Potentiation of Folate-Functionalized PLGA-PEG nanoparticles loaded with metformin for the treatment of breast Cancer: possible clinical application.

AIM: Folate receptor expression increase up to 30% in breast cancer cells and could be used as a possible ligand to couple to folate-functionalized nanoparticles. Metformin (Met) is an anti-hyperglycemic agent whose anti-cancer properties have been formerly reported. Consequently, in the current study, we aimed to synthesize and characterize folate-functionalized PLGA-PEG NPs loaded with Met and evaluate the anti-cancer effect against the MDA-MB-231 human breast cancer cell line. METHODS: FA-PLGA-PEG NPs were synthesized by employing the W1/O/W2 technique and their physicochemical features were evaluated by FE-SEM, TEM, FTIR, and DLS methods. The cytotoxic effects of free and Nano-encapsulated drugs were analyzed by the MTT technique. Furthermore, RT-PCR technique was employed to assess the expression levels of apoptotic and anti-apoptotic genes. RESULT: MTT result indicated Met-loaded FA-PLGA-PEG NPs exhibited cytotoxic effects in a dose-dependently manner and had more cytotoxic effects relative to other groups. The remarkable down-regulation (hTERT and Bcl-2) and up-regulation (Caspase7, Caspase3, Bax, and p53) gene expression were shown in treated MDA-MB-231 cells with Met-loaded FA-PLGA-PEG NPs. CONCLUSION: Folate-Functionalized PLGA-PEG Nanoparticles are suggested as an appropriate approach to elevate the anticancer properties of Met for improving the treatment effectiveness of breast cancer cells.

Cell cycle involvement in cancer therapy; WEE1 kinase, a potential target as therapeutic strategy.

Mitosis is the process of cell division and is regulated by checkpoints in the cell cycle. G1-S, S, and G2-M are the three main checkpoints that prevent initiation of the next phase of the cell cycle phase until previous phase has completed. DNA damage leads to activation of the G2-M checkpoint, which can trigger a downstream DNA damage response (DDR) pathway to induce cell cycle arrest while the damage is repaired. If the DNA damage cannot be repaired, the replication stress response (RSR) pathway finally leads to cell death by apoptosis, in this case called mitotic catastrophe. Many cancer treatments (chemotherapy and radiotherapy) cause DNA damages based on SSBs (single strand breaks) or DSBs (double strand breaks), which cause cell death through mitotic catastrophe. However, damaged cells can activate WEE1 kinase (as a part of the DDR and RSR pathways), which prevents apoptosis and cell death by inducing cell cycle arrest at G2 phase. Therefore, inhibition of WEE1 kinase could sensitize cancer cells to chemotherapeutic drugs. This review focuses on the role of WEE1 kinase (as a biological macromolecule which has a molecular mass of 96 kDa) in the cell cycle, and its interactions with other regulatory pathways. In addition, we discuss the potential of WEE1 inhibition as a new therapeutic approach in the treatment of various cancers, such as melanoma, breast cancer, pancreatic cancer, cervical cancer, etc.