Artemisitene suppresses tumorigenesis by inducing DNA damage through deregulating c-Myc-topoisomerase pathway

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Conventional chemotherapy agents like doxorubicin induce DNA damage but exhibit high toxicity to normal cells.
• Developing novel chemotherapeutic agents with selective cancer cell targeting is crucial for improving treatment efficacy and patient safety.

Purpose of the Study:

• To investigate the potential of artemisitene (ATT), a derivative of artemisinin, as a selective cancer chemotherapeutic agent.
• To elucidate the molecular mechanisms underlying ATT's selective cytotoxicity towards human cancer cells.

Main Methods:

• Evaluating ATT's effect on DNA double-stranded breaks (DSBs) and apoptosis in various human cancer cell lines.
• Assessing ATT's cytotoxicity on normal human cells and mouse tissues (liver and kidney).
• Investigating the role of c-Myc and topoisomerases in ATT-induced cancer cell death, including the involvement of NEDD4-mediated c-Myc ubiquitination.

Main Results:

• ATT selectively induces DSBs and apoptosis in human cancer cells, sparing normal cells and tissues.
• ATT suppresses topoisomerase expression in cancer cells, leading to DNA damage accumulation.
• ATT destabilizes c-Myc in cancer cells by inducing NEDD4, an E3 ligase, promoting c-Myc ubiquitination.

Conclusions:

• Artemisitene (ATT) demonstrates significant selective cytotoxicity against human cancer cells.
• ATT's mechanism involves the destabilization of c-Myc via NEDD4-induced ubiquitination, leading to topoisomerase suppression and cancer cell apoptosis.
• ATT represents a promising chemotherapeutic candidate with a favorable safety profile for minimizing side effects on normal tissues.