ABSTRACT
MicroRNA-21(miRNA-21)is highly expressed in various tumors.Small-molecule inhibition of miRNA-21 is considered to be an attractive novel cancer therapeutic strategy.In this study,fluoroquinolone de-rivatives Al-A43 were synthesized and used as miRNA-21 inhibitors.Compound A36 showed the most potent inhibitory activity and specificity for miRNA-21 in a dual-luciferase reporter assay in HeLa cells.Compound A36 significantly reduced the expression of mature miRNA-21 and increased the protein expression of miRNA-21 target genes,including programmed cell death protein 4(PDCD4)and phos-phatase and tensin homology deleted on chromosome ten(PTEN),at 10 uM in HeLa cells.The Cell Counting Kit-8 assay(CCK-8)was used to evaluate the antiproliferative activity of A36;the results showed that the IC50 value range of A36 against six tumor cell lines was between 1.76 and 13.0 μM.Meanwhile,A36 did not display cytotoxicity in BEAS-2B cells(lung epithelial cells from a healthy human donor).Furthermore,A36 significantly induced apoptosis,arrested cells at the G0/G1 phase,and inhibited cell-colony formation in HeLa cells.In addition,mRNA deep sequencing showed that treatment with A36 could generate 171 dysregulated mRNAs in HeLa cells,while the expression of miRNA-21 target gene dual-specificity phosphatase 5(DUSP5)was significantly upregulated at both the mRNA and protein levels.Collectively,these findings demonstrated that A36 is a novel miRNA-21 inhibitor.
ABSTRACT
Unsymmetrical bisacridines (UAs) are a novel potent class of antitumor-active therapeutics.A significant route of phase II drug metabolism is conjugation with glutathione (GSH),which can be non-enzymatic and/or catalyzed by GSH-dependent enzymes.The aim of this work was to investigate the GSH-mediated metabolic pathway of a representative UA,C-2028.GSH-supplemented incubations of C-2028 with rat,but not with human,liver cytosol led to the formation of a single GSH-related metabolite.Interestingly,it was also revealed with rat liver microsomes.Its formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450 (CYP450) inhibitor 1-aminobenzotriazole.Therefore,the direct conjugation pathway occurred without the prior CYP450-catalyzed bioactivation of the substrate.In turn,incubations of C-2028 and GSH with human recombinant glutathione S-transferase(GST) P1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form,respectively.These findings proved the necessary participation of GST in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate molecule.Another C-2028-GSH S-conjugate was also formed during non-enzymatic reaction.Both GSH S-conju-gates were characterized by combined liquid chromatography/tandem mass spectrometry.Mechanisms for their formation were proposed.The ability of C-2028 to GST-mediated and/or direct GSH conjugation is suspected to be clinically important.This may affect the patient's drug clearance due to GST activity,loss of GSH,or the interactions with GSH-conjugated drugs.Moreover,GST-mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.
ABSTRACT
@#Platinum antitumor drugs are widely used for clinical treatment because of their unique antitumor mechanisms, significant antitumor effects, and broad antitumor spectrum. Yet shortcomings such as toxic side effects, drug resistance and cross-resistance of platinum-based drugs have limited their further application. Platinum-intercalator conjugates possess different antitumor mechanisms from those of classic platinum drugs, and have unique advantages in overcoming the disadvantages of classic platinum antitumor drugs. The platinum-intercalator conjugates can be classified into six categories based on the different DNA-intercalator: platinum-acridine, platinum-quinoline, platinum-indole, platinum-naphthalimides, platinum-anthraquinone and platinum-based antitumor agents containing other types of intercalating groups. This article summarizes the research progress of platinum-based antitumor drugs containing DNA insertion groups in recent years.
ABSTRACT
BACKGROUND: In a previous study, we have shown that quinolones, antibiotics inhibiting topoisomerases, improve survival of tumor cells under hypoxic conditions. In this study, we tested whether antitumor agents such as doxorubicin that inhibit topoisomerases can also improve survival of tumor cells under hypoxic conditions. METHODS: Human hepatocellular carcinoma cells (HepG2) were grown in 4 mL of the culture medium at 2.5x10(5) cells/60 mm culture dish under normoxic conditions for 2 days before being transferred to fresh culture medium with different concentrations of doxorubicin or other antitumor agents under normoxic or hypoxic (1% oxygen concentration in air) conditions. Cell viability and the concentration of glucose and lactic acid in the medium were measured during cell culture. At the same time, the cells in the 60 mm dishes were lysed, and chromosomal DNA was isolated and loaded onto a 1.5% agarose gel for the DNA fragmentation assay. RESULTS: Doxorubicin inhibited cell growth under normoxic condition in a concentration-dependent manner for the 0~100 microgram/mL concentration range. However, doxorubicin improved cell viability under hypoxic conditions for a 0.1~10 microgram/mL concentration range by inhibiting apoptosis. Similar phenomena were observed for other antitumor agents that inhibit topoisomerases. CONCLUSIONS: Solid tumors usually have hypoxic regions in the tumor, under which conditions antitumor agents that inhibit topoisomerases may function to delay tumor cell death. This can reduce the efficacy of the antitumor agents.
Subject(s)
Humans , Hypoxia , Anti-Bacterial Agents , Antineoplastic Agents , Apoptosis , Carcinoma, Hepatocellular , Cell Culture Techniques , Cell Death , Cell Survival , DNA , DNA Fragmentation , Doxorubicin , Glucose , Lactic Acid , Oxygen , Quinolones , SepharoseABSTRACT
Mycoepoxydiene is a novel antitumor agent extracted from marine lignicolous fungi HLY-2, which is Diaporthe phaseolorum by molecule identification. The medium optimization for mycoepoxydiene by orthogonal design and the comparison of submerged fermentation and solid state fermentation were studied. The rusult is that the maximal yield of the compound is 543mg/L, which is 43 times compared to the customary half-seawater PD medium and 15 times to the best submerged condition. This optimum culture medium included potato 250g/L, seawater 300mL/L, glucose 30g/L, lactose 50g/L, KH_ 2 PO_ 4 0.65mmol/L and (NH_ 4 )_ 2 SO_ 4 1g/L in the solid state condition. Differentiation analysis between submerged and solid state fermentation, and antitumor activity of these ferment products were also studied. The antitumor activity of products of the optimum medium approached the pure compound.
ABSTRACT
Probimane was first synthesized and developed in Shanghai Institute of Materia Medica, Chinese Academy of Science as a novel antit umor agent. Male mice were injected iv 〔14C〕 probimane 3.7?105Bq/20g( 5.62? 107Bq/g ) . At 0.5h,higher radioactivities were found in S87 tumor, kidney, bladder, and vertebra, moderate in skim, lung, liver, blood vessel and gut. The radioactivities tended to decre-aseafter 3h except in the tumor, kidney, and gut in which radioactivities persisted. After 12h, only a trace of radioactivity was detected n intestine. The distribution of probimane correlated with its therepeutic efficacy and toxicity.
ABSTRACT
Following the realization that involved in all of the key process within the cell nucleus such as DNA replication,transcription,reorganization,repair,human DNA topoisomerase Ⅰ(Topo Ⅰ) is a useful therapeutic target against tumor growth.Topo Ⅰ inhibitors represent a class of effective agents that have been extensively exploited and used for carcinomachemotherapy.Current Topo Ⅰ inhibitors being clinically used or developed are classified as campotothecins and non-camptothecins.This presentation introduces current status and trends of Topo Ⅰ inhibitors as anti-tumor agents with an emphasis on bioactive and pharmacological properties of these agents.