ABSTRACT
[This corrects the article DOI: 10.18632/oncotarget.9660.].
ABSTRACT
Immunogenic cell death (ICD) of tumor cells occurs via various pathways that activate immune cell systems against cancer. Previous studies have demonstrated that shikonin (SK), a plant secondary metabolite, can confer strong pharmacological activities that activate ICD and strong immunogenicity of tumor cells. However, the exact hierarchical regulatory mechanisms including the molecular targets of SK-activated immunogenicity are still unknown. Here, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific protein target for SK. This binding plays a key role in SK-stimulated ICD activity and the suppression of post-transcriptional mRNA processing, including nuclear export activity of newly synthesized mRNAs in mammary carcinoma cells in vitro. Moreover, it also mechanistically mediates the anti-metastatic effect of a tumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated 4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity of SK-TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1 as the intracellular molecular target provides compelling pharmacology-based knowledge for the potential clinical use of SK-induced immunogenicity. In addition, SK may also serve as a potent suppressor that interferes with specific post-transcriptional activities, a mechanism which may be useful for exploitation in cancer therapeutics.
Subject(s)
Antineoplastic Agents/therapeutic use , Apoptosis/immunology , Breast Neoplasms/therapy , Heterogeneous Nuclear Ribonucleoprotein A1/metabolism , Naphthoquinones/therapeutic use , RNA Processing, Post-Transcriptional/drug effects , Animals , Antineoplastic Agents/immunology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Cancer Vaccines/immunology , Cell Line, Tumor , Dendritic Cells/immunology , Female , Heterogeneous Nuclear Ribonucleoprotein A1/immunology , Humans , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Naphthoquinones/immunology , RNA, Messenger/metabolism , Tandem Mass Spectrometry , Xenograft Model Antitumor AssaysABSTRACT
Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.
Subject(s)
Breast Neoplasms/metabolism , Fibroblasts/metabolism , Interleukins/metabolism , Mammary Neoplasms, Experimental/metabolism , 3T3 Cells , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Blotting, Western , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Female , Fibroblasts/drug effects , Humans , Lignans/chemistry , Lignans/pharmacology , MCF-7 Cells , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/genetics , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasm Metastasis , Survival Analysis , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Compared with the zotarolimus-eluting stent (ZES), the everolimus-eluting stent (EES) has reduced the risk of stent restenosis and thrombosis as found in a number of randomized-controlled trials (RCTs). However, the benefits have been variable. MATERIALS AND METHODS: We evaluate the long-term effect of EES and ZES on the risk of stent thrombosis and target lesion revascularization in patients receiving PCI. We identified RCTs by a systematic search of MEDLINE, EMBASE, and Cochrane Database. RESULTS: Five RCTs (9853 patients) were included. Overall, EES significantly reduced the risk of target lesion revascularization [odds ratio (OR), 0.77; 95% confidence interval (CI), 0.62-0.95; P=0.01] compared with ZES therapy. However, there was no difference in the risk of target vessel revascularization (OR, 0.93; 95% CI, 0.78-1.10; P=0.38) and definite/probable stent thrombosis (OR, 0.83; 95% CI, 0.56-1.25; P=0.37) between the two groups. Furthermore, the risk of mortality (OR, 1.04; 95% CI, 0.84-1.27; P=0.73), myocardial infarction (OR, 0.95; 95% CI, 0.74-1.23; P=0.70), and major adverse cardiac event (OR, 0.96; 95% CI, 0.84-1.10; P=0.53) was similar between the two groups. CONCLUSION: The new-generation Resolute-ZES and EES have a similar long-term safety and efficacy profile.
Subject(s)
Cardiovascular Agents/administration & dosage , Coronary Artery Disease/therapy , Drug-Eluting Stents , Everolimus/administration & dosage , Percutaneous Coronary Intervention/instrumentation , Sirolimus/analogs & derivatives , Chi-Square Distribution , Coronary Artery Disease/diagnosis , Coronary Artery Disease/mortality , Coronary Restenosis/etiology , Coronary Restenosis/mortality , Coronary Restenosis/prevention & control , Coronary Thrombosis/etiology , Coronary Thrombosis/mortality , Coronary Thrombosis/prevention & control , Humans , Myocardial Infarction/etiology , Myocardial Infarction/mortality , Myocardial Infarction/prevention & control , Odds Ratio , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/mortality , Prosthesis Design , Risk Factors , Sirolimus/administration & dosage , Time Factors , Treatment OutcomeABSTRACT
Medicinal herbs and their derivative phytocompounds are being increasingly recognized as useful complementary treatments for cancer. A large volume of clinical studies have reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL) of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. Here, we briefly review some examples of clinical studies that investigated the use of herbal medicines for various cancers and the development of randomized controlled trials (RCTs) in this emerging research area. In addition, we also report recent studies on the biochemical and cellular mechanisms of herbal medicines in specific tumor microenvironments and the potential application of specific phytochemicals in cell-based cancer vaccine systems. This review should provide useful technological support for evidence-based application of herbal medicines in cancer therapy.
