Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss

Abstract

Raghu Nadhanan R, Abimosleh SM, Su YW, Scherer MA, Howarth GS, Xian CJ. Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss. Am J Physiol Endocrinol Metab 302: E1440 -E1449, 2012. First published March 20, 2012; doi:10.1152/ajpendo.00587.2011Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day Ϫ1 ·rat Ϫ1 ) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H2O ϩ Sal, H2O ϩ 5-FU, EO ϩ 5-FU, and EO ϩ Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H2O ϩ 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNF␣, osteoclast marker receptor activator of nuclear factor-B, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss.receptor activator of nuclear factor-B ligand; tumor necrosis factor-␣; anti-inflammatory ANTI-CANCER CHEMOTHERAPY can cause significant adverse effects on tissues, including the bone, in both pediatric and adult cancer patients (25). Short stature, low bone mass or osteoporosis, and/or fractures are some skeletal side effects that are due to chemotherapy among pediatric patients and adult survivors (32, 38, 46). Experimental studies in rats have also shown that drugs such as methotrexate (MTX), cisplatin, doxorubicin, etoposide, cyclophosphamide, and 5-fluorouracil (5-FU) can cause a reduction in bone growth and bone mass (50 -52). 5-FU is an antimetabolite drug commonly used to treat adult patients suffering from colorectal and breast cancer, whereas in children 5-FU is used to treat childhood solid tumours (27, 36). 5-FU inhibits thymidylate synthase, an enzyme required to synthesize thymine nucleotide, which is important for synthesis of DNA and RNA (27). In an acute 5-FU chemotherapy model in rats, reduced primary spongiosa heigh...

Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats

“…Consistent with our histological findings, ex vivo osteoclast formation potential from the bone marrow cells of CEF-treated rats was significantly increased when compared to marrow cells of control rats. In support of our findings, the increased osteoclast formation potential and their density on trabecular bone surfaces, as well as a reduction in bone volume, have been reported previously in other chemotherapy models [11,12,20]. Moreover, the current study revealed a significant increase in the size of osteoclasts formed ex vivo from bone marrow cells of CEF-treated rats.…”

“…While some previous studies have described CEFrelated adverse effects being mainly related to haematological and cardiac toxicity [27][28][29], no studies to date have reported the potential adverse effects of CEF treatment on bone health, although potential direct and indirect bone effects of these drugs individually have been reported previously. For example, a single high-dose injection of 5-FU in young rats was shown to induce severe trabecular bone loss due to enhanced resorption [12]. 5-FU was also shown to cause significant suppression of haematopoietic cell proliferation and impairment of marrow recovery after irradiation [30].…”

“…Clinically, patients receiving chemotherapy and irradiation treatment have also been reported to have an increased marrow fat content [9]. Moreover, enhanced adipogenic differentiation potential of marrow cells by doxorubicin, methotrexate and 5-fluorouracil (5-FU) has been reported in cell culture or animal studies involving usage of these drugs individually [10][11][12], suggesting components of CAF and CMF for adjuvant breast cancer chemotherapy may be associated with increased marrow adiposity. Despite the treatment advances in combating breast cancer in recent years, it remains unclear whether the current preferred CEF regimen is associated with bone and bone marrow toxicities as with CAF or CMF.…”

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

“…Emerging evidence has indicated the involvement of oxidative stress in the pathogenesis of 5-FU-induced renal injury via excessive release of free radicals and ROS [1, 3]. The current findings revealed that 5-FU instigated lipid peroxidation and associated damage to the cellular membranes in addition to depletion of cellular GSH, SOD, GPx and TAC antioxidants; findings that coincide with previous reports [1, 42, 43].…”

“…Evidence has indicated that oxidative stress plays a central role in mediating the 5-FU-induced renal injury [1, 3]. The generation of reactive oxygen species (ROS) incurs membrane lipid peroxidation and oxidative cellular damage.…”