Mortality associated with the use of non-vitamin K antagonist oral anticoagulants in cancer patients: Dabigatran versus rivaroxaban.

OBJECTIVE: This study assesses the mortality outcomes of non-vitamin K antagonist oral anticoagulants (NOACs) in cancer patients with venous thromboembolism (VTE) and atrial fibrillation (AF). METHODS: Medical records of cancer patients receiving NOACs for VTE or AF between January 1, 2011, and December 31, 2016, were retrieved from Taiwan's National Health Institute Research Database. NOACs were compared using the inverse probability of treatment weighting (IPTW) method. The primary outcome was cancer-related death. Secondary outcomes were all-cause mortality, major bleeding, and gastrointestinal (GI) bleeding. RESULTS: Among 202,754 patients who received anticoagulants, 3591 patients (dabigatran: 907; rivaroxaban: 2684) with active cancers were studied. Patients who received dabigatran were associated with lower risks of cancer-related death at one year (HR = 0.71, 95% CI = 0.54-0.93) and at the end of follow-ups (HR = 0.79, 95% CI = 0.64-0.98) compared with rivaroxaban. Patients who received dabigatran were also associated with lower risks of all-cause mortality (HR = 0.81, 95% CI = 0.67-0.97), major bleeding (HR = 0.64, 95% CI = 0.47-0.88), and GI bleeding (HR = 0.57, 95% CI = 0.39-0.84) at the end of follow-ups compared with rivaroxaban. CONCLUSION: Compared with rivaroxaban, the use of dabigatran may be associated with a lower risk of cancer-related death and all-cause mortality.

Danshen Improves Survival of Patients With Breast Cancer and Dihydroisotanshinone I Induces Ferroptosis and Apoptosis of Breast Cancer Cells.

Danshen (salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. However, it is definite clinical effort and mechanism on breast cancer is unclear. In our study, we used the real-world database to investigate in vivo protective effort of danshen in the breast cancer patients through using population-based data from the Taiwan National Health Insurance Research Database (NHIRD). In vitro, human breast cancer cells (MCF-7 cells and MDA-MB-231 cells) were used to investigate the effect and the underlying mechanism through XTT assay, flow cytometry, glutathione peroxidase (GPX) activity assay, GSH (reduced glutathione)/GSSG (oxidized glutathione), malondialdehyde (MDA), and western blot analysis. The in vivo effect was investigated through a xenograft nude mouse model. We found that dihydroisotanshinone I (DT), a pure compound present in danshen, can inhibit the growth of breast carcinoma cells, including MCF-7 cells and MDA-MB-231 cells. Moreover, DT induced apoptosis and ferroptosis in these breast cancer cells. DT also repressed the protein expression of GPX4 (Glutathione peroxidase 4). For in vivo study, DT treatment also significantly inhibited the final tumor volume without adverse effects in a xenograft nude mouse model. In conclusion, danshen has protective efforts in breast cancer patients, which could be attributed to DT through inducing apoptosis and ferroptosis of breast cancer cells.

Antrodia cinnamomea extract inhibits the proliferation of tamoxifen-resistant breast cancer cells through apoptosis and skp2/microRNAs pathway.

BACKGROUND: Breast cancer is the most common cancer in women and affects 1.38 million women worldwide per year. Antiestrogens such as tamoxifen, a selective estrogen receptor (ER) modulator, are widely used in clinics to treat ER-positive breast tumors. However, remissions of breast cancer are often followed by resistance to tamoxifen and disease relapse. Despite the increasing understanding of the resistance mechanisms, effective regimens for treating tamoxifen-resistant breast cancer are limited. Antrodia cinnamomea is a traditional medicinal mushroom native only to Taiwan. In this study, we aimed to examine in vitro effect of antrodia cinnamomea in the tamoxifen-resistant cancer. METHODS: Antrodia cinnamomea was studied for its biological activity against proliferation of tamoxifen-resistant breast cancer by XTT assay. Next, the underlying mechanism was studied by flow cytometry, qPCR and Western's blotting assay. RESULTS: Our results revealed that the ethanol extract of antrodia cinnamomea (AC) can inhibit the growth of breast cancer cells, including MCF-7 cell and tamoxifen-resistant MCF-7 cell lines. Combination treatment with AC and 10- 6 M tamoxifen have the better inhibitory effect on the proliferation of tamoxifen-resistant MCF-7 cells than only AC did. AC can induce apoptosis in these breast cancer cells. Moreover, it can suppress the mRNA expression of skp2 (S-phase kinase-associated protein 2) by increasing the expressions of miR-21-5p, miR-26-5p, and miR-30-5p in MCF-7 and tamoxifen-resistant MCF-7 cells. CONCLUSIONS: These results suggest that the ethanol extract of antrodia cinnamomea could be a novel anticancer agent in the armamentarium of tamoxifen-resistant breast cancer management. Moreover, we hope to identify additional pure compounds that could serve as promising anti-breast cancer candidates for further clinical trials.

