Mechanisms Underlying the Inhibition of Tyrosine Kinase Inhibitor-Induced Anorexia and Fatigue by Royal Jelly in Renal Cell Carcinoma Patients and the Correlation between Macrophage Colony Stimulating Factor and Inflammatory Mediators

Abstract

Inflammation is a common adverse event of anti-cancer therapy. Royal jelly (RJ) modulates inflammation by regulating the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and interleukin (IL)-6 produced by macrophages. Macrophage colony stimulating factor (M-CSF) is a crucial regulator of macrophage activities, and we hypothesized that RJ alters M-CSF levels. In this randomized controlled trial, we investigated the association between M-CSF and adverse events in renal cell carcinoma patients treated with tyrosine kinase inhibitors (TKIs) after an oral intake of RJ (n = 16) or placebo (n = 17). The serum levels of M-CSF, TNF-α, TGF-β, and IL-6 were measured by an enzyme-linked immunosorbent assay, and their temporal changes and correlation between such changes were analyzed. The post-/pretreatment ratio of M-CSF levels was associated with anorexia after 2 weeks and fatigue after 2, 4, and 12 weeks. The M-CSF level in the RJ group was higher than that in the placebo group at the same timepoints. The TNF-α level in the RJ group was lower than that in the placebo group between 6 and 12 weeks, and the TGF-β level in the RJ group was higher than that in the placebo group; however, contrasting findings were detected after 12 weeks. Additionally, the M-CSF level was significantly correlated with the TGF-β level after 4 weeks and IL-6 level after 8 and 10 weeks. Among TNF-α, TGF-β, and IL-6, the post-/pretreatment ratio of TGF-β after 12 weeks was associated with TKI-induced anorexia, and the ratios after 10 and 12 weeks were associated with fatigue. Our results demonstrated that an oral intake of RJ suppressed anorexia and fatigue via complex mechanisms associated with inflammation-related factors, such as M-CSF and TGF-β in renal cell carcinoma patients treated with TKIs. In addition, we newly found that such RJ-related effects were dependent on the treatment duration.

Testosterone for Managing Treatment-related Fatigue in Patients With Metastatic Renal Cell Carcinoma

“…6,7 Finally, fatigue could be developed through complex mechanisms associated with inflammation-related factors, such as macrophage colony-stimulating factor and transforming growth factor-β in RCC patients. 8 Testosterone undecanoate is a testosterone ester with anabolic steroid activity, which is used mainly in androgen replacement therapy. We hypothesized that the anabolic effects of testosterone might contribute to fatigue that develops in RCC patients.…”

The Incidence and Management of Cancer-Related Anorexia During Treatment with Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors

“… 116 Royal jelly affects the regulation of cytokines such as TNF-α and TGF-β; 117 , 118 and it has recently been considered for its potential to prevent TKI-induced anorexia. 116 , 118 Patients with RCC who received pre-treatment with royal jelly before TKIs had a reduction in TNF-α levels and an increase in TGF-β and macrophage colony-stimulating factor levels; however, the effect was transient and did not last beyond 12 weeks. 116 In another study, patients with RCC who received royal jelly had significantly lower rates of TKI-induced anorexia compared with those receiving placebo, 118 and fewer patients who received royal jelly required TKI dose reductions.…”

“… 116 , 118 Patients with RCC who received pre-treatment with royal jelly before TKIs had a reduction in TNF-α levels and an increase in TGF-β and macrophage colony-stimulating factor levels; however, the effect was transient and did not last beyond 12 weeks. 116 In another study, patients with RCC who received royal jelly had significantly lower rates of TKI-induced anorexia compared with those receiving placebo, 118 and fewer patients who received royal jelly required TKI dose reductions. Considering these findings, royal jelly is a promising candidate for its potential in preventing anorexia in patients with cancer.…”

“…Royal jelly, a substance collected from honeybees, has been investigated for interactions with chemotherapeutic agents and potential anti-inflammatory effects, [113][114][115] and a previous study examining royal jelly revealed insights into the mechanism of TKI-induced anorexia. 116 Royal jelly affects the regulation of cytokines such as TNF-α and TGF-β; 117,118 considered for its potential to prevent TKI-induced anorexia. 116,118 Patients with RCC who received pre-treatment with royal jelly before TKIs had a reduction in TNF-α levels and an increase in TGF-β and macrophage colony-stimulating factor levels; however, the effect was transient and did not last beyond 12 weeks.…”