Royal jelly (RJ) is widely used as a food supplement for anti-aging and beauty. However, its use has been linked to asthma and hemorrhagic colitis. Since its mechanisms of toxicity have not been fully identified, we conducted an investigation to elucidate its molecular and cytogenetic effects. Using human lymphocytes in vitro, treatments with RJ (0.0005-5 mg/ml) for 3 h did not induce sister chromatid exchanges until 5 mg/ml was used. Treatments for 24 h showed a dose-dependent reduction in BCL2/BAX, c-MYC/BAX and HO-1/BAX ratios. The exception was the NRF2/BAX ratio, showing a dose-dependent reduction at low doses, but a marked increase at the highest dose. The hTERT/BAX ratio was maintained at approximately a 1.2-fold increase but decreased to nearly normal at the highest dose. Our findings indicated that the lowest dose of RJ treatment provided maximum benefits, mainly through hTERT activation relating to prolonged lifespan. The highest dose of RJ inhibited cell survival, cell proliferation and an antioxidative enzyme; nevertheless, it still activated an antioxidative response through NRF2 and maintained telomeres during cell crisis. RJ treatment at 0.05 mg/ml increased cyclin E, BCL2 and BAX to maximum levels indicating that throughout the active cell cycle, both cell survival and cell apoptosis increased. Using the gene expression ratios over BAX, similar to BCL2/BAX, provided more informative data than using individual protein levels alone. With these informative ratios, our results confirm the potential benefits of RJ in enhancing lifespan and activation antioxidative power. Further, in vivo mechanistic studies will be useful in validating these results.

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Genoprotective effects of royal jelly (RJ) treatments against doxorubicin (DXR), a potent genotoxic chemotherapeutic compound in human lymphocytes were investigated using the sister chromatid exchange (SCE) assay, and their molecular mechanisms were examined by Western blot. Results showed that RJ pretreatments at 0.005 and 0.05 mg/mL significantly decreased DXR-induced SCE levels by 1.2-fold (p<0.05), compared to DXR treatment alone. Co-treatment of RJ (5 mg/mL) with DXR (0.2 µg/mL) increased the ratios of BCL2/BAX (1.5-fold), NRF2/BAX (1.3-fold), and hTERT/BAX (1.1-fold) compared to the DXR alone, suggesting its power in enhancing cell survival, antioxidative potentials, and longevity over cell death. The study suggested that RJ protected human cells from DXR-induced genotoxicity, possibly mediated through anti-apoptotic, anti-oxidative, and anti-aging properties of RJ. However, lower doses of RJ co-treatments enhanced DXR toxicity. Further, in vivo molecular study is required to validate this in vitro study.

Exploration of effective chemotherapy is needed for cancer treatment. 10-hydroxy-2-decenoic acid (10-H2DA), a unique fatty acid from royal jelly (RJ), is reported to have antitumor activities. However, its mechanisms remain under-examined. This study investigated the antiproliferative and cytotoxic efficacy of 10-H2DA treatments and their underlying mechanisms, compared to doxorubicin (DXR), on MCF-7 breast cancer cells.  The antiproliferative effect was determined using the MTS tetrazolium assay.  Cytotoxic activity was performed using a modified MTS assay. Cell cycle progression and cell apoptosis were analyzed by flow cytometry. Pivotal protein expressions were detected by Western blot. Results revealed that 125 µg/mL 10-H2DA treatment significantly inhibited cancer cell growth by 65 %, better than 0.54 µg/mL DXR treatment (48 %), compared to the medium control (p<0.05).  The 50 % lethal concentration (LC50) values of 10-H2DA were 190 µg/mL, representing cytotoxic activity. The underlying antiproliferative and cytotoxic mechanisms of 125 µg/mL 10-H2DA treatment demonstrated that it extensively suppressed c-MYC/BAX and slightly activated p53/BAX, leading to G0/G1 cell cycle arrest (decreased cyclin D1 and CDK4) and cell apoptosis (decreased BCL2/BAX). It slightly limited lifespan extension (decreased hTERT/BAX). Nevertheless, it strongly activated HO-1/BAX and NRF2/BAX, possibly inducing chemoresistance and cell invasion later on. Our findings suggested that 10-H2DA treatments induced antiproliferative effects on MCF-7 breast cancer cells via suppression of c-MYC, CDK4, and cyclin D1, leading to cell cycle arrest and cell apoptosis. However, long-term treatment may increase chemoresistance and cell invasion due to induction of antioxidative power, NRF2/BAX, and HO-1/BAX. Therefore, aggressive treatment for a short period would be recommended for using 10-H2DA as a chemotherapeutic compound to prevent chemoresistance and cell invasion.  Further long-term in vitro and in vivo studies are necessary to confirm its strength and weakness. HIGHLIGHTS 10-hydroxy-2-decenoic acid (10-H2DA), a marker royal jelly acid, effectively inhibited MCF-7 breast cancer cells proliferation and induced cytotoxicity The inhibitory mechanisms involved the high suppression of c-MYC, cyclin D1, and CDK4, which induced cell cycle arrest and cell apoptosis 10-H2DA treatment at proper dose induced high antioxidative potency via activation of NRF2/BAX and HO-1/BAX Limitation of 10-H2DA treatment is that it might induce chemoresistance GRAPHICAL ABSTRACT

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