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Cancer initiating cells (CICs) represent a subpopulation of cancer cells, which are responsible for tumor growth and resistance to chemotherapy. Herein, we first used a cell-based aldehyde dehydrogenase (ALDH) activity assay to identify that YMGKI-2 (also named as Ergone), an active component purified from Antrodia cinnamomea Mycelia extract (ACME)...
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... Moreover, the anticancer efects of AC extract include synergizing chemotherapeutic drugs to increase apoptosis and cell cycle arrest of cancer cells, thereby enhancing the sensitivity of chemotherapy [19,20,25,38,[42][43][44]. AC also enhances the chemotherapy sensitivity of 5-FU of colon cancer [22]. In addition, AC targets cancer-initiating cells by increasing cancer cell differentiation, thereby reducing cancer stemness and tumorigenesis by regulation of STAT3/Src signaling in neck squamous cell carcinoma cells and upregulation of miR-142-3p in colon cancer [22,45]. ...
... We frst found that cisplatin-induced mass loss of quadriceps femoris in mice was restored by EEAC (Figure 1(b)). Tis fnding was supported by an earlier study which indicated that AC extract has an anticachectic efect in lung tumor-bearing mice with chemotherapy [45]. In addition, our fndings indicated that C/G treatment increased levels of cleaved caspase-3 whereas EEAC attenuated this apoptotic efect in both LLC1 and C2C12 cells (Figure 4(a)). ...
Antrodia cinnamomea (AC), a potential medicinal fungus which possesses anti-inflammatory and anticancer activities, has been previously reported to be able to ameliorate muscle wasting in cisplatin-treated lung tumor-bearing mice via AC extract. However, whether AC extract modulates muscle cell differentiation, apoptosis, and cell cycle progression remains unclear. Here, we show that the ethanol extract of AC (EEAC) significantly restored cisplatin-reduced quadricep mass in mice. EEAC attenuated cisplatin/gemcitabine (C/G)-suppressed elongated myotube formation, which is differentiated from C2C12 cells. Moreover, EEAC synergized with C/G to inhibit cell growth of LLC1 cells, whereas EEAC attenuated C/G-reduced proliferation of C2C12 cells. Although EEAC protected C/G-induced apoptosis of both LLC1 and C2C12, EEAC suppressed cyclin D expression in LLC1 while partially restoring C/G-reduced cyclin D level in C2C12 cells. Finally, as p 53 and p 21 participate in inducing skeletal muscle atrophy, we found that C/G induced p 53 and p 21 expression in C2C12 cells but with its effect significantly attenuated by EEAC. Our findings indicate that AC extract is a potential natural agent for attenuating cisplatin-induced muscle atrophy. Practical Applications. Muscle atrophy is one of the major side effects caused by chemotherapy. In addition to inducing cell death, chemotherapeutic agents inhibit cell growth of both cancer and normal cells as well. Our current findings indicated that AC extract attenuates cisplatin-induced muscle wasting and apoptosis of C2C12 cells. AC extract is a potential dietary supplement used for ameliorating chemotherapy-induced muscle atrophy.
... Recent studies have demonstrated that ACEs could inhibit TNF-α-induced migration/invasion in human endothelial cells. There is also evidence demonstrating that ACEs improve therapy efficacy in cancer patients [45,46]. However, the ROS role in cancer therapy is still controversial, and redox regulation in tumor cell epithelial-mesenchymal transition is still being discussed [47]. ...
Radiotherapy for treatment of hepatocellular carcinoma causes severe side effects, including acute hepatitis and chronic fibrosis. Complementary and alternative medicine (CAM) has emerged as an important part of integrative medicine in the management of diseases. Antrodia cinnamomea (AC), a valuable medicinal fungus originally found only in Taiwan, has been shown to possess anti-oxidation, vaso-relaxtation, anti-inflammation, anti-hepatitis, and anti-cancer effects. In this paper we evaluate the protective effects of ethanol extract of Antrodia cinnamomea (ACE) against radiotoxicity both in normal liver cell line CL48 and in tumor-bearing mice. In CL48, ACE protects cells by eliminating irradiation-induced reactive oxygen species (ROS) through the induction of Nrf2 and the downstream redox system enzymes. The protective effect of ACE was also demonstrated in tumor-bearing mice by alleviating irradiation-induced acute hepatitis. ACE could also protect mice from CCl4-induced hepatitis. Since both radiation and CCl4 cause free radicals, these results indicate that ACE likely contains active components that protect normal liver cells from free radical attack and can potentially benefit hepatocellular carcinoma (HCC) patients during radiotherapy.
