek MeSH

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.

• MeSH
• biologické modely MeSH
• fosfatidylethanolaminy MeSH
• kyselina listová metabolismus   MeSH
• lidé MeSH
• liposomy * chemie   ultrastruktura   MeSH
• metalothionein metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• monoklonální protilátky aplikace a dávkování   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   metabolismus   patologie   MeSH
• sarkosin antagonisté a inhibitory   chemie   MeSH
• tumor burden účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zinek metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dioleoyl phosphatidylethanolamine MeSH Prohlížeč
• fosfatidylethanolaminy MeSH
• kyselina listová MeSH
• liposomy * MeSH
• metalothionein MeSH
• monoklonální protilátky MeSH
• sarkosin MeSH
• zinek MeSH