Some cancers like melanoma and pancreatic and ovarian cancers, for example, commonly display resistance to chemotherapy, and this is the major obstacle to a better prognosis of patients. Frequently, literature presents studies in monolayer cell cultures, 3D cell cultures or in vivo studies, but rarely the same work compares results of drug resistance in different models. Several of these works are presented in this review and show that usually cells in 3D culture are more resistant to drugs than monolayer cultured cells due to different mechanisms. Searching for new strategies to sensitize different tumors to chemotherapy, many methods have been studied to understand the mechanisms whereby cancer cells acquire drug resistance. These methods have been strongly advanced along the years and therapies using different drugs have been increasingly proposed to induce cell death in resistant cells of different cancers. Recently, cancer stem cells (CSCs) have been extensively studied because they would be the only cells capable of sustaining tumorigenesis. It is believed that the resistance of CSCs to currently used chemotherapeutics is a major contributing factor in cancer recurrence and later metastasis development. This review aims to appraise the experimental progress in the study of acquired drug resistance of cancer cells in different models as well as to understand the role of CSCs as the major contributing factor in cancer recurrence and metastasis development, describing how CSCs can be identified and isolated.

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Brazilian flora is considered one of the most diverse in the world and represents a source of new molecules with bioactivity against several diseases. 7-epiclusianone, a prenylated benzophenone was isolated from Garcinia brasiliensis, a plant named bacupari in folk medicine. Previous studies showed that this compound has dose-dependent cytotoxic effect in several cell lines derived from human cancers and antiproliferative effect by inducing cell cycle arrest in G1/S and apoptosis in A549 lung cancer cell line. The present study aimed to analyze the cytotoxic and/or antiproliferative potential of 7-epiclusianone in human breast cancer cell lines cultured in monolayer and as spheroids. Monolayer cell cultures are commonly used for testing drug effects largely because of their easy maintenance, but they do not represent the spatial interactions of cells within a tumor. Spheroids in 3D cell cultures can overcome some of those limitations thus mimicking the architecture of solid tumors. Initially the 3D conditions were established for both cell lines MCF7 and Hs578T. Spheroids were morphologically characterized by light and transmission electron microscopy. MCF-7 spheroids showed typical epithelial organization with cohesive cells, in accordance with higher expression levels of E-cadherin compared to monolayer. In Hs578T spheroids, cells assumed fibroblast-like morphology concentrically organized, low E-cadherin expression and synthesis of extracellular matrix components. The IC50 values of 7-epiclusianone were 20 μM for Hs 578T cells and 6 μM for MCF-7 monolayers cell cultures. At this concentration, the compound treatment arrested monolayer cell cultures in G0/G1. 7-epiclusianone reduced the mRNA levels for cyclins D1 and E in line MCF-7, while only cyclin E mRNA in Hs 578T. The compound did not change the microfilaments organization or the nuclear integrity, as observed by laser scanning confocal microscopy. Interestingly, 7-epiclusianone treated cultures exhibit higher senescence indexes while apoptotic cells were not detected. Altogether, these data suggest that 7-epiclusianone is a promising molecule against breast cancer cells. The three-dimensional culture was more resistant to treatment with the compound than the monolayer, therefore more comprehensive studies are needed to understand better the effects of 7-epiclusianone on this type of culture. (Supported by FAPESP and CNPq) Citation Format: Bianca Rocha-Sales, Paula Rezende-Teixeira, Evandro Luís Oliveira Niero, Camila Lauand, Marisa Ionta, Simone SL Hanemann, Glaucia M. Machado-Santelli. Cell senescence and antitumor potential of 7-epiclusianone in human breast cancer cell lines cultured in monolayer and as spheroids. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2844.