... It grows on the inner cavity of Cinnamomum kanehirae Hayata (Lauraceae) and has been used to promote health, treat liver disease, drug and food intoxication, hangover, exhaustion and cancers by the aboriginals in Taiwan for a long time (Wu SHR and Chang 1997;Geethangili and Tzeng 2011;Yue et al. 2012). Several bioactive compounds of T. camphoratus have been identified and the biological functions in immunomodulatory (Song et al. 2014;Kuo et al. 2008;Sheu et al. 2009), anticancer (Huang et al. 2015;Kumar et al. 2015;, antiinflammation (Chen YF et al. 2014;Hsieh et al. 2010), antioxidant (Wu MD et al. 2011;Hseu et al. 2008) and hepatoprotective (Huang CH et al. 2010;Gokila Vani et al. 2014;Chang et al. 2016) effects were widely studied. ...
Taiwanofungus camphoratus is a precious medicinal fungus endemic to Taiwan and has been used as traditional medicine for a long time. Many pharmacological studies have revealed that T. camphoratus possessed various biological activities, such as immunomodulatory effects, anticancer activity and liver protective function. The aim of this study is to investigate the non-specific and antigen (ovalbumin [OVA])-specific immunomodulation effects of solid-state cultivated powder of T. camphoratus (Leader Antrodia cinnamomea [LAC]) in BABL/c male mice. In non-specific and antigen-specific immune function studies, 8-week-old mice were orally administered with LAC for 6 and 8 weeks, respectively. The results have shown that the proliferation of splenic immune cells, phagocytic activity of macrophages and cytolytic activity of natural killer cells were enhanced by LAC. Additionally, LAC increased the levels of IL-2, TNF-α, INF-γ, GM-CSF and serum OVA-IgG and OVA-IgM. These findings provided evidences that LAC had the immunomodulation effects on both antigen-specific and non-specific immune responses in mice.
... Several compounds have been isolated and identified from fruiting bodies of A. cinnamomea including benzenoids, steroids, and triterpenoids [19,20]. The precise compounds and their mode of actions responsible for the observed biological functions have been studied recently [21][22][23][24]. Antcins, steroid-like compounds, exert anti-inflammatory effect and enhance blood circulation [25]. ...
Antcin-H, a natural triterpene, is purified from a famous anticancer medicinal mushroom, Antrodia cinnamomea, in Taiwan. This study showed that antcin-H inhibited the growth of human renal carcinoma 786-0 cells; the IC 50 value (for 48 h) was 170 μ M. Besides, the migration and invasion of 786-0 cells were suppressed by antcin-H under noncytotoxic concentrations (<100 μ M); these events were accompanied by inhibition of FAK and Src kinase activities, decrease of paxillin phosphorylation, impairment of lamellipodium formation, and upregulation of TIMPs and downregulation of MMPs, especially MMP-7 expression. Luciferase reporter assay showed that antcin-H repressed the MMP-7 promoter activity, in parallel to inhibiting c-Fos/AP-1 and C/EBP- β transactivation abilities. Moreover, antcin-H suppressed the activity of ERK1/2 and decreased the binding ability of C/EBP- β and c-Fos on the upstream/enhancer region of MMP-7 promoter. Overall, this study demonstrated that the anti-invasive effect of antcin-H in human renal carcinoma 786-0 cells might be at least in part by abrogating focal adhesion complex and lamellipodium formation through inhibiting the Src/FAK-paxillin signaling pathways and decreasing MMP-7 expression through suppressing the ERK1/2-AP-1/c-Fos and C/EBP- β signaling axis. Our findings provide the evidence that antcin-H may be an active component existing in A. cinnamomea with anticancer effect.
... S5, D and E). This is in line with the recent role that SRC has been proposed to play in both sensitizing cancer cells to chemotherapy (71)(72)(73)(74) and driving ECM-dependent events in PC (75)(76)(77). Additionally, ROCK inhibitors can induce mitotic defects (78)(79)(80)(81), and we therefore assessed early-to-mid and late mitosis in KPC subcutaneous tumors. ...
The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.
