A traditional gynecological medicine inhibits ovarian cancer progression and eliminates cancer stem cells via the LRPPRC-OXPHOS axis.

BACKGROUND: Ovarian cancer (OC) is the most lethal malignant gynecological tumor type for which limited therapeutic targets and drugs are available. Enhanced mitochondrial oxidative phosphorylation (OXPHOS), which enables cell growth, migration, and cancer stem cell maintenance, is a critical driver of disease progression and a potential intervention target of OC. However, the current OXPHOS intervention strategy mainly suppresses the activity of the electron transport chain directly and cannot effectively distinguish normal tissues from cancer tissues, resulting in serious side effects and limited efficacy. METHODS: We screened natural product libraries to investigate potential anti-OC drugs that target OXPHOS. Additionally, LC-MS, qRT-PCR, western-blot, clonogenic assay, Immunohistochemistry, wound scratch assay, and xenograft model was applied to evaluate the anti-tumor mechanism of small molecules obtained by screening in OC. RESULTS: Gossypol acetic acid (GAA), a widely used gynecological medicine, was screened out from the drug library with the function of suppressing OXPHOS and OC progression by targeting the leucine-rich pentatricopeptide repeat containing (LRPPRC) protein. Mechanically, LRPPRC promotes the synthesis of OXPHOS subunits by binding to RNAs encoded by mitochondrial DNA. GAA binds to LRPPRC directly and induces LRPPRC rapid degradation in a ubiquitin-independent manner. LRPPRC was overexpressed in OC, which is highly correlated with the poor outcomes of OC and could promote the malignant phenotype of OC cells in vitro and in vivo. GAA management inhibits cell growth, clonal formation, and cancer stem cell maintenance in vitro, and suppresses subcutaneous graft tumor growth in vivo. CONCLUSIONS: Our study identified a therapeutic target and provided a corresponding inhibitor for OXPHOS-based OC therapy. GAA inhibits OC progression by suppressing OXPHOS complex synthesis via targeting LRPPRC protein, supporting its potential utility as a natural therapeutic agent for ovarian cancer.

Chemo-Phototherapy with Carfilzomib-Encapsulated TiN Nanoshells Suppressing Tumor Growth and Lymphatic Metastasis.

The design of nanomedicine for cancer therapy, especially the treatment of tumor metastasis has received great attention. Proteasome inhibition is accepted as a new strategy for cancer therapy. Despite being a big breakthrough in multiple myeloma therapy, carfilzomib (CFZ), a second-in-class proteasome inhibitor is still unsatisfactory for solid tumor and metastasis therapy. In this study, hollow titanium nitride (TiN) nanoshells are synthesized as a drug carrier of CFZ. The TiN nanoshells have a high loading capacity of CFZ, and their intrinsic inhibitory effect on autophagy synergistically enhances the activity of CFZ. Due to an excellent photothermal conversion efficiency in the second near-infrared (NIR-II) region, TiN nanoshell-based photothermal therapy further induces a synergistic anticancer effect. In vivo study demonstrates that TiN nanoshells readily drain into the lymph nodes, which are responsible for tumor lymphatic metastasis. The CFZ-loaded TiN nanoshell-based chemo-photothermal therapy combined with surgery offers a remarkable therapeutic outcome in greatly inhibiting further metastatic spread of cancer cells. These findings suggest that TiN nanoshells act as an efficient carrier of CFZ for realizing enhanced outcomes for proteasome inhibitor-based cancer therapy, and this work also presents a "combined chemo-phototherapy assisted surgery" strategy, promising for future cancer treatment.

Au Nanobottles with Synthetically Tunable Overall and Opening Sizes for Chemo-Photothermal Combined Therapy.

Highly asymmetric Au nanostructures, such as split Au nanorings and Au nanocups, exhibit attractive plasmonic properties because of their asymmetric geometries. To facilitate their plasmonic applications, effective and facile synthetic methods for producing asymmetric Au nanostructures with controllable sizes and uniform shapes are highly desirable. Herein, we report on an approach for the synthesis of largely asymmetric colloidal Au nanobottles with synthetically tunable overall and opening sizes. Au nanobottles with overall sizes in the range of ∼100-230 nm are obtained through sacrificial templating with differently sized PbS nano-octahedra. The opening sizes of the produced Au nanobottles can be tailored from ∼10 to ∼120 nm by either adjusting the Au/PbS molar ratio in the growth process or controlling the oxidation degree. The achieved size tunability allows the plasmon resonance wavelength of Au nanobottles to be varied in the range of ∼600-900 nm. Our uniform Au nanobottles, which possess controllable sizes, large cavity volumes, and tunable plasmon resonance wavelengths in the visible to near-infrared range, have been further applied for anticancer drug delivery and photothermal therapy. The effects of surface coating and the opening size of Au nanobottles on the drug encapsulation efficiency (EE) and initial burst drug release are systemically evaluated. A high doxorubicin EE and low initial burst drug release are realized with the dense silica-coated Au nanobottles having an opening size of 44 nm. In addition, chemo-photothermal combined therapy has been demonstrated with the doxorubicin-loaded Au nanobottles. Our results will be helpful for the design of Au nanobottles with different sizes and plasmonic properties as well as provide ample opportunities for exploring various plasmon-enabled applications of Au nanobottles.

Total Flavonoids from Carya cathayensis Sarg. Leaves Alleviate H9c2 Cells Hypoxia/Reoxygenation Injury via Effects on miR-21 Expression, PTEN/Akt, and the Bcl-2/Bax Pathway.

This study aimed to investigate whether the total flavonoids (TFs) from Carya cathayensis Sarg. leaves alleviate hypoxia/reoxygenation (H/R) injury in H9c2 cardiomyocytes and to explore potential mechanisms. H9c2 cells pretreated with TFs for 24h were exposed to H/R treatment. The results indicated that TFs significantly alleviate H/R injury, which include inhibiting apoptosis and enhancing antioxidant capacity. The protective effects of TFs resulted in higher expression of miR-21 in H/R-induced H9c2 cells than that of controls, which in turn upregulated Akt signaling activity via suppressing the expression of PTEN together with decreasing the ratio of Bax/Bcl-2, caspase3, and cleaved-caspase3 expression in H/R-induced H9c2 cells. Conversely, blocking miR-21 expression with miR-21 inhibitor effectively suppressed the protective effects of TFs against H/R-induced injury. Our study suggests that TFs can decrease cell apoptosis, which may be mediated by altering the expression of miR-21, PTEN/Akt, and Bcl/Bax.