Inhibition of the rapamycin-insensitive mTORC1 /4E-BP1 axis attenuates TGF-ß1-induced fibrotic response in human Tenon's fibroblasts.

Subconjunctival fibrosis is the major cause of failure in both conventional and modern minimally invasive glaucoma surgeries (MIGSs) with subconjunctival filtration. The search for safe and effective anti-fibrotic agents is critical for improving long-term surgical outcomes. In this study, we investigated the effect of inhibiting the rapamycin-insensitive mTORC1/4E-BP1 axis on the transforming growth factor-beta 1(TGF-ß1)-induced fibrotic responses in human Tenon's fibroblasts (HTFs), as well as in a rat model of glaucoma filtration surgery (GFS). Primary cultured HTFs were treated with 3 ng/mL TGF-ß1 for 24 h, followed by treatment with 10 µM CZ415 for additional 24 h. Rapamycin (10 µM) was utilized as a control for mTORC1/4E-BP1 signaling insensitivity. The expression levels of fibrosis-associated molecules were measured using quantitative real-time PCR, Western blotting, and immunofluorescence analysis. Cell migration was assessed through the scratch wound assay. Additionally, a rat model of GFS was employed to evaluate the anti-fibrotic effect of CZ415 in vivo. Our findings indicated that both rapamycin and CZ415 treatment significantly reduced the TGF-ß1-induced cell proliferation, migration, and the expression of pro-fibrotic factors in HTFs. CZ415 also more effectively inhibited TGF-ß1-mediated collagen synthesis in HTFs compared to rapamycin. Activation of mTORC1/4E-BP signaling following TGF-ß1 exposure was highly suppressed by CZ415 but was only modestly inhibited by rapamycin. Furthermore, CZ415 was found to decrease subconjunctival collagen deposition in rats post GFS. Our results suggest that rapamycin-insensitive mTORC1/4E-BP1 signaling plays a critical role in TGF-ß1-driven collagen synthesis in HTFs. This study demonstrated that inhibition of the mTORC1/4E-BP1 axis offers superior anti-fibrotic efficacy compared to rapamycin and represents a promising target for improving the success rate of both traditional and modern GFSs.

Natural products reverse cancer multidrug resistance.

Cancer stands as a prominent global cause of death. One of the key reasons why clinical tumor chemotherapy fails is multidrug resistance (MDR). In recent decades, accumulated studies have shown how Natural Product-Derived Compounds can reverse tumor MDR. Discovering novel potential modulators to reduce tumor MDR by Natural Product-Derived Compounds has become a popular research area across the globe. Numerous studies mainly focus on natural products including flavonoids, alkaloids, terpenoids, polyphenols and coumarins for their MDR modulatory activity. Natural products reverse MDR by regulating signaling pathways or the relevant expressed protein or gene. Here we perform a deep review of the previous achievements, recent advances in the development of natural products as a treatment for MDR. This review aims to provide some insights for the study of multidrug resistance of natural products.

Ado-tratuzumab emtansine beyond breast cancer: therapeutic role of targeting other HER2-positive cancers.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved by the FDA in 2013 for advanced HER2-positive breast cancer treatment exhibiting promising clinical benefits. However, HER2 overexpression and gene amplification have also been reported in other cancers like gastric cancer, non-small cell lung cancer (NSCLC), and colorectal cancer. Numerous preclinical studies have also revealed the significant antitumor effect of T-DM1 on HER2-positive tumors. With the advancement in research, several clinical trials have been conducted to investigate the antitumor effect of T-DM1. In this review, we briefly introduced the pharmacological effects of T-DM1. We reviewed its preclinical and clinical studies, especially on other HER2-positive cancers, establishing what has been encountered between its preclinical and clinical studies. In clinical studies, we found that T-DM1 has a therapeutic value on other cancers. An insignificant effect was observed on gastric cancer and NSCLC, inconsistent with the preclinical studies.

Ferroptosis in Non-Small Cell Lung Cancer: Progression and Therapeutic Potential on It.

As a main subtype of lung cancer, the current situation of non-small cell lung cancer (NSCLC) remains severe worldwide with a 19% survival rate at 5 years. As the conventional therapy approaches, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, gradually develop into therapy resistance, searching for a novel therapeutic strategy for NSCLC is urgent. Ferroptosis, an iron-dependent programmed necrosis, has now been widely considered as a key factor affecting the tumorigenesis and progression in various cancers. Focusing on its effect in NSCLC, in different situations, ferroptosis can be triggered or restrained. When ferroptosis was induced in NSCLC, it was available to inhibit the tumor progression both in vitro and in vivo. The dominating mechanism was due to a regulation of the classic ferroptosis-repressed GSH-dependent GPX4 signaling pathway instead of other fractional regulating signal axes that regulated ferroptosis via impacting on the ROS, cellular iron levels, etc. In terms of the prevention of ferroptosis in NSCLC, an GSH-independent mechanism was also discovered, interestingly exhibiting the same upstream as the GPX4 signaling. In addition, this review summarizes the progression of ferroptosis in NSCLC and elaborates their association and specific mechanisms through bioinformatics analysis with multiple experimental evidence from different cascades. Finally, this review also points out the possibility of ferroptosis working as a novel strategy for therapy resistance in NSCLC, emphasizing its therapeutic potential.

Tumor-Cell-Surface Adherable Peptide-Drug Conjugate Prodrug Nanoparticles Inhibit Tumor Metastasis and Augment Treatment Efficacy.

Cancer metastasis is the main cause of chemotherapeutic failure. Inhibiting the activity of matrix metalloproteinases (MMPs) is a common strategy for reducing metastasis. However, broad-spectrum MMP-inhibitors (MMPI) may cause undesired side effects. Here, we screened a selective MMP2 inhibitor (CCKIGLFRWR) and linked it with doxorubicin (DOX) to produce an amphiphilic peptide-drug conjugate (PDC). Then novel core-shell nanoparticles were self-assembled from PDC core and modified polylysine (MPL) shell. When the particles were passively targeted to the tumor site, the PDC core was exposed for charge switch of the MPL shell, aggregated for its transformation behavior, and specially adhered to the cell membrane. The disulfide bond between the MMPI peptide and DOX was broken via a low concentration of glutathione-mediated reduction in tumor microenvironment. DOX could effectively enter the tumor cells. Meanwhile, the MMPI peptide could selectively inhibit the activity of the MMP2 and effectively inhibit tumor metastasis.