Anticancer Potential of Temozolomide-Loaded Eudragit-Chitosan Coated Selenium Nanoparticles: In Vitro Evaluation of Cytotoxicity, Apoptosis and Gene Regulation

Resistance to temozolomide (TMZ) is the main cause of death in glioblastoma multiforme (GBM). The use of nanocarriers for drug delivery applications is one of the known approaches to overcome drug resistance. This study aimed to investigate the possible effect of selenium-chitosan nanoparticles loaded with TMZ on the efficacy of TMZ on the expression of MGMT, E2F6, and RELA genes and the rate of apoptosis in the C6 cell line. Selenium nanoparticles (SNPs) were loaded with TMZ and then they were coated by Eudragit(R) RS100 (Eud) and chitosan (C-S) to prepare Se@TMZ/Eud-Cs. Physicochemical properties were determined by scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDAX), thermal gravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) methods. Se@TMZ/Eud-Cs was evaluated for loading and release of TMZ by spectrophotometric method. Subsequently, SNPs loaded with curcumin (as a fluorophore) were analyzed for in vitro uptake by C6 cells. Cytotoxicity and apoptosis assay were measured by MTT assay and Annexin-PI methods. Finally, real-time PCR was utilized to determine the expression of MGMT, E2F6, and RELA genes. Se@TMZ/Eud-Cs was prepared with an average size of 200 nm as confirmed by the DLS and microscopical methods. Se@TMZ/Eud-Cs presented 82.77 +/- 5.30 loading efficiency with slow and pH-sensitive release kinetics. SNPs loaded with curcumin showed a better uptake performance by C6 cells compared with free curcumin (p-value < 0.01). Coated nanoparticles loaded with TMZ showed higher cytotoxicity, apoptosis (p-value < 0.0001), and down-regulation of MGMT, E2F6, and RELA and lower IC50 value (p-value < 0.0001) than free TMZ and control (p-value < 0.0001) groups. Using Cs as a targeting agent in Se@TMZ/Eud-Cs system improved the possibility for targeted drug delivery to C6 cells. This drug delivery system enhanced the apoptosis rate and decreased the expression of genes related to TMZ resistance. In conclusion, Se@TMZ/Eud-Cs may be an option for the enhancement of TMZ efficiency in GBM treatment

A comparative study of combination treatments in metastatic 4t1 cells: everolimus and 5- fluorouracil versus lithium chloride and 5-fluorouracil

Background: Combination therapy has been one of the most pioneering and strategic approaches implemented for malignancy treatment, which can intentionally influence multiple signaling pathways involved in cancer growth and progression. In the present study, the effects of 5-fluorouracil (5FU) in combination with everolimus (EVE) or lithium chloride (LiCl) were evaluated in 4T1 metastatic breast cancer cells and compared to control and each other. Methods and results: The resazurin assay, CompuSyn, flow cytometry, and real-time PCR were used to investigate cell proliferation, drug synergism, apoptosis, and gene expression. In comparison to the ternary combination of the drugs, the findings showed that cytotoxicity (p-value < 0.0001) and apoptosis (p-value < 0.0001) of two-by-two combinations increased dramatically as a consequence of the extreme synergy between 5FU and EVE or LiCl. Moreover, the hypoxiainducible transcription factor 1-alpha (HIF-1 alpha) and the vascular endothelial growth factor ( VEGF) downregulated considerably compared to control (p-value < 0.0001) by combination therapies of EVE-5FU and 5FU-LiCl; however, only VEGF displayed significant downregulation in comparison to single therapies. Conclusion: The findings showed that the combination of 5FU-LiCl increased cell cytotoxicity and apoptosis significantly more than EVE -5FU but suggests a clinical potential for both to treat metastatic breast cancer encouraging validation of these results in pre-clinical models

LncRNA MALAT1 signaling pathway and clinical applications in overcome on cancers metastasis

In spite of its high mortality rate and difficulty in finding a cure, scientific advancements have contributed to a reduction in cancer-related fatalities. Aberrant gene expression during carcinogenesis emphasizes the importance of targeting the signaling networks that control gene expression in cancer treatment. Long noncoding RNAs (lncRNAs), which are transcribed RNA molecules that play a role in gene expression regulation, are a recent innovative therapeutic approach for diagnosing and treating malignancies. MALAT1, a well-known lncRNA, functions in gene expression, RNA processing, and epigenetic control. High expression levels of MALAT1 are associated with several human disorders, including metastasis, invasion, autophagy, and proliferation of cancer cells. MALAT1 affects various signaling pathways and microRNAs (miRNAs), and this study aims to outline its functional roles in cancer metastasis and its interactions with cellular signaling pathways. Moreover, MALAT1 and its interactions with signaling pathways can be promising target for cancer treatment