Colletofragarone A2 and Colletoins A-C from a Fungus Colletotrichum sp. Decrease Mutant p53 Levels in Cells

Area of Science:

• Natural Product Chemistry
• Cancer Biology
• Molecular Oncology

Background:

• Mutant p53 (mut p53) is a key driver of tumor progression, invasion, and metastasis.
• Mut p53 accumulation in cancer cells presents a promising therapeutic target.
• Developing novel strategies to target mut p53 is crucial for effective cancer therapy.

Purpose of the Study:

• To discover natural compounds that specifically target and inhibit mutant p53.
• To identify bioactive compounds from the Colletotrichum sp. extract.
• To evaluate the efficacy of isolated compounds against cancer cells expressing mutant p53.

Main Methods:

• Utilized immunofluorescence staining in Saos-2 cells with doxycycline-inducible p53^R175H.
• Performed bioassay-guided fractionation of an active Colletotrichum sp. extract.
• Determined compound structures using spectroscopic methods and DFT calculations.

Main Results:

• An extract of Colletotrichum sp. (13S020) showed activity against mutant p53-expressing cells.
• Isolated colletofragarone A2 (1) and three new analogues, colletoins A-C (2-4).
• Compounds 1 and 2 inhibited Saos-2 (p53^R175H) cell growth and reduced mutant p53 levels.

Conclusions:

• Colletofragarone A2 and colletoin A are effective in inhibiting the growth of mutant p53-expressing cancer cells.
• These compounds demonstrate potential as therapeutic agents targeting mutant p53.
• Further investigation into these natural products could lead to new anti-cancer drugs.