Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the shortterm and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both in vitro and in vivo using xenograft models. In A375 with B-raf mutation, DAPT decreased the level of NOTCH1, NOTH2, and HES1 as downstream genes of the Notch pathway. This was accompanied by enhanced apoptosis after 24 h treatment, arrest in the G 2− M phase, and impaired ability of colony and melanosphere formation at the short term. Moreover, tumor growth also reduced during 13 days of treatment. However, long-term treatment of DAPT promoted tumor growth in the xenograft model and enhanced the number and size of colonies and spheroids in vitro. The gene expression studies confirmed the up-regulation of Wnt and Notch downstream genes as well as AXIN1, CSNK2A3, and CEBPA2 following the removal of Notch inhibitor in vitro and in the xenograft model. Moreover, the Gompertz-based mathematical model determined a new drug resistance term in the present study. Our data supported that the long-term and not short-term inhibition of Notch by DAPT may enhance tumor growth and motility through up-regulation of AXIN1, CSNK2A3, and CEBPA2 genes in B-raf mutated A375 cells.

Common models used in breast cancer studies, including two-dimensional (2D) cultures and animal models, do not precisely model all aspects of breast tumors. These models do not well simulate the cell–cell and cell–stromal interactions required for normal tumor growth in the body and lake tumor like microenvironment. Three-dimensional (3D) cell culture models are novel approaches to studying breast cancer. They do not have the restrictions of these conventional models and are able to recapitulate the structural architecture, complexity, and specific function of breast tumors and provide similar in vivo responses to therapeutic regimens. These models can be a link between former traditional 2D culture and in vivo models and are necessary for further studies in cancer. This review attempts to summarize the most common 3D in vitro models used in breast cancer studies, including scaffold-free (spheroid and organoid), scaffold-based, and chip-based models, particularly focused on the basic and translational application of these 3D models in drug screening and the tumor microenvironment in breast cancer.

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Polyoxometalates (POMs) are a class of inorganic cytotoxic agents with potential anticancer effects. As the nano-formulation is one of the best approaches to adjust the therapeutic effects along with selective delivery, in this study, a novel biocompatible nano-composite (NC) of Anderson-type manganese polyoxomolybdate (MnMo6) was prepared using chitosan conjugate to achieve better selective cytotoxicity profile.Imidazolium modified chitosan (CSIm) was utilizedto getthe MnMo6 hybridNCs (MnMo6@CSIm NCs).The best resulting NCs were evaluated for their anticancer activity against breast cancer cell lines (MCF-7 & MDA-MB-231) as well as HUVEC normal cells using MTT assay. Furthermore, cellular uptake, apoptosis ratio and cell migration inhibition were evaluated on the MDA-MB-231 cell line as the triple-negative aggressive cell line.The optimized NPs had a zeta potential above +27 mV with a uniform distribution of sizes around 145 nm. The loading content and release efficiency were both satisfying (about 44% and 98%). In the release study, a pH-responsive release was detectedcomparing the neutral conditions.The NCs had a better anticancer activity than free MnMo6 in both cancer cell lines, without detectable cytotoxicity against HUVEC normal cells. The cellular uptake was about 100 %, and apoptosis value was enough high (81%) compared to free MnMo6. Interestingly, the MnMo6 hybrid NCs inhibitedthe cell migration of MDA-MB-231 cell line1.5 times better than the free MnMo6. All of these results are fascinating to follow more pre-clinical studies on this hybrid NC.