Browsing by Subject "drug testing"

Sort by: Order: Results:

Now showing items 1-3 of 3
  • Heredia-Soto, Victoria; Escudero, Javier; Miguel, María; Ruiz, Patricia; Gallego, Alejandro; Berjón, Alberto; Hernández, Alicia; Martínez-Díez, Marta; Zheng, Shuyu; Tang, Jing; Hardisson, David; Feliu, Jaime; Redondo, Andrés; Mendiola, Marta (2022)
    Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation.
  • Sanz, Dafne Jacome; Raivola, Juuli; Karvonen, Hanna; Arjama, Mariliina; Barker, Harlan; Murumägi, Astrid; Ungureanu, Daniela (2021)
    Simple Summary Ovarian cancer (OC) is known for its poor prognosis, due to the absence of reliable biomarkers and its late diagnosis, since the early-stage disease is almost asymptomatic. Lipid metabolism plays an important role in OC progression due to the development of omental metastasis in the abdominal cavity. The aim of our study was to assess the therapeutic role of various enzymes involved in lipid metabolism regulation or synthesis, in different subtypes of OC represented by cell lines as well as patient-derived cancer cell cultures (PDCs). We show that proprotein convertase subtilisin/kexin type 9 (PCSK9), a cholesterol-regulating enzyme, plays a pro-survival role in OC and targeting its expression impairs cancer cell growth. We also tested a small library of metabolic and mTOR-targeting drugs to identify drug vulnerabilities specific to various subtypes of OC. Our results show that in OC cell lines and PDCs the second generation of mTOR inhibitors such as AZD8055, vistusertib, dactolisib and sapanisertib, have higher cytotoxic activity compared to the first generation mTOR inhibitors such as rapalogs. These results suggest that, in the era of precision medicine, it is possible to target the metabolic pathway in OC and identify subtype-specific drug vulnerabilities that could be advanced to the clinic. Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements.
  • Salo, Tuula; Dourado, Mauricio Rocha; Sundquist, Elias; Apu, Ehsanul Hoque; Alahuhta, Ilkka; Tuomainen, Katja; Vasara, Jenni; Al-Samadi, Ahmed (2018)
    Alongside cancer cells, tumours exhibit a complex stroma containing a repertoire of cells, matrix molecules and soluble factors that actively crosstalk between each other. Recognition of this multifaceted concept of the tumour microenvironment (TME) calls for authentic TME mimetics to study cancer in vitro. Traditionally, tumourigenesis has been investigated in non-human, three-dimensional rat type I collagen containing organotypic discs or by means of mouse sarcoma-derived gel, such as Matrigel (R). However, the molecular compositions of these simplified assays do not properly simulate human TME. Here, we review the main properties and benefits of using human leiomyoma discs and their matrix Myogel for in vitro assays. Myoma discs are practical for investigating the invasion of cancer cells, as are cocultures of cancer and stromal cells in a stiff, hypoxic TME mimetic. Myoma discs contain soluble factors and matrix molecules commonly present in neoplastic stroma. In Transwell, IncuCyte, spheroid and sandwich assays, cancer cells move faster and form larger colonies in Myogel than in Matrigel (R). Additionally, Myogel can replace Matrigel (R) in hanging-drop and tube-formation assays. Myogel also suits three-dimensional drug testing and extracellular vesicle interactions. To conclude, we describe the application of our myoma-derived matrices in 3D in vitro cancer assays. This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.