Year: 2005
Type: conference-abstract
Abstract: OBJECTIVE: NF-KB is a transcription factor that induces various cytokines and adhesion proteins.It is also known that NF-KB activates anti-apoptotic proteins and prevents apoptosis induced by TNF-a and anticancer drugs.Therefore, inhibition of NF-KB function might be useful for cancer therapy.Recent in vitro studies have already proved such therapeutic effects of a novel NF-KB inhibitor, dehydroxymethyl derivative of epoxyquinomicin (DHMEQ), which acts at the level of nuclear translocation.The objective of this study is to evaluate an in vivo mechanism of inhibitory effect of DHMEQ on human bladder cancer, in which NF-KB is constitutively activated.METHODS: The human bladder cancer cell line, KU19-19, derived from a patient with an invasive bladder cancer who demonstrated marked level of leukocytosis, produce multiple cytokines.KU19-19 (2XIOE6 cells) was implanted s.c. in the flank of 6-week old nude mice.Daily i.p. administration of 2 mg/kg DHMEQ was started from 7 days after tumor implantation.Animals were carefully monitored and tumor size was measured.Twenty-eight days after tumor transplantation, mice were sacrificed and all the tumors were collected.Microvessels in tumor specimens were counted after immunostaining with an anti-CD34 monoclonal antibody.Microvessel density (MVD) is expressed as the average of the five highest areas identified in the specimen in x200 field.Apoptosis was measured by TUNEL assay using Apoptosis in situ Detection Kit.The average number of positively stained cells was counted and apoptosis index was calculated.RESULTS: Two mg/kg DHMEQ treatment inhibited KU19-19 tumor growth.Average tumor volume at 28 days for the DHMEQ treatment was 3110:!:945 cmm versus 6019:!:2309 cmm of control mice (P<0.05).There was no evidence of drug-related toxicity in any of the animals.Staining with anti-CD34 antibody demonstrated a statistically significant decrease in MVD in DHMEQ-treated tumors.Blood vessels in the tumors derived from control mice showed welldeveloped vascular networks.In contrast, the vessels in the tumors of DHMEQtreated mice consisted of poorly developed networks.The apoptotic index was increased 2.3-fold in DHMEQ-treated tumors than control.CONCLUSIONS: Possible mechanisms underlying the observed suppressive effect of DHMEQ on bladder cancer are induction of cell apoptosis and inhibition of angiogenesis .Blockade of NF-KB function by DHMEQ could be a new molecular targeting anti-cancer therapy against highly aggressive bladder cancer.
Source: The Journal of Urology
Authors: Isla P. Garraway, Chau Tran, Katie Cai, Yu Yang, Massimo Loda, Robert E. Reiter
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2791377147