Danshen improves survival of patients with advanced lung cancer and targeting the relationship between macrophages and lung cancer cells.

In traditional Chinese medicine, Salvia miltiorrhiza Bunge (danshen) is widely used in the treatment of numerous cancers. However, its clinical effort and mechanism in the treatment of advanced lung cancer are unclear. In our study, the in vivo protective effort of danshen in patients with advanced lung cancer were validated using data from the National Health Insurance Research Database in Taiwan. We observed in vitro that dihydroisotanshinone I (DT), a bioactive compound in danshen, exerts anticancer effects through many pathways. First, 10 µM DT substantially inhibited the migration ability of lung cancer cells in both macrophage and macrophage/lung cancer direct mixed coculture media. Second, 10 µM DT repressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3), the protein expression of S-phase kinase associated protein-2 (Skp2), and the mRNA levels of STAT3-related genes, including chemokine (C-C motif) ligand 2 (CCL2). In addition, 10 µM DT suppressed the macrophage recruitment ability of lung cancer cells by reducing CCL2 secretion from both macrophages and lung cancer cells. Third, 20 µM DT induced apoptosis in lung cancer cells. Furthermore, DT treatment significantly inhibited the final tumor volume in a xenograft nude mouse model. In conclusion, danshen exerts protective efforts in patients with advanced lung cancer. These effects can be attributed to DT-mediated interruption of the cross talk between lung cancer cells and macrophages and blocking of lung cancer cell proliferation.

Danshen improves survival of patients with colon cancer and dihydroisotanshinone I inhibit the proliferation of colon cancer cells via apoptosis and skp2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. However, it's definite clinical effect and mechanism on colon carcinoma is unclear. AIM OF THE STUDY: To test the hypothesis that the protective effect of danshen on colon cancer and discover the bioactive compounds through in vitro study. MATERIALS AND METHODS: We conducted a nationwide cohort study by using population-based data from the Taiwan National Health Insurance Research Database (NHIRD). The study cohort comprised patients diagnosed with malignant neoplasm of colon (ICD-9-CM codes:153) in catastrophic illness database between January 1, 2000, and December 31, 2010. We used the Kaplan-Meier method to estimate colon [corrected] cancer cumulative incidences. Next, human colon cancer cells (HCT 116 cells and HT29 cells) were used to investigate the effect of dihydroisotanshinone I (DT) on the proliferation and apoptosis of human colon cancer cells and the underlying mechanism through XTT assay and flow cytometry. The in vivo effect of DT treatment was investigated through a xenograft nude mouse model. RESULTS: In our study, the in vivo protective effect of danshen in the different stage of colon cancer patients was validated through data from the National Health Insurance Research Database in Taiwan. In vitro, we found that dihydroisotanshinone I (DT), a bioactive compound present in danshen, can inhibit the proliferation of colon carcinoma cells, HCT 116 cells and HT-29 cells. Moreover, DT induced apoptosis of colorectal cancer cells. DT also repressed the protein expression of Skp2 (S-Phase Kinase Associated Protein 2) and the mRNA levels of its related gene, Snail1 (Zinc finger protein SNAI1) and RhoA (Ras homolog gene family, member A). In addition, DT also blocked the colon cancer cells recruitment ability of macrophage by decreasing CCL2 secretion in macrophages. DT treatment also significantly inhibited the final tumor volume in a xenograft nude mouse model. CONCLUSION: Danshen has protective effects in colon cancer patients, which could be attributed to DT through blocking the proliferation of colon cancer cells through apoptosis.

Anti-cancer effect of danshen and dihydroisotanshinone I on prostate cancer: targeting the crosstalk between macrophages and cancer cells via inhibition of the STAT3/CCL2 signaling pathway.

Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. In our study, the in vivo protective effect of danshen in prostate cancer patients was validated through data from the National Health Insurance Research Database in Taiwan. In vitro, we discovered that dihydroisotanshinone I (DT), a bioactive compound present in danshen, can inhibit the migration of both androgen-dependent and androgen-independent prostate cancer cells. In addition, we noted that DT substantially inhibited the migratory ability of prostate cancer cells in both a macrophage-conditioned medium and macrophage/prostate cancer coculture medium. Mechanistically, DT both diminished the ability of prostate cancer cells to recruit macrophages and reduced the secretion of chemokine (C-C motif) ligand 2 (CCL2) from both macrophages and prostate cancer cells in a dose-dependent manner. Moreover, DT inhibited the protein expression of p-STAT3 and decreased the translocation of STAT3 into nuclear chromatin. DT also suppressed the expression of tumor epithelial-mesenchymal transition genes, including RhoA and SNAI1. In conclusion, danshen can prolong the survival rate of prostate cancer patients in Taiwan. Furthermore, DT can inhibit the migration of prostate cancer cells by interrupting the crosstalk between prostate cancer cells and macrophages via the inhibition of the CCL2/STAT3 axis. These results may provide the basis for a new therapeutic approach toward the treatment of prostate cancer progression.