Oral cancer is one of the leading causes of cancer-related deaths, and it has become a matter of serious concern due to the alarming rise in its incidence rate worldwide. Despite recent advancements in oral cancer treatment strategies, there are no significant improvements in patient’s survival rate. Among the numerous cell signaling pathways involved in oral cancer development and progression, STAT3 is known to play a multifaceted oncogenic role in shaping the tumor pathophysiology. STAT3 hyperactivation in oral cancer contributes to survival, proliferation, invasion, epithelial to mesenchymal transition, metastasis, immunosuppression, chemoresistance, and poor prognosis. A plethora of pre-clinical and clinical studies have documented the role of STAT3 in the initiation and development of oral cancer and showed that STAT3 inhibition holds significant potential in the prevention and treatment of this cancer. However, to date, targeting STAT3 activation mainly involves inhibiting the upstream signaling molecules such as JAK and IL-6 receptors. The major challenge in targeting STAT3 lies in the complexity of its phosphorylation- and dimerization-independent functions, which are not affected by disrupting the upstream regulators. The present review delineates the significance of the STAT3 pathway in regulating various hallmarks of oral cancer. In addition, it highlights the STAT3 inhibitors identified to date through various preclinical and clinical studies that can be employed for the therapeutic intervention in oral cancer treatment.
Mushrooms are known not only for their taste but also for beneficial effects on health attributed to plethora of constituents. All mushrooms belong to the kingdom of fungi, which also includes yeasts and molds. Each year, hundreds of new metabolites of the main fungal sterol, ergosterol, are isolated from fungal sources. As a rule, further testing is carried out for their biological effects, and many of the isolated compounds exhibit one or another activity. This study aims to review recent literature (mainly over the past 10 years, selected older works are discussed for consistency purposes) on the structures and bioactivities of fungal metabolites of ergosterol. The review is not exhaustive in its coverage of structures found in fungi. Rather, it focuses solely on discussing compounds that have shown some biological activity with potential pharmacological utility.
Oral cancers, hepatocellular carcinoma, and colorectal cancers are the three most common cancers, leading to 18,000 cases of cancer-related mortality in Taiwan per year. To bridge the gap towards clinical translation, we developed a circulating tumor cell (CTC) organoid culture workflow that efficiently expands CTC from patients to test Antrodia Cinnamomea mycelium-derived bioactive compounds. Three ACM-derived bioactive compounds were evaluated for tumor chemosensitization characteristics. Significant and consistent cytotoxic/5-FU sensitizing effects of GKB202 were found on 8 different patient-derived tumors. Acute toxicity profile and hepatic metabolism of GKB202 in rats suggest GKB202 is rapidly cleared by liver and is well tolerated up to the dose of 20 mg/kg. This comprehensive study provides new evidence that liquid fermentation of Antrodia cinnamomea mycelium (ACM) contains bioactive compounds that lead to effective control of CTC, especially when combined with 5-FU. Together, these data suggest ACM-derived GKB202 may be considered for further clinical investigation in the context of 5-FU-based combination therapy.
Head and neck squamous cell carcinoma (HNSCC) is a highly lethal disease with high-level of epidemic both in the world and Taiwan. Previous studies support that head and neck cancer-initiating cells (HN-CICs), a subpopulation of cancer cells with enhanced stemness properties, contribute to therapy resistance and tumor recurrence. Arsenic trioxide (As2O3; ATO) has shown to be an effective anti-cancer drug targeting acute promyelocytic leukemia (APL). Combinatorial treatment with high dose of ATO and cisplatin (CDDP) exert synergistic apoptotic effects in cancer cell lines of various solid tumors, however, it may cause of significant side effect to the patients. Nevertheless, none has reported the anti-cancerous effect of ATO/CDDP targeting HN-CICs. In this study, we aim to evaluate the low dose combination of ATO with conventional chemo-drugs CDDP treatment on targeting HN-CICs. We first analyzed the inhibitory tumorigenicity of co-treatment with ATO and chemo-drugs on HN-CICs which are enriched from HNSCC cells. We observed that ATO/CDDP therapeutic regimen successfully synergized the cell death on HN-CICs with a Combination Index (CI) <1 by Chou-Talalay's analysis in vitro. Interestingly, the ATO/CDDP regimen also induced exaggerated autophagy on HN-CICs. Additionally, this drug combination strategy also empowered both preventive and therapeutic effect by in vivo xenograft assays. Finally, we provide the underlying molecular mechanisms of ATO-based therapeutic regimen on HN-CICs. Together, low dose of combinatorial ATO/CDDP regimen induced cell death as well as exacerbated autophagy via AMPK-STAT3 mediated pathway in HN-CICs.
