Abstract
BackgroundThe use of nutraceuticals is gaining in popularity in human and canine oncology with a relatively limited understanding of the effects in the vastly different tumor types seen in canine oncology. We have previously shown that turmeric root (TE) and rosemary leaf (RE) extracts can work synergistically to reduce neoplastic cell growth, but the mechanisms are poorly understood and require further elucidation.ResultsThree different canine cell lines (C2 mastocytoma, and CMT-12 mammary carcinoma, D17 osteosarcoma) were treated with 6.3 μg mL−1 extract individually, or 3.1 μg mL−1 of each extract in combination based on studies showing synergy of these two extracts. Apoptosis, antioxidant effects, cellular accumulation of curcumin, and perturbation of signaling pathways were assessed. The TE + RE combination treatment resulted in Caspase 3/7 activation and apoptosis in all cell lines, beyond the effects of TE alone with the CMT-12 cell line being most susceptible. Both extracts had antioxidant effects with RE reducing reactive oxygen species (ROS) by 40–50% and TE reducing ROS by 80–90%. In addition RE treatment enhanced the c-jun N-terminal kinase (JNK) activity in the C2 cell line and TE + RE exposure increased activated JNK by 4–5 times in the CMT-12 cell line. Upon further examination, it was found that RE treatment caused a significant increase in the cellular accumulation of curcumin by approximately 30% in the C2 and D17 cell lines, and by 4.8-fold in the CMT-12 cell line. This increase in intracellular curcumin levels may play a role in the synergy exhibited when using TE and RE in combination.ConclusionsThe use of RE in combination with TE induces a synergistic response to induce apoptosis which is better than either extract alone. This appears to be related to a variable increased TE uptake in cells and activation of pathways involved in the apoptotic response.
Highlights
The use of nutraceuticals is gaining in popularity in human and canine oncology with a relatively limited understanding of the effects in the vastly different tumor types seen in canine oncology
Cell cycle dynamics were analyzed after 24 h and 48 h of incubation with the different treatments; no significant difference was seen between these two time-points only data from the 48 h time point is shown (Fig. 1A-B)
Single treatment with 6.3 μg mL−1 turmeric root (TE) resulted in a significant decrease in S phase (DNA replication) in the D17 cell line compared to dimethyl sulfoxide (DMSO) control
Summary
The use of nutraceuticals is gaining in popularity in human and canine oncology with a relatively limited understanding of the effects in the vastly different tumor types seen in canine oncology. The compound of interest in RE, can target a variety of signaling pathways, many of which overlap with those targeted by curcumin The effects of these two compounds in combination have been examined in acute myeloid leukemia cells and breast cancer cells [17, 18], showing synergy in antiproliferative effects and increased pro-apoptotic signaling. The safety of these commonly used feed ingredients and continual synergy between the extracts make them candidates for inclusion in the diet as a potential adjuvant treatment for dogs diagnosed with neoplasia, if appropriate serum concentrations can be achieved
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