Oxymatrine (OMT), one of the main active components of extracts from the dry roots of Sophora flavescens, has been reported to possess many pharmacological properties including cancer-preventive and ...anti-cancer effects. The aim of the present study is to explore the efficiency of combination therapy with OMT and oxaliplatin (OXA) and identify the in vitro and in vivo cytotoxicity on colon cancer lines (HT29 and SW480) and mice model. Cells were treated with OMT and/or OXA and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay and immunohistochemistry. The results demonstrated that OMT and OXA inhibited the proliferation of colon cancer cells, and combination therapy of OMT and OXA resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with OMT and OXA caused G0/G1 phase arrest by upregulating P21, P27 and downregulating cyclin D, and induced apoptosis through decreasing the expression of p-PI3K, p-AKT, p-mTOR, p-p70S6K. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of OXA + OMT, demonstrating the important role of PI3K/AKT in this process. Moreover, in nude mice model, co-treatment displayed more efficient inhibition of tumor weight and volume on SW480 xenograft mouse model than single-agent treatment with OXA or OMT. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which consistent with our in vitro results. In conclusion, our findings highlight that the combination therapy with OMT and OXA exerted synergistic antitumor effects in colon cancer cells through PI3K/AKT/mTOR pathway and combination treatment with OMT and OXA would be a promising therapeutic strategy for colon carcinoma treatment.
Gallbladder cancer is one of the most common malignant tumors in the biliary tract. In recent years, the chemotherapy treatment for gallbladder carcinoma has exhibited obvious characteristics of drug ...resistance and insensitivity, and one of the main factors is the existence of cancer stem cells. Here in this study, the effect of Bufalin on gallbladder cancer (GBC-SD) cells and the related mechanism were studied. The results indicated that Bufalin could inhibit the growth of gallbladder carcinoma both
and
. According to the biological behavior analysis, Bufalin induced apoptosis, inhibited the propagation, migration and invasion of GBC-SD cells, and blocked cell cycle at the G2/M stage. Besides, Bufalin inhibited the tumor sphere formation capability of gallbladder carcinoma in matrigel, reduced the expression of multiple stemness-associated proteins, including Oct4, Sox2 and the stem cell-surface marker proteins CD133 and CD44. Western blot assay showed that Bufalin inhibited MEK/ERK and PI3-K/AKT signaling pathways by inhibiting the expression of p-c-Met, which in turn affected the expression of apoptosis-related protein Mcl-1, and the invasion-associated proteins E-cadherin, MMP9 and Snail. Bufalin was found to have an inhibitory effect on the GBC-SD cell growth and reduce the self-renewal and characteristic of gallbladder cancer stem cells. It enhanced the chemotherapeutic sensitivity and reduced the metastasis of gallbladder carcinoma. In conclusion, Bufalin can be used as a new promising anticancer drug for gallbladder cancer patients who are resistant to traditional chemotherapy.
B7-H3 belongs to the B7 superfamily, a group of molecules that costimulate or downmodulate T cell responses. Although it has been shown that B7-H3 can inhibit T cell responses, several studies, most ...of them performed in murine systems, found B7-H3 to act in a co-stimulatory manner. In addition, B7-H3 is also expressed in various human cancers and is correlated with the poor outcome of cancer patients. The functional role of B7-H3 in cancer is still controversially discussed. In the present study, we compared B7-H3 expression in normal gastric tissues and gastric cancer tissue specimens and determined the effects of low B7-H3 expression on the human gastric cancer cell line SGC-7901 by using RNAi. B7-H3 expression in gastric specimens was determined by tissue qPCR and immunohistochemisty. A SGC-7901 cell line with low B7-H3 expression was established by lentiviral-mediated RNA interference to investigate the effect of B7-H3 on cancer cell migration and invasion in vitro. By establishing an orthotopic transplantation gastric cancer mouse model, the effect of B7-H3 on cell migration and invasion was studied in vivo. B7-H3 expression was significantly higher in the gastric cancer group than that in the normal gaster group. B7-H3 knockdown by RNA interference decreased cell migration and Transwell invasion up to 50% in vitro. In the orthotopic transplantation gastric cancer mouse model, the effect of inhibiting metastasis by knockdown of B7-H3 was assessed in terms of the average postmortem abdominal visceral metastatic tumor weight. The results revealed that inhibition of B7-H3 expression reduced gastric cancer metastasis in vivo. In conclusion, B7-H3 is aberrantly expressed in gastric cancer. In addition to modulating tumor immunity, B7-H3 may have a novel role in regulating SGC-7901 cell metastasis.
