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At least 433 records · Page 24Linked to original sources
PubMed2003

Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1.

The DNA repair enzymes, DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase-1 (PARP-1), are key determinants of radio- and chemo-resistance. We have developed and evaluated novel specific inhibitors of DNA-PK (NU7026) and PARP-1 (AG14361) for use in anticancer therapy. PARP-1- and DNA-PK-deficient cell lines were 4-fold more sensitive to ionizing radiation (IR) alone, and showed reduced potentially lethal damage recovery (PLDR) in G(0) cells, compared with their proficient counterparts. NU7026 (10 micro M) potentiated IR cytotoxicity [potentiation factor at 90% cell kill (PF(90)) = 1.51 +/- 0.04] in exponentially growing DNA-PK proficient but not deficient cells. Similarly, AG14361 (0.4 micro M) potentiated IR in PARP-1(+/+) (PF(90) = 1.37 +/- 0.03) but not PARP-1(-/-) cells. When NU7026 and AG14361 were used in combination, their potentiating effects were additive (e.g., PF(90) = 2.81 +/- 0.19 in PARP-1(+/+) cells). Both inhibitors alone reduced PLDR approximately 3-fold in the proficient cell lines. Furthermore, the inhibitor combination completely abolished PLDR. IR-induced DNA double strand break (DNA DSB) repair was inhibited by both NU7026 and AG14361, and use of the inhibitor combination prevented 90% of DNA DSB rejoining, even 24-h postirradiation. Thus, there was a correlation between the ability of the inhibitors to prevent IR-induced DNA DSB repair and their ability to potentiate cytotoxicity. Thus, individually, or in combination, the DNA-PK and PARP-1 inhibitors act as potent radiosensitizers and show potential as tools for anticancer therapeutic intervention.

Azulenes↗
PubMedDate not supplied

Inhibition of LPS-stimulated NO production in mouse macrophage-like cells by azulenequinones.

Azulenequinone derivatives have been reported to display a broad spectrum of biological activities, but study at the cellular level has been limited. The effect of twenty-seven azulenequinone derivatives on nitric oxide (NO) production by mouse macrophage-like cells Raw 264.7 was investigated in this study. All of these compounds failed to stimulate the Raw 264.7 cells to produce detectable amounts of NO, but did inhibit NO production by lipopolysaccharide (LPS)-activated Raw 264. 7 cells to varying extents. Compounds [7, 8, 9, 13, 16, 25, 27], which showed lesser cytotoxic activity (CC50 = 425, 381, 482, 179, 119, 235, 225 microM, respectively), inhibited NO production to the greatest extent [selectivity index (SI) = 15.4, 26.2, 3.9, 21.6, 3.1, 6.0, 8.4, respectively]. Western blot and RT-PCR analyses demonstrated that the most active derivatives, 3-morpholino-1, 5-azulenequinone [8] and 3,7-dibromo-1, 5-azulenequinone [13], significantly reduced both the intracellular concentration of iNOS protein and the expression of iNOS mRNA. ESR spectroscopy showed that compounds [8, 13] weakly scavenged NO produced by NOC-7, possibly via their general reducing activity. These data suggest that the inhibitory effect of NO production by compounds [8, 13] might be generated mostly via the inhibition of iNOS expression, rather than the radical-mediated mechanism.

Animals↗
PubMedDate not supplied

Apoptosis-inducing activity of trihaloacetylazulenes against human oral tumor cell lines.

Twenty-six trihaloacetylazulene derivatives were investigated for their tumor-specific cytotoxicity and apoptosis-inducing activity against three human normal cells (HGF, HPC, HPLF) and four human tumor cell lines (HSC-2, HSC-3, HSC-4, HL-60). The trichloroacetylazulenes [1b-13b] generally showed higher cytotoxicity as compared to the corresponding trifluoroacetylazulenes [1a-13a]. The trichloroacetylazulenes [1b-13b] also showed higher tumor-specific cytotoxicity (expressed as TS value) than the corresponding trifluoroacetylazulenes [1a-13a]. Especially, 2,3-dimethyl-1-trichloroacetylazulene [5b] and 1,3-ditrichloroacetyl-4,6,8-trimethylazulene [11b] showed the highest cytotoxicity and tumor specificity (TS > 35.6 and > 44.1, respectively). These compounds induced internucleosomal DNA fragmentation in HL-60 cells, but not in HSC-2 and HSC-3 cells, but activated caspase-3, -8 and -9 in all of these cells, suggesting the activation of both mitochondria-independent (extrinsic) and dependent (intrinsic) pathways. Western blot analysis showed that two compounds [5b, 11b] slightly increased the intracellular concentration of pro-apoptotic proteins (Bad, Bax) in HSC-2 cells. None of the 26 compounds showed anti-HIV activity. These results suggest [5b] and [11b] as possible candidates for future cancer chemotherapy.

