Dimethylaminoparthenolide reduces the incidence of dysplasia and ameliorates a wasting syndrome in HPV16-transgenic mice

Abstract

The nuclear factor kappa light chain enhancer of activated B cells (NF-kappa B) has been implicated in the progression of cancers induced by high-risk human papillomaviruses (HPV). In cancer patients, NF-kappa B is also thought to drive a chronic systemic inflammatory status, leading to cachexia. This study addressed the ability of dimethylaminoparthenolide (DMAPT), a water-soluble NF-kappa B inhibitor, to block the development of HPV-induced lesions and wasting syndrome in HPV16-transgenic mice. Mice received DMAPT orally (100 mg/kg/day), once a day, for 6 consecutive weeks. Body weight was monitored weekly along with food and water intake. After 6 weeks the animals were submitted to a grip strength test and sacrificed for specimen collection. Skin samples were analyzed histologically and for expression of NF-kappa B-regulated genes Bcl2 and Bcl2l1. Gastrocnemius muscles were weighted and analyzed for expression of NF-kappa B subunits p50, p52, p65, and Rel-B. DMAPT reduced the incidence of epidermal dysplasia (18.2% versus 33.3% in HPV16(+/-) untreated mice). This was associated with reduced expression of Bcl2 and Bcl2l1 (p = .0003 and p = .0014, respectively) and reduced neutrophilic infiltration (p = .0339). Treated mice also showed partially preserved bodyweight and strength, which were independent of the expression levels of NF-kappa B subunits in skeletal muscle.These results suggest that NF-kappa B inhibition may be a valid strategy against HPV-induced lesions in vivo and warrant further preclinical tests particularly in the set of combination therapies. In addition, the data may support the use of DMAPT to prevent wasting syndrome.