Oxymatrine extracted from Sophora flavescens Ait as a natural polyphenolic phytochemical has been demonstrated to exhibit anti-tumor effects on various cancers, including Gallbladder carcinoma (GBC). ...However, its underlying mechanisms of function are largely unknown in GBC cells. The present study is conducted to investigate the anti-tumor effects and the underlying mechanisms of oxymatrine on GBC cells in vitro and in vivo. The results showed that oxymatrine inhibited cell viability, metastatic ability and induced cell apoptosis in dose-dependent manners. Furthermore, we found that the expression of p-AKT, MMP-2, MMP-9 and the ratio of Bcl-2/Bax were significantly down-regulated, while the expression of PTEN was up-regulated in GBC cells. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly antagonized the oxymatrine-mediated inhibition of GBC–SD cells. Subsequently, our in vivo studies showed that administration of oxymatrine induced a significant dose-dependent decrease in tumor growth. In conclusion, these findings indicated that the inhibition of cells proliferation, migration, invasion and the induction of apoptosis in response to oxymatrine in GBC cells, may function through the suppression of PTEN/PI3K/AKT pathway, which was considered as the vital signaling pathway in regulating tumorigenesis. These results suggested that oxymatrine might be a novel effective candidate as chemotherapeutic agent against GBC.
Lupeol, a dietary triterpene present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including cancer-preventive and anti-cancer effects in vitro and ...in vivo. Here, we investigated the anti-cancer efficacy and adjuvant chemotherapy action of lupeol in gastric cancer (GC) cells (SGC7901 and BGC823) and explored the underlying mechanisms. Cells were treated with lupeol and/or 5-fluorouracil (5-Fu) and subjected to cell viability, colony formation, apoptosis, western blot, semiquantitative RT-PCR, and xenograft tumorigenicity assay. Our results showed that lupeol and 5-Fu inhibited the proliferation of SGC7901 and BGC823 cells, and combination treatment with lupeol and 5-Fu resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with lupeol and 5-Fu induced apoptosis through up-regulating the expressions of Bax and p53 and down-regulating the expressions of survivin and Bcl-2. Furthermore, co-treatment displayed more efficient inhibition of tumor weight and volume on BGC823 xenograft mouse model than single-agent treatment with 5-Fu or lupeol. Taken together, our findings highlight that lupeol sensitizes GC to 5-Fu treatment, and combination treatment with lupeol and 5-Fu would be a promising therapeutic strategy for human GC treatment.
Gemcitabine (GEM) has been widely used for pancreatic cancer (PC) treatment but limited by the development of drug resistance. The agents that reverse its resistance and improve the chemo-sensitivity ...are urgently needed. S-Adenosylmethionine (SAM) is a precursor for polyamine biosynthesis in mammalian cells and plays a key role in biological transmethylation events. It is reported that SAM could be used as a therapeutic reagent for cancer treatments. In this study, we investigated the chemo-sensitization of SAM to potentiate the antitumor effect of GEM in PC. After treating PC cells with GEM and/or SAM, different subsequent experiments were performed. Results showed that SAM plus GEM could significantly inhibit the growth and proliferation of PC cells, and SAM acts synergistically with GEM. The combinative treatment could induce cell apoptosis and inhibit invasion and migration through JAK2/STAT3 inactivation. Inhibition of JAK2/STAT3 pathway significantly enhanced the pro-apoptotic effect of SAM, suggesting the key roles of JAK2/STAT3 in the process. Moreover, co-treatment with GEM and SAM exhibited more efficient inhibition of tumor weight and volume on PANC-1 xenograft mouse model compared to GEM or SAM alone and has no significant effect on the function of the liver and kidney. In general, this study indicated that SAM synergistically enhanced the antitumor effect of GEM against PC through suppressed JAK2/STAT3 pathway, and SAM is applicable as a promising agent to improve the sensitivity of PC to GEM.
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