Apoptosis↗
PubMedDate not supplied

Inhibition of NO production in LPS-stimulated mouse macrophage-like cells by trihaloacetylazulenes.

The effects of 26 trihaloacetylazulene derivatives on nitric oxide (NO) production by the mouse macrophage-like Raw 264.7 cells was investigated. The trichloroacetylazulenes [1b-13b] generally showed higher cytotoxicity as compared with the corresponding trifluoroacetylazulenes [1a-13a]. All the compounds inhibited NO production by lipopolysaccharide (LPS)-activated Raw 264.7 cells to various extents. 3-Trifluoroacetylguaiazulene [8a], 1-trifluoroacetyl-4,6,8-trimethylazulene [10a], 3-methyl-l-trichloroacetylazulene [2b] and 3-ethyl-1-trichloroacetylazulene [3b] showed lower cytotoxic activity and most effectively inhibited NO production. Western blot analysis revealed that compounds [8a, 1Oal dose-dependently reduced the intracellular concentration of inducible NO synthase (iNOS), whereas compounds [2b, 3b] only marginally affected the iNOS protein expression. RT-PCR analysis showed that compounds [8a, 2b] reduced the iNOS mRNA expression by approximately 50%. These compounds affected cyclooxygenase-2 protein and mRNA expression, depending on the concentrations. ESR spectroscopy revealed that compounds [8a, 10a, 2b, 3b] neither produced radical, nor scavenged NO, superoxide anion or diphenyl-2-picrylhydrazyl radicals. The present study showed the inhibitory effects of trifluoroacetylazulenes and trichloroacetylazulenes on NO production by activated macrophages.

Animals↗
PubMed1991

[The structure and absolute configuration of isorupestonic acid from Artemisia rupestris L].

A new sesquiterpene compound named isorupestonic acid was isolated from Artemisia rupestris and its absolute stereostructure was elucidated as 3B by spectral and X-ray crystallographic methods. Interestingly, the isorupestonic acid is based upon an unusual 6, 7 membered ring skeleton differing from the 5, 7 membered ring rupestonic acid although both have the same absolute configuration at C-1. The biogenesis of isorupestonic acid most likely involves breaking the C4-C5 bond of rupestonic skeleton and forming the C5-C14 bond. The absolute configuration of rupestonic acid was also determined as 4C by X-ray analysis and CD data.

Azulenes↗
PubMed1989

[Studies on the chemical constituents of Curcuma kwangsiensis].

A new sesquiterpene lactone named gweicurculactone, along with beta-sitosterol, germacrone, daucosterin and palmitic acid, was isolated from Curcuma kwangsiensis. Its structure has been confirmed by means of spectral and X-ray diffraction analysis.

Azulenes↗
PubMed1989

[The effect of mouthwash on oral malodour production].

Volatile sulphur compounds (VSC), hydrogen sulphide, methyl mercaptan and dimethyl sulphide are by-products derived in oral cavity through putrefactive activity of microorganisms. VSC are the principal cause of physiological oral malodour. There are indications that these compounds are cytotoxic to oral tissues. Hence, it has been considered that the prevention of oral malodour has an important role in preventive dentistry. The objective of this study is to ascertain the effect of two mouthwashes, sodium azulenesulphonic acid and povidone-iodine, which are frequently used in dental clinics, on concentration of VSC in mouth air. The VSC were analyzed using VSC analysis system. VSC were determined at immediately after rince and at one, two and three hours after rince. The results indicated that neither mouthwash was very effective in controlling VSC production. No reduction in VSC was observed at one and two hour post-rinsing with sodium azulenesulphonic acid mouthwash, and only 39% reduction of total sulphur of VSC was observed at one hour following the use of the povidone-iodine containing products. However, this effect was lost within two hours post-rinsing.

Azulenes↗