Cistanche phenylethanoid glycosides induce apoptosis and pyroptosis in T-cell lymphoma.

Cistanche deserticola, known for its extensive history in Traditional Chinese Medicine (TCM), is valued for its therapeutic properties. Recent studies have identified its anticancer capabilities, yet the mechanisms underlying these properties remain to be fully elucidated. In this study, we determined that a mixture of four cistanche-derived phenylethanoid glycosides (CPhGs), echinacoside, acteoside, 2-acetylacteoside, and cistanoside A, which are among the main bioactive compounds in C. deserticola, eliminated T-cell lymphoma (TCL) cells by inducing apoptosis and pyroptosis in vitro and attenuated tumor growth in vivo in a xenograft mouse model. At the molecular level, these CPhGs elevated P53 by inhibiting the SIRT2-MDM2/P300 and PI3K/AKT carcinogenic axes and activating PTEN-Bax tumor-suppressing signaling. Moreover, CPhGs activated noncanonical and alternative pathways to trigger pyroptosis. Interestingly, CPhGs did not activate canonical NLRP3-caspase-1 pyroptotic signaling pathway; instead, CPhGs suppressed the inflammasome factor NLRP3 and the maturation of IL-1ß. Treatment with a caspase-1/4 inhibitor and silencing of Gasdermin D (GSDMD) or Gasdermin E (GSDME) partially rescued CPhG-induced cell death. Conversely, forced expression of NLRP3 restored cell proliferation. In summary, our results indicate that CPhGs modulate multiple signaling pathways to achieve their anticancer properties and perform dual roles in pyroptosis and NLRP3-driven proliferation. This study offers experimental support for the potential application of CPhGs in the treatment of TCL.

Developing a Versatile Multiscale Therapeutic Platform for Osteosarcoma Synergistic Photothermo-Chemotherapy with Effective Osteogenicity and Antibacterial Capability.

Osteosarcoma is a devastating malignant neoplasm that seriously threatens human health. After an osteosarcoma resection, the simultaneous treatment of tumor recurrence, postoperative infection, and large bone loss remains a formidable challenge clinically. Herein, a versatile multiscale therapeutic platform (Fs-BP-DOX@PDA) is engineered based on NiTi alloys with versatile properties for near-infrared (NIR)-mediated osteosarcoma synergistic photothermo-chemotherapy, bone regeneration, and bacterial elimination. First, an intriguing method for fabricating groovelike micro-nanostructures (Fs-NiTi) through femtosecond laser direct writing to enhance osseointegration with strong contact guidance is proposed. Then, black phosphorus (BP) nanosheets as gratifying photothermal conversion agents, osteogenetic agents, and a drug delivery platform are decorated on Fs-NiTi to construct multiscale hierarchical structures (Fs-BP). Finally, the polydopamine (PDA) modification is utilized to enhance the photothermal performance, biocompatibility, and chemical stability of doxorubicin (DOX)-loaded Fs-BP and endow NIR/pH-dual-responsive DOX release properties. Fs-BP-DOX@PDA effectively induces tumor cell (Saos-2 and MDA-MB-231) death in vitro, completely eradicates osteosarcoma in mice, and observably promotes bone-regeneration bioactivity. Furthermore, it possesses prominent antibacterial efficiencies toward Staphylococcus aureus (99.2%) and Pseudomonas aeruginosa (99.6%). Overall, this work presents a smart comprehensive fabrication methodology to construct a versatile multiscale therapeutic platform for multimodal osteosarcoma treatment and biomedical tissue engineering.

Oleandrin sensitizes human osteosarcoma cells to cisplatin by preventing degradation of the copper transporter 1.

A major problem in osteosarcoma treatment is cisplatin resistance. We have reported the anti-osteosarcoma effect of oleandrin; however, whether oleandrin sensitizes osteosarcoma to cisplatin is unknown. We investigated the chemosensitization of oleandrin and potential mechanisms in osteosarcoma cells U-2OS, SaOS-2, and MG-63. The median-effect analysis demonstrated that cisplatin + oleandrin exerted synergistic (U-2OS and MG-63) or additive effects (SaOS-2), which were consistent with the changes of the intracellular accumulation of platinum (Pt) and Pt-DNA adducts. Immunohistochemistry staining showed that the expression level of the mature form CTR1, the major influx transporter of cisplatin, was low in osteosarcoma tissue. However, oleandrin with or without cisplatin significantly increased the expression and membrane localization of the mature CTR1. Furthermore, CTR1 knockdown reversed the synergistic effect and decreased cisplatin uptake. The mRNA microarray analysis suggested that oleandrin downregulated the expression of proteasome-related genes, which was verified by the proteasome activity assay. Besides, the proteasome inhibitor MG132 upregulated the expression of the mature CTR1 in U-2OS and MG-63 cells. Overall, we conclude that oleandrin sensitizes osteosarcoma cells to cisplatin in synergistic or additive manners. The synergy results from the enhanced cisplatin uptake via oleandrin-mediated inhibition of proteasome activity and subsequent blockage of the mature CTR1 degradation.