Hepatocellular carcinoma-targeted drug discovery through image-based phenotypic screening in co-cultures of HCC cells with hepatocytes

Jae Woo Jang, Yeonhwa Song, Kang Mo Kim, Jin Sun Kim, Eun Kyung Choi, Joon Kim, Haengran Seo

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide and is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in HCC patients. Methods: Here, we developed a fluorescence image-based phenotypic screening system in vitro to identify HCC-specific drugs in co-cultures of HCC cells with hepatocytes. To this end, we identified two distinctive markers of HCC, CHALV1 and AFP, which are highly expressed in HCC cell lines and liver cancer patient-derived materials. We applied these markers to an HCC-specific drug screening system. Results: Through pilot screening, we identified three anti-folate compounds that had HCC-specific cytotoxicity. Among them, pyrimethamine exhibited the greatest HCC-specific cytotoxicity. Interestingly, pyrimethamine significantly increased the size and number of lysosomes and subsequently induced the release of cathepsin B from the lysosome to the cytosol, which triggered caspase-3-dependent apoptosis in Huh7 (HCC) but not Fa2N-4 cells (immortalized hepatocytes). Importantly, Fa2N-4 cells had strong resistance to pyrimethamine relative to Huh7 cells in 2D and 3D culture systems. Conclusion: These results demonstrate that this in vitro image-based phenotypic screening platform has the potential to be widely adopted in drug discovery research, since we promptly estimated anticancer activity and hepatotoxicity and elucidated functional roles of pyrimethamine during the apoptosis process in HCC.

Original languageEnglish
Article number810
JournalBMC Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - 2016 Oct 18

Keywords

  • 3D culture systems
  • Co-cultures
  • Hepatocellular carcinoma
  • Phenotypic screening
  • Pyrimethamine

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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