Repositioning of mifepristone as an integrated stress response activator to potentiate cisplatin efficacy in non-small cell lung cancer.

Lung cancer, primarily non-small-cell lung cancer (NSCLC), is a significant cause of cancer-related mortality worldwide. Cisplatin-based chemotherapy is a standard treatment for NSCLC; however, its effectiveness is often limited due to the development of resistance, leading to NSCLC recurrence. Thus, the identification of effective chemosensitizers for cisplatin is of paramount importance. The integrated stress response (ISR), activated by various cellular stresses and mediated by eIF2α kinases, has been implicated in drug sensitivity. ISR activation globally suppresses protein synthesis while selectively promoting the translation of ATF4 mRNA, which can induce pro-apoptotic proteins such as CHOP, ATF3, and TRIB3. To expedite and economize the development of chemosensitizers for cisplatin treatment in NSCLC, we employed a strategy to screen an FDA-approved drug library for ISR activators. In this study, we identified mifepristone as a potent ISR activator. Mifepristone activated the HRI/eIF2α/ATF4 axis, leading to the induction of pro-apoptotic factors, independent of its known role as a synthetic steroid. Our in vitro and in vivo models demonstrated mifepristone's potential to inhibit NSCLC re-proliferation following cisplatin treatment and tumor growth, respectively, via the ISR-mediated cell death pathway. These findings suggest that mifepristone, as an ISR activator, could enhance the efficacy of cisplatin-based therapy for NSCLC, highlighting the potential of drug repositioning in the search for effective chemosensitizers.

Carboxymethyl Cellulose Entrapped in a Poly(vinyl) Alcohol Network: Plant-Based Scaffolds for Cartilage Tissue Engineering.

Cartilage has a limited inherent healing capacity after injury, due to a lack of direct blood supply and low cell density. Tissue engineering in conjunction with biomaterials holds promise for generating cartilage substitutes that withstand stress in joints. A major challenge of tissue substitution is creating a functional framework to support cartilage tissue formation. Polyvinyl alcohol (PVA) was crosslinked with glutaraldehyde (GA), by varying the mole ratios of GA/PVA in the presence of different amounts of plant-derived carboxymethyl cellulose (CMC). Porous scaffolds were created by the freeze-drying technique. The goal of this study was to investigate how CMC incorporation and crosslinking density might affect scaffold pore formation, swelling behaviors, mechanical properties, and potential use for engineered cartilage. The peak at 1599 cm-1 of the C=O group in ATR-FTIR indicates the incorporation of CMC into the scaffold. The glass transition temperature (Tg) and Young's modulus were lower in the PVA/CMC scaffold, as compared to the PVA control scaffold. The addition of CMC modulates the pore architecture and increases the swelling ratio of scaffolds. The toxicity of the scaffolds and cell attachment were tested. The results suggest that PVA/CMC scaffolding material can be tailored in terms of its physical and swelling properties to potentially support cartilage formation.

Combined effects of curcumin and doxorubicin on cell death and cell migration of SH-SY5Y human neuroblastoma cells.

Neuroblastoma is the most common cancer of the sympathetic nervous system in children. Here, the influences of curcumin on survival, apoptosis, migration, and its combined effects with doxorubicin were investigated in SH-SY5Y cells by cell survival assay, flow cytometry, migration assays, and RT-PCR. Curcumin inhibited SH-SY5Y cell growth and induced apoptosis in dose- and time-dependent manners. This apoptotic induction relied on the upregulation of p53 and p21. Moreover, the treatment of curcumin for 24 h significantly suppressed cell migration, together with the downregulation of matrix metalloproteinase-2 (MMP-2) and upregulation of tissue inhibitor of metalloproteinases-1 (TIMP-1). The combination of curcumin augmented the anticancer activity of doxorubicin and significantly induced apoptosis. Pretreatment with curcumin increased the fraction of doxorubicin-induced apoptotic cells from 21.76 ± 0.50 to 57.74 ± 2.68%. Co-treatment with doxorubicin plus curcumin further inhibited 3D tumor migration. Altogether, the results suggest that curcumin suppresses growth and migration of SH-SY5Y cells and enhances the anticancer activity of doxorubicin. The addition of curcumin to therapeutic regimens may be promising for the treatment of neuroblastomas if a number of problems related to its in vivo bioavailability can be resolved. Graphical abstract ᅟ.

Curcumin attenuates paraquat-induced cell death in human neuroblastoma cells through modulating oxidative stress and autophagy.

Paraquat is a neurotoxic agent, and oxidative stress plays an important role in neuronal cell death after paraquat exposure. In this study, we assessed the neuroprotective effect of curcumin against paraquat and explored the underlying mechanisms of curcumin in vitro. Curcumin treatment prevented paraquat-induced reactive oxygen species (ROS) and apoptotic cell death. Curcumin also exerted a neuroprotective effect by increasing the expression of anti-apoptotic and antioxidant genes. The pretreatment of curcumin significantly decreased gene expression and protein production of amyloid precursor protein. The activation of autophagy process was found defective in paraquat-induced cells, indicated by the accumulation and reduction of LC3I/II. Noteworthy, curcumin restored LC3I/II expression after the pretreatment. Collectively, curcumin demonstrated as a prominent suppressor of ROS, and could reverse autophagy induction in SH-SY5Y cells. The consequences of this were the reduction of APP production and prevention of SH-SY5Y cells from apoptosis. Altogether, curcumin potentially serves as a therapeutic agent of neurodegenerative diseases, associated with ROS overproduction and autophagy dysfunction.