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- Pellegrini, Paola, et al.
(författare)
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A drug screening assay on cancer cells chronically adapted to acidosis
- 2018
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Ingår i: Cancer Cell International. - : BMC. - 1475-2867. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. Methods: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. Results: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. Conclusions: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells.
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| 2. |
- Serviss, Jason T
(författare)
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Long non-coding RNAs and cellular interactions : investigating underlying mechanisms of oncogenesis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a leading cause of death worldwide with one in 8 men and one in 11 women dying from the disease (World Health Organization, 2018). Despite vast improvements in cancer diagnosis and therapy, the global cancer burden continues to rise in unison with population growth and longevity. Although cancer presents itself as a heterogeneous group of diseases, often divided by tissue of origin, tumor characterization increasingly identifies molecular level commonalities and patterns that are similar across all cancers. Expanding our knowledge of these molecular characteristics, together with the development of new tools and technologies, has historically been one of the most efficient ways to increase the effectivity of cancer therapies and thus, decrease the cancer burden of the population. This thesis investigates two newly identified molecular mechanisms, long non-coding RNAs and cell-cell interactions, whose role are increasingly appreciated in tumor progression and development. In addition, the thesis reports the development of methods and tools that have been established to facilitate further investigation of cancers molecular attributes by the scientific community.
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