Shikonin and 4-hydroxytamoxifen synergistically inhibit the proliferation of breast cancer cells through activating apoptosis signaling pathway in vitro and in vivo.

BACKGROUND: Tamoxifen (TAM) is a cell type-specific anti-estrogen and is applied to improve the survival of patients with estrogen receptor positive (ER +) breast cancer. However, long-term TAM use can induce serious drug resistance, leading to breast cancer recurrence and death in patients. Further, it is almost useless among patients with estrogen receptor negative (ER -) breast cancer. Shikonin (SK) is a natural product broadly explored in cancer therapy. Some studies have demonstrated the combined treatment of SK and clinical anticancer drugs including TAM on various tumors. However, the combined effect of SK and 4-hydroxytamoxifen (4-OHT) on ER- breast cancer is not known. The current study aimed to assess the combination effects of SK and 4-OHT on human breast cancer cells, MCF-7 (ER +) and MDA-MB-435S (ER -), in vitro and in vivo and to investigate the underlying mechanisms. METHODS: CCK-8 assays and flow cytometry were conducted to determine the cell viability and apoptotic profiles of human breast cancer cell lines (MCF-7 and MDA-MB-435S) treated with SK, 4-OHT, and the combination. ROS and JC-1 assays were used to determine ROS level and mitochondrial membrane potential. Western blot analysis was performed to investigate proteins that are associated with apoptosis. Haematoxylin & Eosin (HE) staining was used to detect the tumor and kidney morphology of mice. TUNEL and immunohistochemical staining were performed to detect Ki67 expression level and cell apoptotic profile in tumor tissues. RESULTS: SK and 4-OHT synergistically inhibited MCF-7 and MDA-MB-435S cell proliferation and promoted apoptosis by reducing mitochondrial membrane potential and increasing the intracellular ROS level. The combination of SK and 4-OHT activated the mitochondrial-dependent apoptosis and the death receptor pathways, significantly regulating the PI3K/AKT/Caspase 9 signaling pathway. Compared with SK and 4-OHT alone, the combination of SK and 4-OHT could better inhibit tumor growth in mice. CONCLUSION: The combination of SK and 4-OHT shows highly efficient anticancer effects on breast cancer therapy. SK may be a promising candidate as an adjuvant to 4-OHT for breast cancer treatments, especially for ER- breast cancer.

Preparation and Properties of Polydimethylsiloxane (PDMS)/Polyethylene Glycol (PEG)-Based Amphiphilic Polyurethane Elastomers.

Amphiphilic polyurethane elastomers (APUE) were synthesized using a two-step polyaddition reaction based on the hydroxyl-terminated polydimethylsiloxane (PDMS) and polyethylene glycol (PEG) soft segments with the molecular weights (Mw's) of 2000 and 1000, respectively. The effects of the PDMS/PEG contents on the properties and structures of the APUE were investigated. It was found that the APUE possessed high elongation, moderate tensile strength, and good thermal properties. In addition, the APUE showed tunable oxygen permeability (Dk) and water vapor transmission rate (WVTR), and a similar WVTR to that of skin could be obtained for the optimized sample (APUE2). Importantly, APUE also exhibited excellent antibacterial efficacy against two kinds of bacteria along with impressive cytocompatibility. All of the results demonstrated that the synthesized APUE will hold substantial potential for biomaterial applications.

Self-healing zwitterionic sulfobetaine nanocomposite hydrogels with good mechanical properties.

The development of zwitterionic hydrogels possessing both excellent self-healing and mechanical properties is of great significance. Herein, a class of zwitterionic sulfobetaine nanocomposite hydrogels was prepared by UV-initiated copolymerisation of zwitterionic sulfobetaine monomer N,N-dimethyl-N-(3-methacrylamidopropyl)-N-(3-sulfopropyl) ammonium betaine (DMAPMAPS) and 2-hydroxyethyl methacrylate (HEMA) in the presence of exfoliated clay platelets uniformly dispersed in an aqueous medium. The effects of the hydrogel compositions, including the DMAPMAPS/HEMA mass ratio and the amount of clay, on the self-healing behaviors and mechanical properties of the nanocomposite hydrogels were investigated. The results indicate that the fabricated zwitterionic sulfobetaine nanocomposite hydrogels can autonomously repair incisions or cracks at ambient temperature without the need for any stimulus and possess excellent mechanical properties.

Novel Podophyllotoxin Derivatives as Potential Tubulin Inhibitors: Design, Synthesis, and Antiproliferative Activity Evaluation.

A number of podophyllotoxin derivatives (3A-3J) had been designed and synthesized, and their biological activities were evaluated in this study. Moreover, the antiproliferation activities of these compounds against four human cancer cell lines (HepG2, HeLa, A549, and MCF-7) were also tested. The results indicated that the most promising compound 3D displayed potent inhibitory activity over the four human cancer cell lines and was further demonstrated to have potent tubulin polymerization inhibitory effects without damaging the non-cancer cells. Additionally, 3D was verified to effectively interfere with tubulin and could prevent the mitosis of cancer cells, leading to cell cycle arrest and eventually inducing apoptosis in a dose- and time-dependent manner. Moreover, the Western blotting and siRNA results showed that Bcl-2 was downregulated in HepG2 cells treated with 3D. Finally, the molecular docking simulation results revealed that 3D could fit well in the colchicine-binding pocket. Taken together, this study has provided certain novel antitubulin agents for possible cancer chemotherapy.