Notch signaling dysregulation encourages breast cancer progression through different mechanisms such as stem cell maintenance, cell proliferation and migration/invasion. Furthermore, Notch is a crucial driver regulating juxtracrine and paracrine communications between tumor and stroma. The complex interplay between the abnormal Notch pathway orchestrating the activation of other signals and cellular heterogeneity contribute towards remodeling of the tumor microenvironment. These changes, together with tumor evolution and treatment pressure, drive breast cancer drug resistance. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance, reducing or eliminating breast cancer stem cells. In the present review, we will summarize the current scientific evidence that highlights the involvement of Notch activation within the breast tumor microenvironment, angiogenesis, extracellular matrix remodeling, and tumor/stroma/immune system interplay and its involvement in mechanisms of therapy resistance.

Various literature data show how a diet rich in vegetables could reduce the incidence of several cancers due to the contribution of the natural polyphenols contained in them. Polyphenols are attributed multiple pharmacological actions such as anti-inflammatory, anti-oxidant, antibiotic, antiseptic, anti-allergic, cardioprotective and even anti-tumor properties. The multiple mechanisms involved in their anti-tumor action include signaling pathways modulation associated with cell proliferation, differentiation, migration, angiogenesis, metastasis and cell death. Since the dysregulation of death processes is involved in cancer etiopathology, the natural compounds able to kill cancer cells could be used as new anticancer agents. Apoptosis, a programmed form of cell death, is the most potent defense against cancer and the main mechanism used by both chemotherapy agents and polyphenols. The aim of this review is to provide an update of literature data on the apoptotic molecular mechanisms induced by some representative polyphenol family members in cancer cells. This aspect is particularly important because it may be useful in the design of new therapeutic strategies against cancer involving the polyphenols as adjuvants.

Plant-derived bioactive compounds are gaining wide attention for their multiple health-promoting activities and in particular for their anti-cancer properties. Several studies have highlighted how they can prevent cancer initiation and progression, improve the effectiveness of chemotherapy, and, in some cases, limit some of the side effects of chemotherapy agents. In this paper, we provide an update of the literature on the anti-cancer effects of three extensively studied plant-derived compounds, namely resveratrol, epigallocatechin gallate, and curcumin, with a special focus on the anti-cancer molecular mechanisms inducing apoptosis in the major types of cancers globally.

The current therapeutic protocols and prognosis of gliomas still depend on clinicopathologic and radiographic characteristics. For high-grade gliomas, the standard of care is resection followed by radiotherapy plus temozolomide chemotherapy. However, treatment resistance develops due to different mechanisms, among which is the dynamic interplay between the tumor and its microenvironment. Different signaling pathways cause the proliferation of so-called glioma stem cells, a minor cancer cell population with stem cell-like characteristics and aggressive phenotype. In the last decades, numerous studies have indicated that Notch is a crucial pathway that maintains the characteristics of resistant glioma stem cells. Data obtained from preclinical models indicate that downregulation of the Notch pathway could induce multifaceted drug sensitivity, acting on the expression of drug-transporter proteins, inducing epithelial–mesenchymal transition, and shaping the tumor microenvironment. This review provides a brief overview of the published data supporting the roles of Notch in drug resistance and demonstrates how potential novel strategies targeting Notch could become an efficacious action to improve the therapy of high-grade glioma to overcome drug resistance.

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.