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‐κB) has been implicated in the progression of cancers induced by high‐risk human papillomaviruses (HPV). In cancer patients, NF‐κB 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‐κB 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‐κB‐regulated genes Bcl2 and Bcl2l1. Gastrocnemius muscles were weighted and analyzed for expression of NF‐κB 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‐κB subunits in skeletal muscle.These results suggest that NF‐κB 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.

Human Papillomavirus 16-Transgenic Mice as a Model to Study Cancer-Associated Cachexia

“…The authors also observed muscle wasting in the Apc Min/+ mice compared to controls [ 39 ]. The results from this study also agree with previous data from our group obtained from HPV16-transgenic female mice [ 14 , 25 ]. It would now be interesting to compare the wasting process in males and females using this mouse strain.…”

“…In fact, these mice present HPV16-induced lesions in different locations besides the uterine cervix, and advanced lesions were recently identified in characteristic head-and-neck sites [ 21 , 22 , 23 , 24 ]. Interestingly, the presence of a wasting syndrome in HPV + female mice has also been suggested by our group [ 14 , 25 ].…”

“…The lack of in-depth knowledge about cachexia’s pathophysiology remains a limiting factor for the diagnosis and treatment of this syndrome [ 8 , 33 , 34 , 35 ]. Animal models play an essential role in translational research and preclinical tests for novel therapies [ 14 , 25 , 36 ], and a number of them are available for studying cancer cachexia, predominantly tumor xenograft and syngeneic mouse models [ 37 , 38 ]. However, these types of models present significant limitations including their short time courses (2–25 days), often-extreme tumor burdens and excessive inflammatory status phenotypes [ 39 , 40 ].…”

“…The K14-HPV16 mice used in this study could also provide such a model of progressive development [ 17 , 18 ]. We recently described that these mice develop severe systemic inflammation coupled with reduced grip strength, which are important features of cachexia ( Figure 10 ) [ 14 , 25 ]. The present results help to further characterize this model, describing key molecular and morphological characteristics that help to validate it for the study of cancer cachexia.…”

Penicillium purpurogenumexerts antitumor effects and ameliorates inflammations in Erlich mice model

“…However, the specific characterisitcs of the MA52 strain which allow it to survive in this polluted environment have not yet been described. New drugs are being developed from secondary metabolites in search of less toxic and more effective compounds compared with traditional cancer therapies [13]. Also, some natural products become important nutraceutics with cancer chemopreventive properties [14,15].…”