Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Biochem Biophys Res Commun ; 414(1): 123-8, 2011 Oct 14.
Article in English | MEDLINE | ID: mdl-21945437

ABSTRACT

NKX3.1 is an androgen-regulated homeobox gene that encodes a tissue-restricted transcription factor, which plays an important role in the differentiation of the prostate epithelium. Thus, the role of NKX3.1 as a functional topoisomerase I activity enhancer in cell cycle regulation and the DNA damage response (DDR) was explored in prostate cancer cell lines. As an early response to DNA damage following CPT-11 treatment, we found that there was an increase in the γH2AX(S139) foci number and that total phosphorylation levels were reduced in PC-3 cells following ectopic NKX3.1 expression as well as in LNCaP cells following androgen administration. Furthermore, upon drug treatment, the increase in ATM(S1981) phosphorylation was reduced in the presence of NKX3.1 expression, whereas DNA-PKcs expression was increased. Additionally, phosphorylation of CHK2(T68) and NBS1(S343) was abrogated by ectopic NKX3.1 expression, compared with the increasing levels in control PC-3 cells in a time-course experiment. Finally, NKX3.1 expression maintained a high cyclin D1 expression level regardless of drug treatment, while total γH2AX(S139) phosphorylation remained depleted in PC-3, as well as in LNCaP, cells. Thus, we suggest that androgen regulated NKX3.1 maintains an active DDR at the intra S progression and contributes to the chemotherapeutic resistance of prostate cancer cells to DNA damaging compounds.


Subject(s)
DNA Damage , Homeodomain Proteins/physiology , Prostatic Neoplasms/pathology , S Phase , Transcription Factors/physiology , Androgens/pharmacology , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Cell Line, Tumor , Histones/pharmacology , Homeodomain Proteins/genetics , Humans , Irinotecan , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Transcription Factors/genetics
2.
Biochem Biophys Res Commun ; 409(4): 738-44, 2011 Jun 17.
Article in English | MEDLINE | ID: mdl-21624350

ABSTRACT

Endemic Alkanna cappadocica was used to isolate novel antitumor molecules from Turkish landscapes in our previous studies. In this study, deoxyalkannin (ALCAP1), ß,ß-dimethylacrylalkannin (ALCAP2), acetylalkannin (ALCAP3), and alkannin (ALCAP4) as well as the novel isolated compounds 5-methoxydeoxyalkannin (ALCAP5), 8-methoxydeoxyalkannin (ALCAP6), 5-methoxyacetylalkannin (ALCAP7), 5-methoxy-ß,ß-dimethylacrylalkannin (ALCAP8) were characterized. The topoisomerase I (topo I) inhibitory activity of ALCAPs was investigated using in vitro plasmid relaxation assay and found that ALCAP2, 3, 4 and 7 were potent inhibitors at 2-6µM concentrations. Further, DNA damage response to ALCAP treatments was also studied by measuring the H2AX((S139)) and ATM((S1981)) phosphorylations. ALCAP2, 7 and 8 induced the DNA damage and apoptosis, consistently resulted in PARP cleavage at nanomolar concentrations in K562 leukemia cells. Moreover, when the free radical (ROS) generating capacity of the compounds was studied by 2',7'-dichlorofluorescein-diacetate assay using flow cytometry, we found that a known antioxidant N-acetyl-cysteine almost completely abrogated the H2AX((S139)) phosphorylations and the caspase 3 cleavage and activation. Thus, γH2AX((S139)) foci formation remained higher than the control, and an increase in CHK2((T68)) phosphorylation was observed by ALCAP2 and 7 treatments suggested that, these compounds can be potential therapeutics against tumor cell growth because of their unique DNA damaging abilities additional to enzyme inhibition similar to those of doxorubicin.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis , Boraginaceae/chemistry , Mitochondria/drug effects , Naphthoquinones/pharmacology , Topoisomerase I Inhibitors/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Damage , DNA Topoisomerases, Type I/metabolism , Histones/metabolism , Humans , Naphthoquinones/chemistry , Naphthoquinones/isolation & purification , Reactive Oxygen Species/metabolism , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/isolation & purification
SELECTION OF CITATIONS
SEARCH DETAIL
...