Synergistic Effect of Layered Double Hydroxides Nanodosage Form to Induce Apoptosis and Ferroptosis in Breast Cancer.

Background: Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy. Methods: In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer. Results: The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe2+ in cells through the release of Fe3+, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis. Conclusion: In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.

Exosome-derived miR-372-5p promotes stemness and metastatic ability of CRC cells by inducing macrophage polarization.

Colorectal cancer (CRC) is the most common malignancy in the digestive system, and tumor metastasis is the main cause of death in clinical patients with CRC. It has been shown that exosomes promote phenotypic changes in macrophages and tumor metastasis in the CRC tumor microenvironment. In this study, we used miRNA-seq technology to screen out the highly expressed miR-372-5p among the miRNAs differentially expressed in plasma exosomes of clinical CRC patients. It was found that miR-372-5p highly expressed in HCT116 exosomes could be phagocytosed by macrophages and promote their polarization into M2 macrophages by regulating the PTEN/AKT pathway. Meanwhile, co-culture of CRC cells with conditioned medium (CM) of macrophages enhanced the EMT, stemness and metastasis of CRC cells. Mechanistically, CRC cells exosome-derived miR-372-5p induced polarized M2 macrophages to secrete chemokine C-X-C-Motif Ligand 12 (CXCL12), which activated the WNT/ß-catenin pathway to promote the EMT, stemness and metastatic ability of CRC cells. In summary, this study elucidated the molecular mechanism of exosomal miR-372-5p promoting metastasis and stemness in CRC, which may provide new therapeutic targets for CRC metastasis and prognosis assessment.

Colorectal cancer tumor cell-derived exosomal miR-203a-3p promotes CRC metastasis by targeting PTEN-induced macrophage polarization.

(1) Background: Tumor-associated macrophages (TAMs) are important immunocytes associated with liver metastasis of colorectal cancer (CRLM). However, the molecular processes underpinning the interaction between the TME and the tumour-derived exosomal miRNAs in CRLM are not being fully understood; (2) Methods: Transmission electron microscopy was utilized to confirm the existence of exosomes after differential ultracentrifugation. To determine the roles of exosomal miR-203a-3p, an in vivo and in vitro investigation was conducted. The mechanism by which exosomal miR-203a-3p governs the interaction between CRC cells and M2 macrophages was investigated using a dual-luciferase reporter assay, western blot, and other techniques; (3) Results: Overexpression of miR-203a-3p was associated with poor prognosis and liver metastasis in CRC patients. Exosomal miR-203a-3p was upregulated in the plasma of CRC patients and highly metastatic CRC cells HCT116, and it could be transported to macrophages via exosomes. Exosomal miR-203a-3p induced M2 polarization of macrophages by controlling PTEN and activating the PI3K/Akt signaling pathway. M2-polarized macrophages secreted the CXCL12, which increased cancer metastasis and resulted in pre-metastatic niches in CRLM by CXCL12/CXCR4/NF-κB signaling pathway. Co-culture of macrophages with miR-203a-3p-transfected or exosome-treated cells increased the ability of HCT116 cells to metastasize both in vitro and in vivo; (4) Conclusions: Exosomes produced by highly metastatic CRC cells and rich in miR-203a-3p may target PTEN and alter the TME, promoting liver metastasis in CRC patients. These findings offer fresh understanding of the liver metastatic process in CRC.

Exosomal lncRNA NEAT1 induces paclitaxel resistance in breast cancer cells and promotes cell migration by targeting miR-133b.

The lncRNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) has been associated with the development, metastasis and drug resistance of breast cancer (BC). However, the mechanisms underlying NEAT1-induced paclitaxel resistance in the microenvironment of BC remain unclear. In this study, NEAT1 expression was found to be high in paclitaxel-resistant BC cells (SKBR3/PR cells) and exosomes derived from these cells. NEAT1 promoted the migration of BC cells and their resistance to paclitaxel, whereas its downregulation reduced the drug resistance. In addition, downregulation of NEAT1 decreased the migration and proliferation of BC cells by inhibiting the expression of CXCL12 by reducing the adsorption of miR-133b. Furthermore, inhibition of miR-133b reversed the interference of NEAT1 and CXCL12 in paclitaxel resistance, migration and proliferation of BC cells. Knockdown of NEAT1 in a xenograft-bearing mouse model remarkably inhibited cancer progression and improved the response to paclitaxel. Altogether, this study revealed that SKBR3/PR cell-derived exosomal lncRNA NEAT1 can induce paclitaxel resistance and cell migration and growth in the tumour microenvironment of BC and may serve as a new target for the clinical treatment of BC.