Abstract
Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.
Highlights
Bleomycin (BLM), a glycopetide originally isolated from Streptomyces verticillus [1], is a clinical anti-cancer drug primarily used for the treatment of hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC)
The expression of miR-29b levels was dramatically enhanced when CISCFE was coupled with BLM. These results indicated that CISCFE combined with BLM affected the miR-29b expression, and regulated the balance between p53 and TGF-β1 signaling pathways in hepatoma 22 (H22) tumor-bearing mice
Mouse tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) the enzyme-linked immunosorbent assay (ELISA) reagents were purchased from eBioscience (San Diego, CA, USA); Myeloperoxidase (MPO) and malondiadehyde (MDA) Colorimetric Activity Assay Kits were obtained from Jiancheng Institution of Biotechnology (Nanjing, China)
Summary
Bleomycin (BLM), a glycopetide originally isolated from Streptomyces verticillus [1], is a clinical anti-cancer drug primarily used for the treatment of hepatocellular carcinoma (HCC) and nasopharyngeal carcinoma (NPC). Pulmonary fibrosis is a severe form of lung toxicity, which was induced by BLM [2]. The development of a drug that confers lung protection during BLM treatment and improves the chemotherapeutic efficacy of BLM in cancer is essential. Sun et al reported that p53 was essential for doxorubicin-induced apoptosis via the TGF-β signaling pathway in osteosarcoma-derived cells [9]. Substances with an effect on the regulation of p53 and TGF-β signaling pathways may be beneficial for improving the chemotherapeutic efficacy of BLM or alleviating the pulmonary toxicity induced by BLM. We used the classical H22 ascites tumor-bearing mice model [20,21] to explore the potential synergistic effect of CISCFE combined with BLM and investigate the underlying mechanism in the treatment of cancer
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