Authors:

Camila Gutierrez

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About Paper:

Three cytotoxic topoisomerase 1 (TOP1)-inhibiting indenoisoquinolines, I400 (indotecan), I776 (indimitecan), and I744, have demonstrated anticancer activity in preclinical and clinical trials. These drugs have recently been found to strongly bind to the MYC promoter G-quadruplex and potently downregulate the expression of MYC. MYC is a crucial oncogene overexpressed in most cancers; the G-quadruplex secondary structures in the promoter region acts as a transcriptional silencer. Osteosarcoma (OS) is a rare, aggressive primary bone cancer with a low survival rate of approximately 60% due to cancer metastasis. Though no new effective therapies for this cancer have emerged over 40 years, the overexpression of MYC is common in OS and may be a therapeutic target in this cancer. Naturally-occurring OS in pet dogs is a relevant animal model for the human disease, and is also characterized by MYC overexpression. We hypothesized that MYC-inhibitory indenoisoquinoline analogs would have antiproliferative effects on canine osteosarcoma cell lines. This study aimed to provide proof-of-concept for the efficacy of indenoisoquinoline drugs in canine OS. Two osteosarcoma cell lines, D-17 and OSCA-8, were treated with three indenoisoquinolines to calculate the percent growth inhibition. Cell-based cytotoxicity screening with sulforhodamine B colorimetric assays was used as a measurement of cellular protein content to identify the IC50 of each drug in the concentration range of 2 to 2000 nM. The results are expected to contribute to the design of follow-up studies in canine comparative oncology models with the goal of supporting further research on MYC-targeting agents in both canine and human OS.

Source:

Purdue University / 2023

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Co-authors:

Camila Gutierrez