Ferroptosis as a novel form of regulated cell death: Implications in the pathogenesis, oncometabolism and treatment of human cancer.

The treatment of cancer mainly involves surgical excision supplemented by radiotherapy and chemotherapy. Chemotherapy drugs act by interfering with tumor growth and inducing the death of cancer cells. Anti-tumor drugs were developed to induce apoptosis, but some patient's show apoptosis escape and chemotherapy resistance. Therefore, other forms of cell death that can overcome the resistance of tumor cells are important in the context of cancer treatment. Ferroptosis is a newly discovered iron-dependent, non-apoptotic type of cell death that is highly negatively correlated with cancer development. Ferroptosis is mainly caused by the abnormal increase in iron-dependent lipid reactive oxygen species and the imbalance of redox homeostasis. This review summarizes the progression and regulatory mechanism of ferroptosis in cancer and discusses its possible clinical applications in cancer diagnosis and treatment.

Trends in Deep Vein Thrombosis Prophylaxis and Deep Vein Thrombosis Rates After Total Hip and Knee Arthroplasty.

INTRODUCTION: Patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) are at high risk of deep vein thrombosis (DVT) postoperatively, necessitating the use of prophylaxis medications. This investigation used a large claims database to evaluate trends in postoperative DVT prophylaxis and rates of DVT within 6 months after THA or TKA. METHODS: Truven Health MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases were reviewed from 2004 to 2013 for patients who underwent THA or TKA. Data were collected on patient age, sex, Charlson Comorbidity Index, and hypercoagulability diagnoses. Postoperative medication claims were reviewed for prescribed aspirin, warfarin, enoxaparin, fondaparinux, rivaroxaban, and dabigatran. RESULTS: A total of 369,483 patients were included in the analysis, of which 239,949 patients had prescription medication claims. Warfarin was the most commonly prescribed anticoagulant. Patients with a hypercoagulable diagnosis had markedly more DVTs within 6 months after THA or TKA. More patients with a hypercoagulable diagnosis were treated with warfarin or lovenox than other types of anticoagulants. A multivariate regression analysis was performed, showing that patients prescribed aspirin, fondaparinux, and rivaroxaban were markedly less likely than those prescribed warfarin or enoxaparin to have a DVT within 6 months after THA or TKA. CONCLUSION: After THA and TKA, warfarin is the most commonly prescribed prophylaxis. Patients with hypercoagulability diagnoses are at a higher risk of postoperative DVT. The likelihood of DVT within 6 months of THA and TKA was markedly higher in patients treated with warfarin and lovenox and markedly lower in those treated with aspirin, fondaparinux, and rivaroxaban. LEVEL OF EVIDENCE: Level III.

BMP-9 induced osteogenic differentiation of mesenchymal stem cells: molecular mechanism and therapeutic potential.

Promoting osteogenic differentiation and efficacious bone regeneration have the potential to revolutionize the treatment of orthopaedic and musculoskeletal disorders. Mesenchymal Stem Cells (MSCs) are bone marrow progenitor cells that have the capacity to differentiate along osteogenic, chondrogenic, myogenic, and adipogenic lineages. Differentiation along these lineages is a tightly controlled process that is in part regulated by the Bone Morphogenetic Proteins (BMPs). BMPs 2 and 7 have been approved for clinical use because their osteoinductive properties act as an adjunctive treatment to surgeries where bone healing is compromised. BMP-9 is one of the least studied BMPs, and recent in vitro and in vivo studies have identified BMP-9 as a potent inducer of osteogenic differentiation in MSCs. BMP-9 exhibits significant molecular cross-talk with the Wnt/ ß-catenin and other signaling pathways, and adenoviral expression of BMP-9 in MSCs increases the expression of osteogenic markers and induces trabecular bone and osteiod matrix formation. Furthermore, BMP-9 has been shown to act synergistically in bone formation with other signaling pathways, including Wnt/ ß-catenin, IGF, and retinoid signaling pathways. These results suggest that BMP-9 should be explored as an effective bone regeneration agent, especially in combination with adjuvant therapies, for clinical applications such as large segmental bony defects, non-union fractures, and/or spinal fusions.

Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ß-catenin signaling.

Colorectal cancer (CRC) is one of the most common and deadly malignancies in the world. Most CRCs are initiated by aberrant activation of the Wnt/ß-catenin signaling pathway. Despite the advances in its early diagnosis, optimized surgical approaches, and chemotherapies, the clinical management of advanced CRC requires effective adjuvant agents. Ginsenoside Rg3 is a single compound isolated from American ginseng (Panax quinquefolius L., Araliaceae) and Asian ginseng (Panax ginseng C. A. Meyer). We investigated the anticancer activity of Rg3 on colon cancer cells and its potential molecular mechanism behind Rg3's anticancer activity. We found that Rg3 inhibits cell proliferation and viability of cancer cells in vitro. This inhibitory effect of Rg3 is, at least in part, mediated by blocking nuclear translocation of the ß-catenin protein and hence inhibiting ß-catenin/Tcf transcriptional activity. Allelic deletion of the oncogenic ß-catenin in HCT116 cells renders the cells more sensitive to Rg3-induced growth inhibition. Using the xenograft tumor model of human colon cancer, we have demonstrated that Rg3 effectively inhibits the growth of tumors derived from the human colon cancer cell line HCT116. Histologic examination revealed that Rg3 inhibits cancer cell proliferation, decreases PNCA expression and diminishes nuclear staining intensity of ß-catenin. Taken together, our results strongly suggest that the anticancer activity of Rg3 may be in part caused by blocking the nuclear translocation of ß-catenin in colon cancer cells. This line of investigation may lead to the development of novel therapies in which Rg3 can be used as an effective adjuvant agent for the clinical management of colorectal cancers.

Therapeutic Implications of PPARgamma in Human Osteosarcoma.

Osteosarcoma (OS) is the most common nonhematologic malignancy of bone in children and adults. Although dysregulation of tumor suppressor genes and oncogenes, such as Rb, p53, and the genes critical to cell cycle control, genetic stability, and apoptosis have been identified in OS, consensus genetic changes that lead to OS development are poorly understood. Disruption of the osteogenic differentiation pathway may be at least in part responsible for OS tumorigenesis. Current OS management involves chemotherapy and surgery. Peroxisome proliferator-activated receptor (PPAR) agonists and/or retinoids can inhibit OS proliferation and induce apoptosis and may inhibit OS growth by promoting osteoblastic terminal differentiation. Thus, safe and effective PPAR agonists and/or retinoid derivatives can be then used as adjuvant therapeutic drugs for OS therapy. Furthermore, these agents have the potential to be used as chemopreventive agents for the OS patients who undergo the resection of the primary bone tumors in order to prevent local recurrence and/or distal pulmonary metastasis.

Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the beta-catenin signaling activity.

Beta-Catenin is a critical transducer of the Wnt signal pathway and plays an important role in many developmental and cellular processes. Deregulation of beta-catenin signaling has been observed in a broad range of human tumors. In this report, we investigated whether tyrosine kinase inhibitor STI-571 could inhibit the beta-catenin signaling activity and hence suppress cell proliferation. Our results demonstrated that STI-571 effectively inhibited the constitutive activity of beta-catenin signaling in human colon cancer cells as well as the Wnt1-induced activation of beta-catenin signaling in HOS, HTB-94, and HEK 293 cells. Furthermore, STI-571 was shown to effectively suppress the proliferation of human colon cancer cells. Finally, we demonstrated that the Wnt1-mediated activation of a GAL4-beta-catenin heterologous transcription system was effectively inhibited by STI-571. Thus, our findings suggest that tyrosine phosphorylation may play an important role in regulating beta-catenin signaling activity, and inhibition of this signaling pathway by STI-571 may be further explored as an important target for alternative/adjuvant treatments for a broader range of human cancer.