The central problem in cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues. Invariably the side effects impose dose reduction, treatment delay, or discontinuance of therapy. To limit the adverse side effects of cancer chemotherapy on healthy organs, we proposed a drug delivery system (DDS) with specific targeting ligands for cancer cells. The proposed DDS minimizes the uptake of the drug by normal cells and enhances the influx and retention of the drug in cancer cells. This delivery system includes three main components: (i) an apoptosis-inducing agent (anticancer drug), (ii) a targeting moiety-penetration enhancer, and (iii) a carrier. We describe one of the variants of such a system, which utilizes camptothecin as an apoptosis-inducing agent and poly(ethylene glycol) as a carrier. Luteinizing hormone-releasing hormone ( adverse side effects ͉ apoptosis ͉ cancer ͉ targeted drug delivery T he efficacy of cancer chemotherapy is limited by severe adverse side effects induced by anticancer drugs (1-4). The cytotoxic effect on healthy organs can be significantly diminished by employing special drug delivery systems (DDS) targeted specifically to cancer cells (5, 6). Targeting is especially important in circumstances where a localized tumor is removed surgically, and chemotherapy is prescribed as a follow-up preventive against potential metastases.Cancer targeting is usually achieved by adding to the DDS a ligand moiety specifically directed to certain types of binding sites on cancer cells. Several different targeting moieties were examined, including sugars (7-11), lectins (12-14), receptor ligands (5, 15-18), and antibodies (19-23) and their fragments (24). Recently, we found that the receptors for luteinizing hormone-releasing hormone (LHRH) are overexpressed in breast, ovarian, and prostate cancer cells (5,15,25). LHRH receptors (LHRHRs) are not expressed detectably in most visceral organs. We have taken advantage of this differential receptor expression and used a modified LHRH peptide as a targeting moiety on DDS to enhance drug uptake by the mentioned cancer cells and reduce the relative availability of the toxic drug to normal cells. We constructed and evaluated in vitro targeted DDS, which included (i) poly(ethylene glycol) (PEG) polymer as a carrier; (ii) camptothecin (CPT) as an anticancer drug; and (iii) modified LHRH peptide as a targeting moiety (5,15). In vitro evaluations confirmed the high anticancer activity of such conjugates against human ovarian, breast, and prostate cancer cells (15). Further, it was demonstrated that the cytotoxicity of the LHRH-targeted conjugates in human cancer cells was competitively inhibited by free LHRH peptide (25). The present investigations were aimed at evaluating the antitumor activity and apoptosis-induction capacity of the conjugates in experiments on mice bearing xenografts of human ovarian carcinoma. Tumor and organ distribution profiles of the targeted and nontargeted conjugates were also determined in these mice for cau...
Adrenomedullin (ADM) exerts anti-oxidant, anti-inflammatory and anti-apoptotic effects in Leydig cells. However, the role and mechanism of ADM in the pyroptosis of Leydig cells are poorly understood. This study first showed the protective effects of ADM on the pyroptosis and biological functions of Leydig cells exposed to lipopolysaccharide (LPS) by promoting autophagy. Primary rat Leydig cells were treated with various concentrations of LPS and ADM, together with or without N-acetyl-L-cysteine (NAC) or 3-methyladenine (3-MA). Cell proliferation was detected through CCK-8 and BrdU incorporation assays, and ROS level was measured with the DCFDA assay. Real-time PCR, western blot, immunofluorescence, transmission electron microscopy, TUNEL and flow cytometry were performed to examine ADM’s effect on the pyroptosis, autophagy and steroidogenic enzymes of Leydig cells and AMPK/mTOR signalling. Like NAC, ADM dose-dependently reduced LPS-induced cytotoxicity and ROS overproduction. ADM also dose-dependently ameliorated LPS-induced pyroptosis by reversing the increased expression of NLRP3, ASC, caspase-1, IL-1β, IL-18, GSDMD, caspase-3, caspase-7, TUNEL-positive and PI and active caspase-1 double-stained positive rate, DNA fragmentation and LDH concentration, which could be rescued via co-incubation with 3-MA. ADM dose-dependently increased autophagy in LPS-induced Leydig cells, as confirmed by the increased expression of LC3-I/II, Beclin-1 and ATG-5; decreased expression of p62 and autophagosomes formation; and increased LC3-II/LC3-I ratio. However, co-treatment with 3-MA evidently decreased autophagy. Furthermore, ADM dose-dependently rescued the expression of steroidogenic enzymes, including StAR, P450scc, 3β-HSD and CYP17, and testosterone production in LPS-induced Leydig cells. Like rapamycin, ADM dose-dependently enhanced AMPK phosphorylation but reduced mTOR phosphorylation in LPS-induced Leydig cells, which could be rescued via co-incubation with 3-MA. In addition, pyroptosis was further decreased, and autophagy was further promoted in LPS-induced Leydig cells upon co-treatment with ADM and rapamycin. ADM may protect the steroidogenic functions of Leydig cells against pyroptosis by activating autophagy via the ROS–AMPK–mTOR axis.
The results obtained demonstrate that the binding of CPT to PEG/PEG-biotin polymers increases its cytotoxicity, ability to induce apoptosis by the activation of caspase-dependent cell death signaling pathway and simultaneous suppression of antiapoptotic cellular defense. This suggests that the targeting approach utilizing transporters such as SMVT may substantially improve the delivery of CPT and its anticancer activity by enhancing cellular permeability and possibly retention of CPT.
The PI3K/Akt signal transduction pathway is involved in the regulation and release of pro-inflammatory cytokines such as TNF-α and plays an important role in the development and progression of UC.
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