Abstract
Antrodan, a unique protein-bound polysaccharide derived from the fungal mycelia of Antrodia cinnamomea, has been reported to exhibit antitumor and anti-metastatic effects on Lewis lung carcinoma (LLC) cells through direct action and immunomodulation in vitro. In this study, we investigated the combined treatment of antrodan with an anti-cancer drug—cisplatin—and its underlying molecular mechanisms of action in a mouse xenograft tumor model. C57BL/6 mice were implanted (s.c.) with LLCs for nine days, before administration with only antrodan (20 mg/kg and 40 mg/kg; p.o.) daily, only cisplatin (1 mg/kg; i.p.) twice per week, or a combination of both for an additional 28 days. As expected, antrodan on its own significantly inhibited metastasis of lung and liver tissues, while treatment with cisplatin only merely inhibited metastasis of the liver. Antrodan exhibited efficient adjuvant therapy in combination with cisplatin, by inhibiting the activities of the plasma urokinase plasminogen activator (uPA) and the liver matrix metalloproteinase 9 (MMP-9), as well as by inhibiting the phosphorylation of p38 and extracellular signal-regulated kinase 2 (ERK2) in lung and liver tissues. In addition, antrodan effectively ameliorated cisplatin-induced kidney dysfunction when treated combinatorially, as evidenced by a decrease in cisplatin-induced blood urea nitrogen (BUN) levels in plasma and in the level of p38 phosphorylation in the kidney. Mechanistically, the actions of antrodan on its own involved (i) reducing the activities of uPA and MMP-2 and -9 in plasma; (ii) reducing protein expression of MMP-2/9, and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 in lung and liver tissues; and (iii) enhancing immune system functions resulting in the promotion of an anti-metastatic response through immunomodulation, by increasing interferon-γ (IFN-γ) levels and decreasing interleukin-6 (IL-6) levels in plasma. These results demonstrated that antrodan provides a novel, complementary therapeutic strategy against cancer metastasis, by attenuating the activities of MMP-2 and -9 through the modulation of STAT3/MAPK/ERK/JNK signaling pathways, and of the host’s immune system.
Highlights
Metastatic cancers are one of the leading causes of death
As the signal transducer and activator of transcription 3 (STAT3) pathway is mainly responsible for the regulation of cell proliferation, invasion, and angiogenesis, many reports have shown that its sustained activation promotes the metastasis of many cancers, including thymic tumors, colorectal cancers, and squamous cell carcinomas of the skin
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Summary
Metastatic cancers are one of the leading causes of death. Statistical data indicate that tumor metastasis is responsible for approximately 90% of all cancer-related deaths [1]. Matrix metalloproteinases (MMPs) degrade the extracellular matrix, and secrete the vascular endothelial growth factor (VEGF) responsible for providing nutrients to cancer cells, and for inducing vascular proliferation. These tumor cells may undergo migration and invasion, traveling through the blood or lymphatic vessels, eventually leaving the blood or lymphatic vessels, before adhering to and growing at a distal site [2,3]. As the STAT3 pathway is mainly responsible for the regulation of cell proliferation, invasion, and angiogenesis, many reports have shown that its sustained activation promotes the metastasis of many cancers, including thymic tumors, colorectal cancers, and squamous cell carcinomas of the skin. The oncogenic functions of JNKs are mostly based on their ability to phosphorylate Jun, and to activate AP1, promoting cancer cell growth [14]
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